txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations...

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Idle ...... Corneal TI'lIIIlIIII apter 104 txt:ernal Eye Manifestations of Chemical d Biological Warfare ig A. Skolnick spectrum of blologicaJ and chem ical agents that can used in warfa re is frigh te njn g, Healthcare providers be alert to patterns o f Illness and the constellation of find in gs associated with an outbreak of biological chemJcaJ warfare. The intentiona l release of an unu sual in/,m'Dm agent can be difficult to recognize since many the commonly used organisms are rarely seen in their form. When used as weapons, there is potential for immense number of casualties due to ease of dispersal, i onset of efied, and lack of preparation for contaln- and defense. Timely recognItion of symptoms and treatment are key to victim survival. Background deliberate use of microorganisms and toxins as weapons dates back to the middle ages. During the 14th-cenrury siege of KaHa (now Feodossla, Ukraine), the attacking Tatars catapulted plague-infested cadavers into the city in order to initiate an epidemic. I South American aborlginals are well known for using curare and amphjbian-derived toxins as arrow and British forces used sma llpo1t against Dative North Americans during the French a nd Indian War of the mid-18th century. The advent of modem micro- biology and Koc h 's postulates during the 19th century afforded the opportunity to isolate and produce stockpiles of specific pathogens. There is evidence that Germany develo ped an aggressive biological warfare program during World War I, including operations to infect livestock and co ntaminate animal feed of the Allied forces using Baal/us anthracis and BUlkholderia (pseudomonas) mallei, the etiologic agents of anthrax and glanders. The first vvidespread use of chemical weapons oc'curred during World War I, when mo re than 1 million casualties from the use of sulfur, mustard, and chlorine gases. These horrors led to the first international diplomatic efforts to limit weapons of mass destruction. The 1925 Geneva Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous, or Other Gases. and of Bacterio- logical Methods of Warfa re was enacted to prohibit the use of biological weapons.! Unfortunately . there were no provisions fOT inspection, and m any counlTi es that ratified the treal:y still began research programs to develop biological weapons. During World War II . Japan conducted experiments in wh i ch prisoners were Infected with various bacteriaL pathogens, which led to at least 10000 deaths.] Many Chinese cities were anacked by co ntaminating water supplies and food items with pure cultures o( B. anthracis, Vibrio Shigella spp. Salmonella spp. and Yersin;Q pestis. Internati onal concern heightened during the late 1960$, which led to the Signing of the1972 Biological and Toxin Weapons Convention. The treaty prohibited the development, possession, and stockpiling of pathogens or toxins in "quantities that have no Justification for prophy- lactic, protective or other peaceful purposes.I!4 Transferring technology or expertise between countries was also prohibited . 10 19 79. the ineffectiveness of the convention was demon strated by an accidental airborne release of anthrn spores by a Sov1et military microbiology facility in $verdlovsk (now Ekaterinburg, Russia), which led to numerous deaths. s Non-state-sponsored biological terrorism began to surface In the 19805, which culminated with the 1995 sarin gas attack of the TOkyo. Japan, subway system by the Aum Shinrikyo cult. Mechanism of Attack A biological weapon Is more than a microorganism or toxin. It Is a system composed of fow major components - payload (the biolOgical agent), munition (a container that keeps the payload intact and virulent during delivery), delivery system (missile, artillery shell, aircraft, etc.), and dispersal mechani sm {an explosive force or spray device to dispense the agent to the target populatlon).6 Certain agents are attractive because of low visibility, small volume, high potency, and easy delivery. Aerosolization would be the predomlnant method of dissemination because advanced delivery systems are not required, and small quantities make transportation and concealment quite easy. In 1970, the World Health Organization predicted the effect of an aerosol release of SO kg of biological weapon over a city of 500 000 people (rable t 04 . t ).7.8 Highly contagious organisms with delayed onset of symptoms make ideal weapons for a covert attack. In an overt attack. chemical agents are likely to be deployed, caUSing rapid onset of symptoms and an overwhelming demand for eme.rgency medical services. Both biological and chemical weapons can incapacitate . 12 -'- "

Transcript of txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations...

Page 1: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

Idle Corneal TIlIIIlIIII

apter 104

txternal Eye Manifestations of Chemical d Biological Warfare ig A Skolnick

spectrum of blologicaJ and chemical agents that can used in warfa re is frigh tenjng Healthcare providers

be alert to patterns o f Illness and the constellation of find ings associated with an outbreak of biological

chemJcaJ warfare The intentional release of an unusual inmDm agent can be difficult to recognize since many

the commonly used organisms are rarely seen in their form When used as weapons there is potential for

immense number of casualties due to ease of dispersal i onset of efied and lack of preparation for contaln shy

and defense Timely recognItion of symptoms and treatment are key to victim survival

Background deliberate use of microorganisms and toxins as weapons

dates back to the middle ages During the 14th-cenrury siege of KaHa (now Feodossla Ukraine) the attacking Tatars catapulted plague-infested cadavers into the city in order to initiate an epidemic I South American aborlginals are well known for using curare and amphjbian-derived toxins as arrow pol~ons and British forces used smallpo1t against Dative North Americans during the French and Indian War of the mid-18th century The advent of modem microshybiology and Kochs postulates during the 19th century afforded the opportunity to isolate and produce stockpiles of specific pathogens There is evidence that Germany developed an aggressive biological warfare program during World War I including operations to infect livestock and contaminate animal feed of the Allied forces using Baalus anthracis and BUlkholderia (pseudomonas) mallei the etiologic agents of anthrax and glanders

The first vvidespread use of chemica l weapons occurred during World War I when mo re than 1 million casualties ~ulted from the use of sulfur mustard and chlorine gases These horrors led to the first international diplomatic efforts to limit weapons of mass destruction The 1925 Geneva Protocol for the Prohibition of the Use in War of Asphyxiating Poisonous or Other Gases and of Bacterioshylogical Methods of Warfa re was enacted to pro hibit the use of biological weapons Unfortunately there were no provisions fOT inspection and many counlTies that ratified the trealy still began research programs to develop biological weapons

During World War II Japan conducted experiments in which prisoners were Infected with various bacteriaL pathogens which led to at least 10000 deaths] Many Chinese cities were anacked by contaminating water supplies and food items with pure cultures o( B anthracis Vibrio dlolera~ Shigella spp Salmonella spp and YersinQ pestis International concern heightened during the late 1960$ which led to the Signing of the1972 Biological and Toxin Weapons Convention The treaty prohibited the development possession and stockpiling of pathogens or toxins in quantities that have no Justification for prophyshylactic protective or other peaceful purposesI4 Transferring technology or expertise between countries was also prohibited 10 1979 the ineffectiveness of the convention was demonstrated by an accidental airborne release of anthrn spores by a Sov1et military microbiology facility in $verdlovsk (now Ekaterinburg Russia) which led to numerous deathss Non-state-sponsored biological terrorism began to surface In the 19805 which culminated with the 1995 sarin gas attack o f the TOkyo Japan subway system by the Aum Shinrikyo cult

Mechanism of Attack A biological weapon Is more than a microorganism or toxin It Is a system composed of fow major components - payload (the biolOgical agent) munition (a container that keeps the payload intact and virulent during delivery) delivery system (missile artillery shell aircraft etc) and dispersal mechanism an explosive force or spray device to dispense the agent to the target populatlon)6 Certain agents are attractive because of low visibility small volume high potency and easy delivery Aerosolization would be the predomlnant method of dissemination because advanced delivery systems are not required and small quantities make transportation and concealment quite easy In 1970 the World Health Organization predicted the effect of an aerosol release of SO kg of biological weapon over a city of 500 000 people (rable t 04 t )78 Highly contagious organisms with delayed onset of symptoms make ideal weapons for a covert attack In an overt attack chemical agents are likely to be deployed caUSing rapid onset of symptoms and an overwhelming demand for emergency medical services Both biological and chemica l weapons can incapacitate 12 bull

--

TQIe 1041 Estimated ~llies fOf ill hypothetical biological warfare attack on a city of 500 000middot - Do__1d

Rift Valley I~r

rudI (km)

1

lt00

No bull kKaclbted

)5 000

Tkkmiddotbomr encephltlli(i5

1 9500 35000

Typhus

Brucellosis

5

10

19000

SOD

85000

100000

Q lever 20 150 125000

Tularemitl 20 30 000 125000

Anthrall 20 950000 125000

ThIS mod~ OJWrrnS 111m $0 Jg 01 agmt is depJoy~ from PI oirtraft aoog ) km line upwind from Ihf city from ~ftrt1U 8 po~ J I) robr 2 AkCovtm rw Christophe Cw lJlJtfl EM CIIlOtltOUJ nif~oiom 01 biolo9lCai worlore and ftkntd IhrlaquoJI ogtnil ell Oemlalol IJS-JIImiddot122 1999 Copyfighl e (999) Americon ~1f1CUl AsSlaquoialoOl All nght$ revrwd

an entire dry and impede the mobilization of military personnel

Warning Signs In mder to recognize a bioterror anack one must be familiar with the various clini cal presentations of these agents The American College of PhYSicians and the American Society of Intern al Medicine have suggested that the follOwing epidemiological clues be considered 1 Unusual temporal or geographic clustering of illn ess 2 Unusual age distribution of common disease (Le an

illness that appears to be ch ickenpox in adults but is really smaUpox)

3 Large epidemic wi th greater case loads than expected especia lly in a discrete population

4 More severe disease than expected 5 Unusualwute of ex posure 6 A disea se that is outside its normal transmission

season or is impossible to transmit naturaly in the absence of its normal vector

7 Multiple simultaneous epidemics of different diseases 8 A disea se outbreak with health consequences to

humans and animals 9 Unusual strains or variants of organisms o r

antim icrobial resistance patterns The Cent ers for Disease Control and Prevemi on

(CDC) of the United States has listed the high-priority biological dIseases (Box 1041)10 that pose significant risk to national security based on the onowing can be easily disseminated ando r tlansmitlelti from person to person result in high mortality rates and have the paten rial for major public health Impact oUght cause public pani c and

Box 1041

Biological d lseaMs

Anthrax (80cilIJSanthracis)

Botulism (CcstridilJm botlJiinlJm toxin) Pla9ue (Yeninio pt1fis)

Smallpollt (Variola maior and minor) Tularemia (Fronciseiio wiarensil)

Vir~l hemorrhagic fever

Filoviruse~ - Eboia Mltlrbu(g

ArenavirU5e~ - Lassa Junin Machupo Guanarito S~bia

Adllpted from reference~ 10 and 73 Table 1 Center for 0Iserse Cootrolnl Pfevention Siological DiseJosesJAgents WL A3i Lable at hltpflwwwbIcdcgoyIAgenllagelaquoJistup Ian updated 1010402

Boric L (nQ~Oy T Peter q et aI Hemorrhagic fever viNi I I bioIoglul weapons medical and pUblk ~eal1h mn~gemen t JAMA 287(18)2391-2405 2002

social disruption and require special action for health preparedness 1 I Most of these aglnts have signitishyca nl ophthalmic manifestations that may aid in diagnosis o r compli cate management

Biological Diseases Anthrax B(lcillus onthracis is the ideal biologic weapon because stabili ty in spore fo rm its ease to grow in culture bullbull bull of natural immunity In many industrialized nations the severity of infection

Microbiologyepidemiology Badlus anthracis is an encapsulated aerobic GrarrmiddotpiI~ spore-forming rod-shaped bacterium Spores form environmental nutrients are deple ted such as dry soil the narural reservoir Spores can survive in contaminated ~lIs or workplaces and can resist

13 Irures of over IOOdegC for prolonged periods 12middot

can OCCUT fro m animaJ products such as wool fibers bo ne meal leading to o utbreaks in slaugh terhouses industries and tanneries 14 Herbivores such as canle and sheep ingest spores and selVe as the natural mitten of infection Humans become in fected direct contact lith contaminated carcasses or iTom infected meat Animal h usbandm en butchen and adam are most susceptible 12

Clinical manifestations Three prin cipal forms of anthrax occur in cutaneous inhalationaI and gastroi ntestinal The of naturally occurring disease is cutaneous compOSil mo re than 95 of casesY Inhalalional anthrax is likely to result hom a large-scale biological anack sent In mailed letters or packages can lead to cutaneous or InhalaUona l anthrax

296

Irt~~ mthraxkr disease begins as a small painless pruritic red

that progresses 10 a papule which vesiculates and ulcerates It thell forms a classic 1- 5 em brown

c~)-t)k eschar surrounded by slgn ilic3m non pitting The term anUuax is derived from the Gleek

meaning coal It appears at the site of inoeushy(spor~ o r badlli) within 3 to 10 days The edema

spread and lIansluctnt epidermal bullae vesides often the lesion _ the so-called pearly wreath ll After

4 weeks the eschar sloughs away leaving an exposed of granulation tissue Although fatalities due to

disease 3re rare 10 to 20 of untreated patients malignant edema septicemia shock renal failure

death

manifestations findings in rutaneOU$ anthrax rtlate to eyelid

~~~~Il IS-I The roain complication is cicatricial tt due to late eyelid scarring (Fig 1041) 11 Lid malshy

causes exposure keratopathy which can lead to lial breakdown and secondary infectious keratitis

scarring is more likely to occur in patients who late wHhout treatment during the acute stage It that upper eyeJid involvement Is more like1y to

in ectropion Severely affected patients have undershyrelease of connactuces and fuU-thickness postauricuLar

with satisfactory resolution of ectropion ll Temshymery infIammation has been reported as a complishyof oVNlying cutaneous anthrax2(l

Cowpox an uncommon infectio n transmitted by the cat can mimic an anthrax lesion 21- U The dlffershy

1041 Cutmeow anthrax A Swelling and cf)thema in he early I Crntral ulceration with black nccJolk tiuu~ in the latter (From reference 19 page 1007 Figure I NOeller TP 8iological

~ 7~~~~~~~~=~ri$m recognition and management Cleve (lin J 11 62001

External Eye Manifestations of ClMmkal and Biotogkal Warfare

ential diagnosis of cutaneous anthra-x also Includes spider bite ecthyma gangrenosum u1ceroglandular tularemia plague scrub typhus rickettsial spotted fever rat bite fever staphylococcal or streptococcal ceUuJitis and herpes simplex viTUS24bullU

Gastrointestinal anthrax Gastrointestinal anthrax liIoely results from the in gestion of latge numbers of vegetative bacilli from poorly cooked Infected meat2S The oral-pharyngeal form of disease results in an oral or esophageal ulcer which leads to the develOpshyment of regional lymphadenopathy edema and sepsis Disease In the terminal Ileum or cecum presents yentith nausea vomiting and malaise and progresses rapidly to bloody d iarrhea acute abdomen and sepsisu

InhalaUonal anthrax InhaJation anthrax or wool-sorters disease genera lly presents as a two-stage illness A prodromal stage begins With nonspecific symptoms of fever cough malaise headshyache and dyspnea l ~ Some patients have transient improveshyment after 2 to 4 days but the fulminant stage often ensues rapidly with respiratory distress diaphoresiS shock and death Inhaled spores germnate In hilar nodes and cause mecUastinal lymphadenopathy and hemorrhage lhis Is detected radiographically by a widened med iastinum and pleural effusions which may be hemorrhagic 27 Metamiddot static infection results in hemorrhagic menJngitti in up to sO of cases leading 10 meningismus delirium and obtundatton 9

DiagnOSiS Anth rax bacilli can be vi~ualized by Wright or Gram stain of peripheral blood or isolated by blood culture_ DlagnosNc testing (or cutaneous disease includes Gram stain and culture of vesicular fluid and tissue biopsy ImmunolOgiC tests indude specihc enzyme-linked immunosocbent assays (ELISAs) to measure antibody titers immunomagnetic shyelectrochemilumlnescence (EeL) assays for antigen detecshytion and polymerase chain reaction (peR) for nucleic add detecrion 14 Spores have a diameter of 2 to 6 mm which is Ideal for entrapment in the lower respiratory tract The time for infection is variable because spores must germinate into badlli aher phagocytOSIS by tissue macrophages The dose of anthrax in an exposure is inversely correlatelt with incubation lime Cases In the accidental release In Sverdlovsk developed 2 to 43 days after exposure Thus il may be hard 10 ITace the onset of an attack maklng response and containment more dlfficult

Treatment Treatment or inhalationa l and gasnointesrinal anthrax should begin with intravenous ciproOoxacin 400 mg every 12 hours (Table 104 2)19 Doxycycline lOOmg every 12 hou rs can be used but has poorer centra l nervous system peuetration One Dr (0 of the following additional antishybiotics should be added until susceptibility testing is performed rifampin vancomycin penicillin ampicillin chloramphenicol imipenem cUndamycin and clarithroshymycin Cu taneous disease can be treated with either oral

1297

THie 1042 CDC recommendations for anlimicrolXitl thtrapy 19Iinn anthrax

PO~lexpowre

CutaneoUl ~ nthru

Inhalational anthrax

OR

PLUS (tor either drug)

middotCiplollooClCn dmt It (fIIJdrrn 001 10 excffii I gldcry

mg by mouth twice a day

Doxycycline 100 mg by mouth twice a day

mg

Doxycycline 100 mg by mOUlh twice a day

mg every 12 hrs

DOxycycline 100 mg intravenously every 12 hli

One or two additional antibiotics (eg rifampin vilncomycin penlcillin ampicillin chloramphenicol imipenem clindamycin clarimomycin)

by mouth every OR Doxycycline 8 yrs and gt45 kg 100 mg by mouth every 12 hn gt8 yli and $45 kg 22 mglkg by mouth every 12 hrs ~8 yli 22 mgkg by mouth every 12 hrs

mgkg by mouth every t2 hrs OR DoKycycline 8 yJ$ and gt45 kg 100 mg by mouth every 12 hrs XI yr~ and ~5 kg 22 mgkg by mOuth fNfry 12 hIS s8 yrs 22 mgkg by mouth every 12 hrs

10-15 mgkg lntravenomfy every 12 hIS

Ooxyltyltline 8 yrs and gt45 kg 100 mg intravenou~ly every 12 hrs 8 yrs and ~5 kg 22 mgkg intraveou~1y every 12 hn s8 yli 22 mgkg intravenously every 12 hrs PLUS (for either dNg) One or two addit ional antibiotiCS

rom~ 19 ~ 1008 1~ 1 Hod~ TP BioIogl(OJotKIchemi(Ol~iJtn t(0gn4ion lNldrnonogtmtnl Cleve Ctin I Med 611(11J IQOI-IOI6 1001

ciprofloxacin or dOlCcycline alone Treatment should be continued for 60 days because of the possibility o( delayed germination of spores2S Direct contact with wound or wound drainage should be avoided when caring for a patient with cutaneous anthrax

Despite aggressive supportive therapy and antibiotics fatality is very high In the 2Oth-century series of 18 patients in the Uni ted States the mortality rate of occupationally acquired inhalational anthrax was 89 but the malority of these cases occurred before the development of critical care units and antibiotics2S After Ihe September 2001 terrorist attacks on the United Stales anthrax spores were sent to various locations via the postal service resultlng In 11 cases of inhalatlon al anthrax with five deaths25

Prevention Since there aTe no data to support personmiddot la-person transshymission of anthrax patient contacts do not need immushynization or prophylactic treatment unless they were exposed 10 the aerosol or surface contamination al the liJne o f attack

A vaccine derived fTOm an attenuated stra in of anthrax is available and studies in rhesus monkejs indicate that it is protective (or inhalational anthrax29 Should an anack occur those exposed must be vaccinated and receive

chemoprophylaxis with either dlofloxaon m dCIIctinlt orally until a l least three doses of vaccine have administeredu The safety of the vaccine was studied ill military personnel and 1 of inocul ations were associated with one or more systemiC events (ie headache blurred vis ion nausea) Interestingly two cases of bullbull Optic neuritis have been reported after anthrax

YIvacctnation One patient resolved without nmn~ the other had bilateral involvement that reqUired immunosuppression to maintain vision Retinal and nerve autoanlibodies were presenl in this patient 0 of unilateral optic neuropathy bilateral anter10r bIlateral posterior scleritis bilateral sensorineural loss and focal segmental giomerulosclerosis has also reported likely due to an Immune-mediated eaction the vaccine l l

Botulism

Borulism is a serious paralytic illness caused by a toxln produced by the bacterium Clostridium be It poses a major bioweapons threat because of its

potency and lethality its ease of production IPDtatloo and misuse and the need for prolonged intensive among affected personsll

298

~~~~Ibo~ruinum is a rod-shaped spore-formioamp obli shyanaerobe commo nly fouod jn soil There are seven of toxin designated A th rough G wh ich are defined

their absence of cross-neutralization (Le anti-A antlshydoes not neutralize toxin types S-G)32 Types A B

E account for greater than 9m of human botulisrn ll A toxJ o is the most potent poison known to humans

times more toxic than sarin nerve gasY Once the toxin is catred via the blood to peripheral synapses It irreversibly binds to the presynapUc

junction where it is internalized and blocks release causing paralysis Interestingly a vlal Botoxreg (Allerga n Irvine CA USA) contains

about 0301 the estimated human le thal inhaJationaJ and 0005 of the estimated lethal ora~ dosel]

fcnns o f narurally OCCUrring botulism exist foodshywound and intestinal The o ldest and most commiddot

form observed on a worldwide basis is foodmiddotbome occurs after ingestion of food that contains premiddot neurotoxin 33 Typical cases result from ingestion

improperly prepared hOme-canned food The m ost ro~~ form of botulism reponed in the United States is in intestinal botulism14 Unlike the foodmiddot borne rype

infant form is a combination of iniection and intoximiddot resulting from ingestion of C botulinum spores germinate within the gastrointestinal tract and

produgt toxin locally Honey consumption is a significant factor and Is not reltommended fot children under age of 1 year35 Wound infection with C botlliinum

can occur under conditions of tissue necrosis and

~~~~~ Spores can germinate in vivo and produce n which leads to the same chnica features as

seen In Cood-bome botulism except for the acute gaonn symptoms l3

CIiic1 manifestations an attack botulinum toxin would likely be used as

inhalal lonal agent or 10 deliberately contaminate food since it does not penetrate lntact skin and is n ot t ransmiddot mitted from person to perso n12 Symptoms generally begin 12 to 72 hours after ingeStion The time of onset after an inhalational exposure is not known but experimentally is Millar to foodmiddotborne exposureY

Botutism classically presents as an acute afebrile symmiddot merrie descending flaccid paralysis that always begins in the bulbar musculature (Box 1042)3ZmiddotlJ Patients have a dear sensorium because the toxin does not penetrate the brain tissue The prominent bulbar palsies (4 Os) include diplopia dysarthria dysphonia and dysphagia If the origin is foodmiddotborne the neurologic signs may be preceded by alxlominal cramps nausea vontiting or diarrheaYgt Sensory changes are not present As the disease progresses weakshyness extends below the neck with loss of deep tendon retlexes constipation and unsteady gait Severe cases lead to respi ratory collapse (rom diaphragm and intercostal muscle involvement and a irway obsrructlon fro m pharyn-

External Eye Manifestations of Chemical and BJoiogical Warfare

Box 1042

Signs and lYptoms of food-bome and wound botulllm

Signs Ventilatory (rlspiratory) problems Extraocular muscle paresis or paralysis (including eyelids) Muscle paresis or paralysis Dry mucous membranes in mouth throat Dilated fixed pupils Ataxia Somnolence Hypotlnsion (including postural) Nystagmus ~crNsed to absectent deep tendon reflexes Fever (more common for wound botulism) 5ensoty deficits (very rare)

Symptoms Visual disturbances (blurred vision diplopla photophobia) Dy~phagia Dry mouth Generalired weakness (tnUally bilateral) Nau~a or vomiting Dizziness or vertigo Abdominal pain cramps discomfort Oiantlea Urinary retention or incontinence Sore throat Constipation ParlISthesias

Adapted from ~ference )3 pampge 28 Table$ 1 and 2 Caya IG Clostridium IgtoMirom and the ophthal~ a ~ of boWIiirn including bIoIogIuI warfom ramifiutions of botulinum toxirI SuN OphhoIrno( 62~)ltI 2001

geal musde paralysis32 Autonomic nervous system lnvolvemiddot ment can lead to cardiovascular lability

Ophthalmic manifestations Visual symptoms of diplopia photophobia and blurred vision are present early (fable 1043)33 Accommodative paresis and mydriaSiS account for the blurred vision and photophObia respectively Blepharoptosis gaze paralysis pupillary dilation and nystagmus are common ophthalmic signs Dry eye and dry mouth trom parasympathetic cholinergic blockade can also be proQlinent

Uncommon neuro-ophthalmic manifestations include complete bilateral inlemal ophthalmop legia)] whIch can indude both permanent18 and transienrl9 tonic pupilS A dilated and poorly reactive pupil wi th loss of accommoshydation are typical findings Lightmiddotnea r dissociation ~ctoral iris COntractions and supersensitivity of the iris sphincter muscle to weak mimics (pilocarpine 01) are also hallshymark findings of a tonic pupil

Diagnosis Early diagnosis of botu lism is made by the history and physical exam The differential diagnosis includes GuHlainmiddot Barre and the Miller-Fisher variant myasthenia gravis Lambert-Eaton syndrqme tick paraliS stroke and various central nervous system disorders 19 1 80tulism differs from other causes of flacCid paralyses in that there is the presence

1299

T 1041 Ophthalmic signs and symptoms of botulism

S9n 1iJ- -6u~ vision PloJojs 0 Diplopia 59

Abnormal pupil re~dion to light 9

Impaired accommodation 9 Nystagmus MydriasiJ 2

poundXtraocvlar muscle dysfunction on eltAm 3

Mopsrd hom rtf~renCpound 33 pOgf 31 Table 8 Coyo jG Clostridium boIulinum and tilfI ophlhtllmoiogiIl a fevtW of bolu~Jm ilduding bigkal worfall ramiflcolon 01 botulinum I~n SIIV Clphlhalmol 4615-34 1001

of symmetry absence of sensory nerve damage and disprOshyportionate involvement of cranial nerves compared to muscles below the neck l 2

Demonstration of toxin by mouse bioassay is diagnostic in samples of serum stool gastric aspirate and suspect food 32 Studies suggest that aerosolized toxin is usually not identifiable in serum or stOol but may be present on nasal mucous membranes and detected by ELISA for up to 24 hours after exposure 27 Fecal wound and gastric sped mens can be cultured anaerobica lly if a food-borne or wound source of C botulinum is suspected An electroshymyogram can show characteristic findings which include normal nerve conduction velocity normal sensory nerve function a pattern of brief sma llmiddotampLitude motor potenshytials and most distinctiveLy an incremental response to repetitive stimulation often seen only at SO HZ40

Treatment Management is primarily supportive with ventilatory assistance essential in advanced cases Ea rly ad ministration with equlne-deTived trivalent (types A B E) antitoxin can minlmile subsequent nerve damage and severity of d isease but Will not reverse existing paralysis which can last from weeks to monthsH Wound-relat ed botulism reqUires debridement and antibiotics for secondary infections In a large outbreak of botulism the need for mechanical ventishylators critical care beds and sldlJed personnel might quickly exceed capacity Research directed at recombinant vaccines and human antibody may eventually minimize the threat of borulinum toxin as a weapon of mass destruction

Smallpox SmatJpox is one of the most dreaded diseases in the history

1300 of humankind It raged in epidemic and endemic forms fOr more than 3000 years killing hundreds of millions of

people In 1966 the World Health Organization established a middotvaccination program with extensive educational and surveillance programs for global eradication Smallpox was successfully eradicated in 1977 with the last case docushymented in Somalia42

Microbiology Variola is a large double-SlJanded DNA virus and member of the genus orthopoxVirus The viruses are complex and the virion is brick-shaped with a diameter of about 200 nmj

Three other members of this genus (monkeypox vaccinia and cowpox) can infect humans but are not high1y contagiousiJ

Epidemiology There are two clini cal forms of smallpox variola major and a much milder form variola minor TypicaL varl ola major epidemics resulted ill mortaLity rates of greater than 30 among unvaconated persons H Smallpox spreads from person to person primarily in droplet form or aerosols expelled from the oropharynx of infected persons Conshytaminated bedding and clothing can also spread the virus via direct contact44 Smallpox would likely be used in aerosol form during a biologica l assault given bolh iU small iruectious dose and sign ificant stabili ty

Clinical manifestations After an incubation period of about 12 days patients febole and often develop severe constitutional symptoms Headache backache vomiting abdominal pa in and malaise afe common The clinical presentation ofsmaUpox is heralded by a diffu se maculopapular rash begtnn lng to 3 days after this prodroma l phase~ Lesions first on the mucous memb ranes of the oropharynx Skin appear mostly o n the head torso and extremities in centrifugal pattern evolving from a flat rash to a papUle vesicle and then a pustule which becomes crusted scabbed This leads to permanent scarring usually extensive on the face Classically the lesions are at stage of deveLopment at a given point and can affelt1 palms and sales Chickenpox (varicella) the disease frequently confused with smallpox differs in that are In middotarious stages of development at a given Varicella lesions are more superficial rarely fou nd on palms and soles and the distribution is centripetal the trunk affected more than the (ace and extremitiesw

Nearly one-third of patients with smaUpox will usually during the second week of illness This most

results from the toxemia and C~d~io~vla~s~CU~~Ia~~i~~~ associated with circulating immune variola antigens t3 PneumOn ia encephalitis o rchitis sepsis and overwhelming hemorrhage into skin and mucous membranes can complicate infection 41 Variola mino r the less severe form of pox results in milder symplOms 1th only a sparse and less than 1 mortaUty 13

Patients are most infectious during the first week iUness however some risk of transmission is all scabs have fallen Off4~ It is thought that Ismallpoxcaru~

I

transmitted until the onset of the rash Z~ so diagnosis the prodromal stage with subsequent quarantine

be essential to limit additional exposure

lp~~~~I~~~ manifestations In led to blindness in 2 to 5 of students in blind

of developing countries in Africa 48-30 Typically a conjunctivitis appears around the fifth day of illness subconju nctival hemo rrhage in some cases Actual

whIch resemble phlyctenules may form on the or tarsal conjunctiva and even involve the limbus~l lesions are very inflamed and painful and can lead I and ulceration of the cornea Less frequently

imerSlitial 01 disciform keratitis evolves (Fig 1042) Lid and punctal stenosis may result when pustules

the cUla and punda respectively Ankyloblepharon also been reported due to severe eyelid adhesions

the upper and lower canthiY Secondary infectious can ocCur late and lead to significant morbid ity

~me antibiotic prophylaxis is warranted Dense comeaJ can leave patient s phthiSical and blind

beatorv diagnosis of smallpox can be confi rmed with microscopy of vesicular o r pustular nuld or

~~sect~Guamieri bodies can be visualized under lightVirus culture of skin lesions oropharynx

and urine is definitive peR techniques ca n ~ between strains and offer a more rapid

rne and vaccination is no specific systemic or ocular treatment for smallshy

although cidofovir has In vitro and In vivo activity

External Eye Mlfestatlons of Chemical and Blologkal Warfare

against Poxviridae P 1n 1796 Edwardjenner demonstrated that an Lniection caused by cowpox protected against smallshypox wh ich led to the worldwide practice of vacdnatiooS3

Curremly smallpox vaccine is prepared from live vaccinia virus using cell culture techniquesl4

The interval between an aerosol release of variola and diagnosis of the first cases is as much as 2 weeksH Fortushynately the virus is Inactivated after 2 days eliminating further exposure Individuals in whom infection is suspected should be vaccinat ed within 4 days o f exposure and placed under surveillance Vaccination programs ended in 1972 in the United States and it Is presumed that few people who wefe vaccinated have lasting protective levels of immunity

Complications of vaccination Vaccination is not without risk Life-threatening encephalshyitis occurs at a rate of 1 case per 300 OOOH ProgreSSive vaccinia or vaccinia gangrenosum results from neaogtls of the skin at the vacd nation site with advanced cases involving underlying bone and viscera Patient s wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites (Fig 1043) In some vaccine recipients blood-bome dissemimiddot nation of virus leads to a self-limiting generalized vactinial rash TransmISSion of vaccinia froro the site of vaccination to close contacts or autoinoculatjon to sites such as face mouth eyelid aod genitalia can take place Vaccinia immune globulin is used to treat these complications with variable success

Vaccinia ophthalmic manifestations Inadvertent autoinoculation of vaccinia from the deltoid site accounts for the ophthalmic co mpUcations of vaccishynation The majority of patients have vaccinia of the eyelidgt or conjunctiva but a smaller percenlage have comeal involvement ss Typically patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and

Ag 1042 ilfiol (smallpox) This patient demonstmtes a centrlll Fig 1043 Eczema vaCtinllll)nl Vaccinial skin leJioru extending (Ver the not scar from a sm~lIpox or variola infection area currently afflicted with eczema (Courtl$) of Rkhard K Forster MD)

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

I Ou$Iophtr GW Ci~l1k T) P~v1111 JA el Oll 81eloglcotl wariall l hIsIotlcal pmpeGive lAMA 273(S)412-11 7 1991

2 Gfoiraquolf E 8ioogual and fI)~ill _pam rodily ~ York NY 1986 Oxford Unlvenlry Preraquo

3 HrTU S Japa~ blologllta1 warlue re~arch on humans a CiCie $rultI) of mlcroblology and ethio tirln N Y Acad So 66621-5Z 1992

4 Slnu NA n~ diplomacy of biological d1samamal New York NY 1983 Plenum Pteraquo

5 Meseuon M Guillemln J HughmiddotJones M et i l The Sverdlovs~ anthux OUibreu of 197J Sdmct 266 I lQZ-l 208 1994

6 ZllJns~ RA lqmiddot~ biological up0n5 thf past as fulUl1 JAt4 278(S)laquo I8-424 1997

7 WHO Group of ConmltaJl lJ Ht(llh r15pertl 0 rllmlical iUld biologicill wapon Geneva SwlUerland 1970 World HeMth Organization pp72-99

8 McGovern TW Chrlnophcr CW Eitzen EM Culolneou~ mallifesIilTioJ) at biologiCiI mace am t tltlted lhlUt Jgen l$ An-I Dmnmoi 1353 11-3U 1999

9 American Colleg~ of PhysKin~middotAmtIiClUl Soot) 0( Inlemal Medldn~ AC pmiddotASJMmiddot Guide 10 8)Otenorhm ldoen t l-ticotlon 2002

]0 Cenltrs for OiseltlSl Control and Prev~ntlon BIOlogical DI5e~IAgent5 UsC Available at http wwwbICdcgovIAgemagentlhl llp laM updlted 10040Z

I I lttn ten for Oi$eaSl Conn-ol and Prevention Chemical Agent~ Ult aoa Infomudon Avillabl at httpwwwIxcdcgovAgUltfagen UiSKhemasp lAS t updated 1009OZ

12 K10t SA An thrax In GOlbach 5 Banlom J Bbcklow N editon In(WIow diJ~ltlJ(S PhilMelptUa PA 1992 WB ~undm pp 1291- I29J

13 Youton 0 Fmter A CUUIlKlUS anthrax leadlng to Ul rneai scarrtng from deatrldal ectropion Sr f Oplllllalmol 73809-8 11 1989

H 8rouswd iJ Biological agenu wapon of warfase and bio~rTOtJsm

)lt) DIltun 6(4)1Z3-1J1 ZOOI 15 Q-Iebl S Ayun U AiagOt G et Ill Palpebral antJuax W OphlJlalmol

11 (2) ]71- 174 ZOO I 16 5oysl HG Kirntli H Rlaquo-ep O f Anth rax as ure ca~ 01 prewptal

cclIulJtJs and cicatricial ectropion Ada OplhalmtJl SeaId 79(2) 208-209 ZOOI

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85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

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87 Thbbara kF Al-KaWmi H Orulat bruc eUo$b j t I Ophrhillmal i4(4) 249- lS0 1990

88 Woolth AC NUIJDub r )era liUs anO ocular brocellogtls Aidgt Ophlhalmol l 549(l 1946

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93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

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11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

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113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

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l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

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117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

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Page 2: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

TQIe 1041 Estimated ~llies fOf ill hypothetical biological warfare attack on a city of 500 000middot - Do__1d

Rift Valley I~r

rudI (km)

1

lt00

No bull kKaclbted

)5 000

Tkkmiddotbomr encephltlli(i5

1 9500 35000

Typhus

Brucellosis

5

10

19000

SOD

85000

100000

Q lever 20 150 125000

Tularemitl 20 30 000 125000

Anthrall 20 950000 125000

ThIS mod~ OJWrrnS 111m $0 Jg 01 agmt is depJoy~ from PI oirtraft aoog ) km line upwind from Ihf city from ~ftrt1U 8 po~ J I) robr 2 AkCovtm rw Christophe Cw lJlJtfl EM CIIlOtltOUJ nif~oiom 01 biolo9lCai worlore and ftkntd IhrlaquoJI ogtnil ell Oemlalol IJS-JIImiddot122 1999 Copyfighl e (999) Americon ~1f1CUl AsSlaquoialoOl All nght$ revrwd

an entire dry and impede the mobilization of military personnel

Warning Signs In mder to recognize a bioterror anack one must be familiar with the various clini cal presentations of these agents The American College of PhYSicians and the American Society of Intern al Medicine have suggested that the follOwing epidemiological clues be considered 1 Unusual temporal or geographic clustering of illn ess 2 Unusual age distribution of common disease (Le an

illness that appears to be ch ickenpox in adults but is really smaUpox)

3 Large epidemic wi th greater case loads than expected especia lly in a discrete population

4 More severe disease than expected 5 Unusualwute of ex posure 6 A disea se that is outside its normal transmission

season or is impossible to transmit naturaly in the absence of its normal vector

7 Multiple simultaneous epidemics of different diseases 8 A disea se outbreak with health consequences to

humans and animals 9 Unusual strains or variants of organisms o r

antim icrobial resistance patterns The Cent ers for Disease Control and Prevemi on

(CDC) of the United States has listed the high-priority biological dIseases (Box 1041)10 that pose significant risk to national security based on the onowing can be easily disseminated ando r tlansmitlelti from person to person result in high mortality rates and have the paten rial for major public health Impact oUght cause public pani c and

Box 1041

Biological d lseaMs

Anthrax (80cilIJSanthracis)

Botulism (CcstridilJm botlJiinlJm toxin) Pla9ue (Yeninio pt1fis)

Smallpollt (Variola maior and minor) Tularemia (Fronciseiio wiarensil)

Vir~l hemorrhagic fever

Filoviruse~ - Eboia Mltlrbu(g

ArenavirU5e~ - Lassa Junin Machupo Guanarito S~bia

Adllpted from reference~ 10 and 73 Table 1 Center for 0Iserse Cootrolnl Pfevention Siological DiseJosesJAgents WL A3i Lable at hltpflwwwbIcdcgoyIAgenllagelaquoJistup Ian updated 1010402

Boric L (nQ~Oy T Peter q et aI Hemorrhagic fever viNi I I bioIoglul weapons medical and pUblk ~eal1h mn~gemen t JAMA 287(18)2391-2405 2002

social disruption and require special action for health preparedness 1 I Most of these aglnts have signitishyca nl ophthalmic manifestations that may aid in diagnosis o r compli cate management

Biological Diseases Anthrax B(lcillus onthracis is the ideal biologic weapon because stabili ty in spore fo rm its ease to grow in culture bullbull bull of natural immunity In many industrialized nations the severity of infection

Microbiologyepidemiology Badlus anthracis is an encapsulated aerobic GrarrmiddotpiI~ spore-forming rod-shaped bacterium Spores form environmental nutrients are deple ted such as dry soil the narural reservoir Spores can survive in contaminated ~lIs or workplaces and can resist

13 Irures of over IOOdegC for prolonged periods 12middot

can OCCUT fro m animaJ products such as wool fibers bo ne meal leading to o utbreaks in slaugh terhouses industries and tanneries 14 Herbivores such as canle and sheep ingest spores and selVe as the natural mitten of infection Humans become in fected direct contact lith contaminated carcasses or iTom infected meat Animal h usbandm en butchen and adam are most susceptible 12

Clinical manifestations Three prin cipal forms of anthrax occur in cutaneous inhalationaI and gastroi ntestinal The of naturally occurring disease is cutaneous compOSil mo re than 95 of casesY Inhalalional anthrax is likely to result hom a large-scale biological anack sent In mailed letters or packages can lead to cutaneous or InhalaUona l anthrax

296

Irt~~ mthraxkr disease begins as a small painless pruritic red

that progresses 10 a papule which vesiculates and ulcerates It thell forms a classic 1- 5 em brown

c~)-t)k eschar surrounded by slgn ilic3m non pitting The term anUuax is derived from the Gleek

meaning coal It appears at the site of inoeushy(spor~ o r badlli) within 3 to 10 days The edema

spread and lIansluctnt epidermal bullae vesides often the lesion _ the so-called pearly wreath ll After

4 weeks the eschar sloughs away leaving an exposed of granulation tissue Although fatalities due to

disease 3re rare 10 to 20 of untreated patients malignant edema septicemia shock renal failure

death

manifestations findings in rutaneOU$ anthrax rtlate to eyelid

~~~~Il IS-I The roain complication is cicatricial tt due to late eyelid scarring (Fig 1041) 11 Lid malshy

causes exposure keratopathy which can lead to lial breakdown and secondary infectious keratitis

scarring is more likely to occur in patients who late wHhout treatment during the acute stage It that upper eyeJid involvement Is more like1y to

in ectropion Severely affected patients have undershyrelease of connactuces and fuU-thickness postauricuLar

with satisfactory resolution of ectropion ll Temshymery infIammation has been reported as a complishyof oVNlying cutaneous anthrax2(l

Cowpox an uncommon infectio n transmitted by the cat can mimic an anthrax lesion 21- U The dlffershy

1041 Cutmeow anthrax A Swelling and cf)thema in he early I Crntral ulceration with black nccJolk tiuu~ in the latter (From reference 19 page 1007 Figure I NOeller TP 8iological

~ 7~~~~~~~~=~ri$m recognition and management Cleve (lin J 11 62001

External Eye Manifestations of ClMmkal and Biotogkal Warfare

ential diagnosis of cutaneous anthra-x also Includes spider bite ecthyma gangrenosum u1ceroglandular tularemia plague scrub typhus rickettsial spotted fever rat bite fever staphylococcal or streptococcal ceUuJitis and herpes simplex viTUS24bullU

Gastrointestinal anthrax Gastrointestinal anthrax liIoely results from the in gestion of latge numbers of vegetative bacilli from poorly cooked Infected meat2S The oral-pharyngeal form of disease results in an oral or esophageal ulcer which leads to the develOpshyment of regional lymphadenopathy edema and sepsis Disease In the terminal Ileum or cecum presents yentith nausea vomiting and malaise and progresses rapidly to bloody d iarrhea acute abdomen and sepsisu

InhalaUonal anthrax InhaJation anthrax or wool-sorters disease genera lly presents as a two-stage illness A prodromal stage begins With nonspecific symptoms of fever cough malaise headshyache and dyspnea l ~ Some patients have transient improveshyment after 2 to 4 days but the fulminant stage often ensues rapidly with respiratory distress diaphoresiS shock and death Inhaled spores germnate In hilar nodes and cause mecUastinal lymphadenopathy and hemorrhage lhis Is detected radiographically by a widened med iastinum and pleural effusions which may be hemorrhagic 27 Metamiddot static infection results in hemorrhagic menJngitti in up to sO of cases leading 10 meningismus delirium and obtundatton 9

DiagnOSiS Anth rax bacilli can be vi~ualized by Wright or Gram stain of peripheral blood or isolated by blood culture_ DlagnosNc testing (or cutaneous disease includes Gram stain and culture of vesicular fluid and tissue biopsy ImmunolOgiC tests indude specihc enzyme-linked immunosocbent assays (ELISAs) to measure antibody titers immunomagnetic shyelectrochemilumlnescence (EeL) assays for antigen detecshytion and polymerase chain reaction (peR) for nucleic add detecrion 14 Spores have a diameter of 2 to 6 mm which is Ideal for entrapment in the lower respiratory tract The time for infection is variable because spores must germinate into badlli aher phagocytOSIS by tissue macrophages The dose of anthrax in an exposure is inversely correlatelt with incubation lime Cases In the accidental release In Sverdlovsk developed 2 to 43 days after exposure Thus il may be hard 10 ITace the onset of an attack maklng response and containment more dlfficult

Treatment Treatment or inhalationa l and gasnointesrinal anthrax should begin with intravenous ciproOoxacin 400 mg every 12 hours (Table 104 2)19 Doxycycline lOOmg every 12 hou rs can be used but has poorer centra l nervous system peuetration One Dr (0 of the following additional antishybiotics should be added until susceptibility testing is performed rifampin vancomycin penicillin ampicillin chloramphenicol imipenem cUndamycin and clarithroshymycin Cu taneous disease can be treated with either oral

1297

THie 1042 CDC recommendations for anlimicrolXitl thtrapy 19Iinn anthrax

PO~lexpowre

CutaneoUl ~ nthru

Inhalational anthrax

OR

PLUS (tor either drug)

middotCiplollooClCn dmt It (fIIJdrrn 001 10 excffii I gldcry

mg by mouth twice a day

Doxycycline 100 mg by mouth twice a day

mg

Doxycycline 100 mg by mOUlh twice a day

mg every 12 hrs

DOxycycline 100 mg intravenously every 12 hli

One or two additional antibiotics (eg rifampin vilncomycin penlcillin ampicillin chloramphenicol imipenem clindamycin clarimomycin)

by mouth every OR Doxycycline 8 yrs and gt45 kg 100 mg by mouth every 12 hn gt8 yli and $45 kg 22 mglkg by mouth every 12 hrs ~8 yli 22 mgkg by mouth every 12 hrs

mgkg by mouth every t2 hrs OR DoKycycline 8 yJ$ and gt45 kg 100 mg by mouth every 12 hrs XI yr~ and ~5 kg 22 mgkg by mOuth fNfry 12 hIS s8 yrs 22 mgkg by mouth every 12 hrs

10-15 mgkg lntravenomfy every 12 hIS

Ooxyltyltline 8 yrs and gt45 kg 100 mg intravenou~ly every 12 hrs 8 yrs and ~5 kg 22 mgkg intraveou~1y every 12 hn s8 yli 22 mgkg intravenously every 12 hrs PLUS (for either dNg) One or two addit ional antibiotiCS

rom~ 19 ~ 1008 1~ 1 Hod~ TP BioIogl(OJotKIchemi(Ol~iJtn t(0gn4ion lNldrnonogtmtnl Cleve Ctin I Med 611(11J IQOI-IOI6 1001

ciprofloxacin or dOlCcycline alone Treatment should be continued for 60 days because of the possibility o( delayed germination of spores2S Direct contact with wound or wound drainage should be avoided when caring for a patient with cutaneous anthrax

Despite aggressive supportive therapy and antibiotics fatality is very high In the 2Oth-century series of 18 patients in the Uni ted States the mortality rate of occupationally acquired inhalational anthrax was 89 but the malority of these cases occurred before the development of critical care units and antibiotics2S After Ihe September 2001 terrorist attacks on the United Stales anthrax spores were sent to various locations via the postal service resultlng In 11 cases of inhalatlon al anthrax with five deaths25

Prevention Since there aTe no data to support personmiddot la-person transshymission of anthrax patient contacts do not need immushynization or prophylactic treatment unless they were exposed 10 the aerosol or surface contamination al the liJne o f attack

A vaccine derived fTOm an attenuated stra in of anthrax is available and studies in rhesus monkejs indicate that it is protective (or inhalational anthrax29 Should an anack occur those exposed must be vaccinated and receive

chemoprophylaxis with either dlofloxaon m dCIIctinlt orally until a l least three doses of vaccine have administeredu The safety of the vaccine was studied ill military personnel and 1 of inocul ations were associated with one or more systemiC events (ie headache blurred vis ion nausea) Interestingly two cases of bullbull Optic neuritis have been reported after anthrax

YIvacctnation One patient resolved without nmn~ the other had bilateral involvement that reqUired immunosuppression to maintain vision Retinal and nerve autoanlibodies were presenl in this patient 0 of unilateral optic neuropathy bilateral anter10r bIlateral posterior scleritis bilateral sensorineural loss and focal segmental giomerulosclerosis has also reported likely due to an Immune-mediated eaction the vaccine l l

Botulism

Borulism is a serious paralytic illness caused by a toxln produced by the bacterium Clostridium be It poses a major bioweapons threat because of its

potency and lethality its ease of production IPDtatloo and misuse and the need for prolonged intensive among affected personsll

298

~~~~Ibo~ruinum is a rod-shaped spore-formioamp obli shyanaerobe commo nly fouod jn soil There are seven of toxin designated A th rough G wh ich are defined

their absence of cross-neutralization (Le anti-A antlshydoes not neutralize toxin types S-G)32 Types A B

E account for greater than 9m of human botulisrn ll A toxJ o is the most potent poison known to humans

times more toxic than sarin nerve gasY Once the toxin is catred via the blood to peripheral synapses It irreversibly binds to the presynapUc

junction where it is internalized and blocks release causing paralysis Interestingly a vlal Botoxreg (Allerga n Irvine CA USA) contains

about 0301 the estimated human le thal inhaJationaJ and 0005 of the estimated lethal ora~ dosel]

fcnns o f narurally OCCUrring botulism exist foodshywound and intestinal The o ldest and most commiddot

form observed on a worldwide basis is foodmiddotbome occurs after ingestion of food that contains premiddot neurotoxin 33 Typical cases result from ingestion

improperly prepared hOme-canned food The m ost ro~~ form of botulism reponed in the United States is in intestinal botulism14 Unlike the foodmiddot borne rype

infant form is a combination of iniection and intoximiddot resulting from ingestion of C botulinum spores germinate within the gastrointestinal tract and

produgt toxin locally Honey consumption is a significant factor and Is not reltommended fot children under age of 1 year35 Wound infection with C botlliinum

can occur under conditions of tissue necrosis and

~~~~~ Spores can germinate in vivo and produce n which leads to the same chnica features as

seen In Cood-bome botulism except for the acute gaonn symptoms l3

CIiic1 manifestations an attack botulinum toxin would likely be used as

inhalal lonal agent or 10 deliberately contaminate food since it does not penetrate lntact skin and is n ot t ransmiddot mitted from person to perso n12 Symptoms generally begin 12 to 72 hours after ingeStion The time of onset after an inhalational exposure is not known but experimentally is Millar to foodmiddotborne exposureY

Botutism classically presents as an acute afebrile symmiddot merrie descending flaccid paralysis that always begins in the bulbar musculature (Box 1042)3ZmiddotlJ Patients have a dear sensorium because the toxin does not penetrate the brain tissue The prominent bulbar palsies (4 Os) include diplopia dysarthria dysphonia and dysphagia If the origin is foodmiddotborne the neurologic signs may be preceded by alxlominal cramps nausea vontiting or diarrheaYgt Sensory changes are not present As the disease progresses weakshyness extends below the neck with loss of deep tendon retlexes constipation and unsteady gait Severe cases lead to respi ratory collapse (rom diaphragm and intercostal muscle involvement and a irway obsrructlon fro m pharyn-

External Eye Manifestations of Chemical and BJoiogical Warfare

Box 1042

Signs and lYptoms of food-bome and wound botulllm

Signs Ventilatory (rlspiratory) problems Extraocular muscle paresis or paralysis (including eyelids) Muscle paresis or paralysis Dry mucous membranes in mouth throat Dilated fixed pupils Ataxia Somnolence Hypotlnsion (including postural) Nystagmus ~crNsed to absectent deep tendon reflexes Fever (more common for wound botulism) 5ensoty deficits (very rare)

Symptoms Visual disturbances (blurred vision diplopla photophobia) Dy~phagia Dry mouth Generalired weakness (tnUally bilateral) Nau~a or vomiting Dizziness or vertigo Abdominal pain cramps discomfort Oiantlea Urinary retention or incontinence Sore throat Constipation ParlISthesias

Adapted from ~ference )3 pampge 28 Table$ 1 and 2 Caya IG Clostridium IgtoMirom and the ophthal~ a ~ of boWIiirn including bIoIogIuI warfom ramifiutions of botulinum toxirI SuN OphhoIrno( 62~)ltI 2001

geal musde paralysis32 Autonomic nervous system lnvolvemiddot ment can lead to cardiovascular lability

Ophthalmic manifestations Visual symptoms of diplopia photophobia and blurred vision are present early (fable 1043)33 Accommodative paresis and mydriaSiS account for the blurred vision and photophObia respectively Blepharoptosis gaze paralysis pupillary dilation and nystagmus are common ophthalmic signs Dry eye and dry mouth trom parasympathetic cholinergic blockade can also be proQlinent

Uncommon neuro-ophthalmic manifestations include complete bilateral inlemal ophthalmop legia)] whIch can indude both permanent18 and transienrl9 tonic pupilS A dilated and poorly reactive pupil wi th loss of accommoshydation are typical findings Lightmiddotnea r dissociation ~ctoral iris COntractions and supersensitivity of the iris sphincter muscle to weak mimics (pilocarpine 01) are also hallshymark findings of a tonic pupil

Diagnosis Early diagnosis of botu lism is made by the history and physical exam The differential diagnosis includes GuHlainmiddot Barre and the Miller-Fisher variant myasthenia gravis Lambert-Eaton syndrqme tick paraliS stroke and various central nervous system disorders 19 1 80tulism differs from other causes of flacCid paralyses in that there is the presence

1299

T 1041 Ophthalmic signs and symptoms of botulism

S9n 1iJ- -6u~ vision PloJojs 0 Diplopia 59

Abnormal pupil re~dion to light 9

Impaired accommodation 9 Nystagmus MydriasiJ 2

poundXtraocvlar muscle dysfunction on eltAm 3

Mopsrd hom rtf~renCpound 33 pOgf 31 Table 8 Coyo jG Clostridium boIulinum and tilfI ophlhtllmoiogiIl a fevtW of bolu~Jm ilduding bigkal worfall ramiflcolon 01 botulinum I~n SIIV Clphlhalmol 4615-34 1001

of symmetry absence of sensory nerve damage and disprOshyportionate involvement of cranial nerves compared to muscles below the neck l 2

Demonstration of toxin by mouse bioassay is diagnostic in samples of serum stool gastric aspirate and suspect food 32 Studies suggest that aerosolized toxin is usually not identifiable in serum or stOol but may be present on nasal mucous membranes and detected by ELISA for up to 24 hours after exposure 27 Fecal wound and gastric sped mens can be cultured anaerobica lly if a food-borne or wound source of C botulinum is suspected An electroshymyogram can show characteristic findings which include normal nerve conduction velocity normal sensory nerve function a pattern of brief sma llmiddotampLitude motor potenshytials and most distinctiveLy an incremental response to repetitive stimulation often seen only at SO HZ40

Treatment Management is primarily supportive with ventilatory assistance essential in advanced cases Ea rly ad ministration with equlne-deTived trivalent (types A B E) antitoxin can minlmile subsequent nerve damage and severity of d isease but Will not reverse existing paralysis which can last from weeks to monthsH Wound-relat ed botulism reqUires debridement and antibiotics for secondary infections In a large outbreak of botulism the need for mechanical ventishylators critical care beds and sldlJed personnel might quickly exceed capacity Research directed at recombinant vaccines and human antibody may eventually minimize the threat of borulinum toxin as a weapon of mass destruction

Smallpox SmatJpox is one of the most dreaded diseases in the history

1300 of humankind It raged in epidemic and endemic forms fOr more than 3000 years killing hundreds of millions of

people In 1966 the World Health Organization established a middotvaccination program with extensive educational and surveillance programs for global eradication Smallpox was successfully eradicated in 1977 with the last case docushymented in Somalia42

Microbiology Variola is a large double-SlJanded DNA virus and member of the genus orthopoxVirus The viruses are complex and the virion is brick-shaped with a diameter of about 200 nmj

Three other members of this genus (monkeypox vaccinia and cowpox) can infect humans but are not high1y contagiousiJ

Epidemiology There are two clini cal forms of smallpox variola major and a much milder form variola minor TypicaL varl ola major epidemics resulted ill mortaLity rates of greater than 30 among unvaconated persons H Smallpox spreads from person to person primarily in droplet form or aerosols expelled from the oropharynx of infected persons Conshytaminated bedding and clothing can also spread the virus via direct contact44 Smallpox would likely be used in aerosol form during a biologica l assault given bolh iU small iruectious dose and sign ificant stabili ty

Clinical manifestations After an incubation period of about 12 days patients febole and often develop severe constitutional symptoms Headache backache vomiting abdominal pa in and malaise afe common The clinical presentation ofsmaUpox is heralded by a diffu se maculopapular rash begtnn lng to 3 days after this prodroma l phase~ Lesions first on the mucous memb ranes of the oropharynx Skin appear mostly o n the head torso and extremities in centrifugal pattern evolving from a flat rash to a papUle vesicle and then a pustule which becomes crusted scabbed This leads to permanent scarring usually extensive on the face Classically the lesions are at stage of deveLopment at a given point and can affelt1 palms and sales Chickenpox (varicella) the disease frequently confused with smallpox differs in that are In middotarious stages of development at a given Varicella lesions are more superficial rarely fou nd on palms and soles and the distribution is centripetal the trunk affected more than the (ace and extremitiesw

Nearly one-third of patients with smaUpox will usually during the second week of illness This most

results from the toxemia and C~d~io~vla~s~CU~~Ia~~i~~~ associated with circulating immune variola antigens t3 PneumOn ia encephalitis o rchitis sepsis and overwhelming hemorrhage into skin and mucous membranes can complicate infection 41 Variola mino r the less severe form of pox results in milder symplOms 1th only a sparse and less than 1 mortaUty 13

Patients are most infectious during the first week iUness however some risk of transmission is all scabs have fallen Off4~ It is thought that Ismallpoxcaru~

I

transmitted until the onset of the rash Z~ so diagnosis the prodromal stage with subsequent quarantine

be essential to limit additional exposure

lp~~~~I~~~ manifestations In led to blindness in 2 to 5 of students in blind

of developing countries in Africa 48-30 Typically a conjunctivitis appears around the fifth day of illness subconju nctival hemo rrhage in some cases Actual

whIch resemble phlyctenules may form on the or tarsal conjunctiva and even involve the limbus~l lesions are very inflamed and painful and can lead I and ulceration of the cornea Less frequently

imerSlitial 01 disciform keratitis evolves (Fig 1042) Lid and punctal stenosis may result when pustules

the cUla and punda respectively Ankyloblepharon also been reported due to severe eyelid adhesions

the upper and lower canthiY Secondary infectious can ocCur late and lead to significant morbid ity

~me antibiotic prophylaxis is warranted Dense comeaJ can leave patient s phthiSical and blind

beatorv diagnosis of smallpox can be confi rmed with microscopy of vesicular o r pustular nuld or

~~sect~Guamieri bodies can be visualized under lightVirus culture of skin lesions oropharynx

and urine is definitive peR techniques ca n ~ between strains and offer a more rapid

rne and vaccination is no specific systemic or ocular treatment for smallshy

although cidofovir has In vitro and In vivo activity

External Eye Mlfestatlons of Chemical and Blologkal Warfare

against Poxviridae P 1n 1796 Edwardjenner demonstrated that an Lniection caused by cowpox protected against smallshypox wh ich led to the worldwide practice of vacdnatiooS3

Curremly smallpox vaccine is prepared from live vaccinia virus using cell culture techniquesl4

The interval between an aerosol release of variola and diagnosis of the first cases is as much as 2 weeksH Fortushynately the virus is Inactivated after 2 days eliminating further exposure Individuals in whom infection is suspected should be vaccinat ed within 4 days o f exposure and placed under surveillance Vaccination programs ended in 1972 in the United States and it Is presumed that few people who wefe vaccinated have lasting protective levels of immunity

Complications of vaccination Vaccination is not without risk Life-threatening encephalshyitis occurs at a rate of 1 case per 300 OOOH ProgreSSive vaccinia or vaccinia gangrenosum results from neaogtls of the skin at the vacd nation site with advanced cases involving underlying bone and viscera Patient s wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites (Fig 1043) In some vaccine recipients blood-bome dissemimiddot nation of virus leads to a self-limiting generalized vactinial rash TransmISSion of vaccinia froro the site of vaccination to close contacts or autoinoculatjon to sites such as face mouth eyelid aod genitalia can take place Vaccinia immune globulin is used to treat these complications with variable success

Vaccinia ophthalmic manifestations Inadvertent autoinoculation of vaccinia from the deltoid site accounts for the ophthalmic co mpUcations of vaccishynation The majority of patients have vaccinia of the eyelidgt or conjunctiva but a smaller percenlage have comeal involvement ss Typically patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and

Ag 1042 ilfiol (smallpox) This patient demonstmtes a centrlll Fig 1043 Eczema vaCtinllll)nl Vaccinial skin leJioru extending (Ver the not scar from a sm~lIpox or variola infection area currently afflicted with eczema (Courtl$) of Rkhard K Forster MD)

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

86 Walke J Sharma Of Ra o NA BrureUo~ ls a nd uvei1~ Am IOphllullmo 114(3 )]14-]75 1992_

87 Thbbara kF Al-KaWmi H Orulat bruc eUo$b j t I Ophrhillmal i4(4) 249- lS0 1990

88 Woolth AC NUIJDub r )era liUs anO ocular brocellogtls Aidgt Ophlhalmol l 549(l 1946

89 G(ingor K Beki NA Namldwv M Re(I~n l episdetlds asoctal ld wlIh bruoelCKI Aaa OplltJwJmoI sca lld 19 76-78 2001

90 Putg Sollnes M Heatley J mnilS F el al Orolar com plicati ons In brulaquolIoill Am I Ophrhalmol 3667s-QS9 1953

9 Btki l NA GungJ K Si d lClal dacryoaderU lj woclated Wllh bru~Uosh A a OpirrJQmoJi Scnd 77(3)357-358 1999

92 al fa ran Mf BnK~lIa mfiUn$u ( ndogenogtn rndophltulmlUS OpIhalmologicn ZOl i l )19- ZZ 1990

93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 3: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

Irt~~ mthraxkr disease begins as a small painless pruritic red

that progresses 10 a papule which vesiculates and ulcerates It thell forms a classic 1- 5 em brown

c~)-t)k eschar surrounded by slgn ilic3m non pitting The term anUuax is derived from the Gleek

meaning coal It appears at the site of inoeushy(spor~ o r badlli) within 3 to 10 days The edema

spread and lIansluctnt epidermal bullae vesides often the lesion _ the so-called pearly wreath ll After

4 weeks the eschar sloughs away leaving an exposed of granulation tissue Although fatalities due to

disease 3re rare 10 to 20 of untreated patients malignant edema septicemia shock renal failure

death

manifestations findings in rutaneOU$ anthrax rtlate to eyelid

~~~~Il IS-I The roain complication is cicatricial tt due to late eyelid scarring (Fig 1041) 11 Lid malshy

causes exposure keratopathy which can lead to lial breakdown and secondary infectious keratitis

scarring is more likely to occur in patients who late wHhout treatment during the acute stage It that upper eyeJid involvement Is more like1y to

in ectropion Severely affected patients have undershyrelease of connactuces and fuU-thickness postauricuLar

with satisfactory resolution of ectropion ll Temshymery infIammation has been reported as a complishyof oVNlying cutaneous anthrax2(l

Cowpox an uncommon infectio n transmitted by the cat can mimic an anthrax lesion 21- U The dlffershy

1041 Cutmeow anthrax A Swelling and cf)thema in he early I Crntral ulceration with black nccJolk tiuu~ in the latter (From reference 19 page 1007 Figure I NOeller TP 8iological

~ 7~~~~~~~~=~ri$m recognition and management Cleve (lin J 11 62001

External Eye Manifestations of ClMmkal and Biotogkal Warfare

ential diagnosis of cutaneous anthra-x also Includes spider bite ecthyma gangrenosum u1ceroglandular tularemia plague scrub typhus rickettsial spotted fever rat bite fever staphylococcal or streptococcal ceUuJitis and herpes simplex viTUS24bullU

Gastrointestinal anthrax Gastrointestinal anthrax liIoely results from the in gestion of latge numbers of vegetative bacilli from poorly cooked Infected meat2S The oral-pharyngeal form of disease results in an oral or esophageal ulcer which leads to the develOpshyment of regional lymphadenopathy edema and sepsis Disease In the terminal Ileum or cecum presents yentith nausea vomiting and malaise and progresses rapidly to bloody d iarrhea acute abdomen and sepsisu

InhalaUonal anthrax InhaJation anthrax or wool-sorters disease genera lly presents as a two-stage illness A prodromal stage begins With nonspecific symptoms of fever cough malaise headshyache and dyspnea l ~ Some patients have transient improveshyment after 2 to 4 days but the fulminant stage often ensues rapidly with respiratory distress diaphoresiS shock and death Inhaled spores germnate In hilar nodes and cause mecUastinal lymphadenopathy and hemorrhage lhis Is detected radiographically by a widened med iastinum and pleural effusions which may be hemorrhagic 27 Metamiddot static infection results in hemorrhagic menJngitti in up to sO of cases leading 10 meningismus delirium and obtundatton 9

DiagnOSiS Anth rax bacilli can be vi~ualized by Wright or Gram stain of peripheral blood or isolated by blood culture_ DlagnosNc testing (or cutaneous disease includes Gram stain and culture of vesicular fluid and tissue biopsy ImmunolOgiC tests indude specihc enzyme-linked immunosocbent assays (ELISAs) to measure antibody titers immunomagnetic shyelectrochemilumlnescence (EeL) assays for antigen detecshytion and polymerase chain reaction (peR) for nucleic add detecrion 14 Spores have a diameter of 2 to 6 mm which is Ideal for entrapment in the lower respiratory tract The time for infection is variable because spores must germinate into badlli aher phagocytOSIS by tissue macrophages The dose of anthrax in an exposure is inversely correlatelt with incubation lime Cases In the accidental release In Sverdlovsk developed 2 to 43 days after exposure Thus il may be hard 10 ITace the onset of an attack maklng response and containment more dlfficult

Treatment Treatment or inhalationa l and gasnointesrinal anthrax should begin with intravenous ciproOoxacin 400 mg every 12 hours (Table 104 2)19 Doxycycline lOOmg every 12 hou rs can be used but has poorer centra l nervous system peuetration One Dr (0 of the following additional antishybiotics should be added until susceptibility testing is performed rifampin vancomycin penicillin ampicillin chloramphenicol imipenem cUndamycin and clarithroshymycin Cu taneous disease can be treated with either oral

1297

THie 1042 CDC recommendations for anlimicrolXitl thtrapy 19Iinn anthrax

PO~lexpowre

CutaneoUl ~ nthru

Inhalational anthrax

OR

PLUS (tor either drug)

middotCiplollooClCn dmt It (fIIJdrrn 001 10 excffii I gldcry

mg by mouth twice a day

Doxycycline 100 mg by mouth twice a day

mg

Doxycycline 100 mg by mOUlh twice a day

mg every 12 hrs

DOxycycline 100 mg intravenously every 12 hli

One or two additional antibiotics (eg rifampin vilncomycin penlcillin ampicillin chloramphenicol imipenem clindamycin clarimomycin)

by mouth every OR Doxycycline 8 yrs and gt45 kg 100 mg by mouth every 12 hn gt8 yli and $45 kg 22 mglkg by mouth every 12 hrs ~8 yli 22 mgkg by mouth every 12 hrs

mgkg by mouth every t2 hrs OR DoKycycline 8 yJ$ and gt45 kg 100 mg by mouth every 12 hrs XI yr~ and ~5 kg 22 mgkg by mOuth fNfry 12 hIS s8 yrs 22 mgkg by mouth every 12 hrs

10-15 mgkg lntravenomfy every 12 hIS

Ooxyltyltline 8 yrs and gt45 kg 100 mg intravenou~ly every 12 hrs 8 yrs and ~5 kg 22 mgkg intraveou~1y every 12 hn s8 yli 22 mgkg intravenously every 12 hrs PLUS (for either dNg) One or two addit ional antibiotiCS

rom~ 19 ~ 1008 1~ 1 Hod~ TP BioIogl(OJotKIchemi(Ol~iJtn t(0gn4ion lNldrnonogtmtnl Cleve Ctin I Med 611(11J IQOI-IOI6 1001

ciprofloxacin or dOlCcycline alone Treatment should be continued for 60 days because of the possibility o( delayed germination of spores2S Direct contact with wound or wound drainage should be avoided when caring for a patient with cutaneous anthrax

Despite aggressive supportive therapy and antibiotics fatality is very high In the 2Oth-century series of 18 patients in the Uni ted States the mortality rate of occupationally acquired inhalational anthrax was 89 but the malority of these cases occurred before the development of critical care units and antibiotics2S After Ihe September 2001 terrorist attacks on the United Stales anthrax spores were sent to various locations via the postal service resultlng In 11 cases of inhalatlon al anthrax with five deaths25

Prevention Since there aTe no data to support personmiddot la-person transshymission of anthrax patient contacts do not need immushynization or prophylactic treatment unless they were exposed 10 the aerosol or surface contamination al the liJne o f attack

A vaccine derived fTOm an attenuated stra in of anthrax is available and studies in rhesus monkejs indicate that it is protective (or inhalational anthrax29 Should an anack occur those exposed must be vaccinated and receive

chemoprophylaxis with either dlofloxaon m dCIIctinlt orally until a l least three doses of vaccine have administeredu The safety of the vaccine was studied ill military personnel and 1 of inocul ations were associated with one or more systemiC events (ie headache blurred vis ion nausea) Interestingly two cases of bullbull Optic neuritis have been reported after anthrax

YIvacctnation One patient resolved without nmn~ the other had bilateral involvement that reqUired immunosuppression to maintain vision Retinal and nerve autoanlibodies were presenl in this patient 0 of unilateral optic neuropathy bilateral anter10r bIlateral posterior scleritis bilateral sensorineural loss and focal segmental giomerulosclerosis has also reported likely due to an Immune-mediated eaction the vaccine l l

Botulism

Borulism is a serious paralytic illness caused by a toxln produced by the bacterium Clostridium be It poses a major bioweapons threat because of its

potency and lethality its ease of production IPDtatloo and misuse and the need for prolonged intensive among affected personsll

298

~~~~Ibo~ruinum is a rod-shaped spore-formioamp obli shyanaerobe commo nly fouod jn soil There are seven of toxin designated A th rough G wh ich are defined

their absence of cross-neutralization (Le anti-A antlshydoes not neutralize toxin types S-G)32 Types A B

E account for greater than 9m of human botulisrn ll A toxJ o is the most potent poison known to humans

times more toxic than sarin nerve gasY Once the toxin is catred via the blood to peripheral synapses It irreversibly binds to the presynapUc

junction where it is internalized and blocks release causing paralysis Interestingly a vlal Botoxreg (Allerga n Irvine CA USA) contains

about 0301 the estimated human le thal inhaJationaJ and 0005 of the estimated lethal ora~ dosel]

fcnns o f narurally OCCUrring botulism exist foodshywound and intestinal The o ldest and most commiddot

form observed on a worldwide basis is foodmiddotbome occurs after ingestion of food that contains premiddot neurotoxin 33 Typical cases result from ingestion

improperly prepared hOme-canned food The m ost ro~~ form of botulism reponed in the United States is in intestinal botulism14 Unlike the foodmiddot borne rype

infant form is a combination of iniection and intoximiddot resulting from ingestion of C botulinum spores germinate within the gastrointestinal tract and

produgt toxin locally Honey consumption is a significant factor and Is not reltommended fot children under age of 1 year35 Wound infection with C botlliinum

can occur under conditions of tissue necrosis and

~~~~~ Spores can germinate in vivo and produce n which leads to the same chnica features as

seen In Cood-bome botulism except for the acute gaonn symptoms l3

CIiic1 manifestations an attack botulinum toxin would likely be used as

inhalal lonal agent or 10 deliberately contaminate food since it does not penetrate lntact skin and is n ot t ransmiddot mitted from person to perso n12 Symptoms generally begin 12 to 72 hours after ingeStion The time of onset after an inhalational exposure is not known but experimentally is Millar to foodmiddotborne exposureY

Botutism classically presents as an acute afebrile symmiddot merrie descending flaccid paralysis that always begins in the bulbar musculature (Box 1042)3ZmiddotlJ Patients have a dear sensorium because the toxin does not penetrate the brain tissue The prominent bulbar palsies (4 Os) include diplopia dysarthria dysphonia and dysphagia If the origin is foodmiddotborne the neurologic signs may be preceded by alxlominal cramps nausea vontiting or diarrheaYgt Sensory changes are not present As the disease progresses weakshyness extends below the neck with loss of deep tendon retlexes constipation and unsteady gait Severe cases lead to respi ratory collapse (rom diaphragm and intercostal muscle involvement and a irway obsrructlon fro m pharyn-

External Eye Manifestations of Chemical and BJoiogical Warfare

Box 1042

Signs and lYptoms of food-bome and wound botulllm

Signs Ventilatory (rlspiratory) problems Extraocular muscle paresis or paralysis (including eyelids) Muscle paresis or paralysis Dry mucous membranes in mouth throat Dilated fixed pupils Ataxia Somnolence Hypotlnsion (including postural) Nystagmus ~crNsed to absectent deep tendon reflexes Fever (more common for wound botulism) 5ensoty deficits (very rare)

Symptoms Visual disturbances (blurred vision diplopla photophobia) Dy~phagia Dry mouth Generalired weakness (tnUally bilateral) Nau~a or vomiting Dizziness or vertigo Abdominal pain cramps discomfort Oiantlea Urinary retention or incontinence Sore throat Constipation ParlISthesias

Adapted from ~ference )3 pampge 28 Table$ 1 and 2 Caya IG Clostridium IgtoMirom and the ophthal~ a ~ of boWIiirn including bIoIogIuI warfom ramifiutions of botulinum toxirI SuN OphhoIrno( 62~)ltI 2001

geal musde paralysis32 Autonomic nervous system lnvolvemiddot ment can lead to cardiovascular lability

Ophthalmic manifestations Visual symptoms of diplopia photophobia and blurred vision are present early (fable 1043)33 Accommodative paresis and mydriaSiS account for the blurred vision and photophObia respectively Blepharoptosis gaze paralysis pupillary dilation and nystagmus are common ophthalmic signs Dry eye and dry mouth trom parasympathetic cholinergic blockade can also be proQlinent

Uncommon neuro-ophthalmic manifestations include complete bilateral inlemal ophthalmop legia)] whIch can indude both permanent18 and transienrl9 tonic pupilS A dilated and poorly reactive pupil wi th loss of accommoshydation are typical findings Lightmiddotnea r dissociation ~ctoral iris COntractions and supersensitivity of the iris sphincter muscle to weak mimics (pilocarpine 01) are also hallshymark findings of a tonic pupil

Diagnosis Early diagnosis of botu lism is made by the history and physical exam The differential diagnosis includes GuHlainmiddot Barre and the Miller-Fisher variant myasthenia gravis Lambert-Eaton syndrqme tick paraliS stroke and various central nervous system disorders 19 1 80tulism differs from other causes of flacCid paralyses in that there is the presence

1299

T 1041 Ophthalmic signs and symptoms of botulism

S9n 1iJ- -6u~ vision PloJojs 0 Diplopia 59

Abnormal pupil re~dion to light 9

Impaired accommodation 9 Nystagmus MydriasiJ 2

poundXtraocvlar muscle dysfunction on eltAm 3

Mopsrd hom rtf~renCpound 33 pOgf 31 Table 8 Coyo jG Clostridium boIulinum and tilfI ophlhtllmoiogiIl a fevtW of bolu~Jm ilduding bigkal worfall ramiflcolon 01 botulinum I~n SIIV Clphlhalmol 4615-34 1001

of symmetry absence of sensory nerve damage and disprOshyportionate involvement of cranial nerves compared to muscles below the neck l 2

Demonstration of toxin by mouse bioassay is diagnostic in samples of serum stool gastric aspirate and suspect food 32 Studies suggest that aerosolized toxin is usually not identifiable in serum or stOol but may be present on nasal mucous membranes and detected by ELISA for up to 24 hours after exposure 27 Fecal wound and gastric sped mens can be cultured anaerobica lly if a food-borne or wound source of C botulinum is suspected An electroshymyogram can show characteristic findings which include normal nerve conduction velocity normal sensory nerve function a pattern of brief sma llmiddotampLitude motor potenshytials and most distinctiveLy an incremental response to repetitive stimulation often seen only at SO HZ40

Treatment Management is primarily supportive with ventilatory assistance essential in advanced cases Ea rly ad ministration with equlne-deTived trivalent (types A B E) antitoxin can minlmile subsequent nerve damage and severity of d isease but Will not reverse existing paralysis which can last from weeks to monthsH Wound-relat ed botulism reqUires debridement and antibiotics for secondary infections In a large outbreak of botulism the need for mechanical ventishylators critical care beds and sldlJed personnel might quickly exceed capacity Research directed at recombinant vaccines and human antibody may eventually minimize the threat of borulinum toxin as a weapon of mass destruction

Smallpox SmatJpox is one of the most dreaded diseases in the history

1300 of humankind It raged in epidemic and endemic forms fOr more than 3000 years killing hundreds of millions of

people In 1966 the World Health Organization established a middotvaccination program with extensive educational and surveillance programs for global eradication Smallpox was successfully eradicated in 1977 with the last case docushymented in Somalia42

Microbiology Variola is a large double-SlJanded DNA virus and member of the genus orthopoxVirus The viruses are complex and the virion is brick-shaped with a diameter of about 200 nmj

Three other members of this genus (monkeypox vaccinia and cowpox) can infect humans but are not high1y contagiousiJ

Epidemiology There are two clini cal forms of smallpox variola major and a much milder form variola minor TypicaL varl ola major epidemics resulted ill mortaLity rates of greater than 30 among unvaconated persons H Smallpox spreads from person to person primarily in droplet form or aerosols expelled from the oropharynx of infected persons Conshytaminated bedding and clothing can also spread the virus via direct contact44 Smallpox would likely be used in aerosol form during a biologica l assault given bolh iU small iruectious dose and sign ificant stabili ty

Clinical manifestations After an incubation period of about 12 days patients febole and often develop severe constitutional symptoms Headache backache vomiting abdominal pa in and malaise afe common The clinical presentation ofsmaUpox is heralded by a diffu se maculopapular rash begtnn lng to 3 days after this prodroma l phase~ Lesions first on the mucous memb ranes of the oropharynx Skin appear mostly o n the head torso and extremities in centrifugal pattern evolving from a flat rash to a papUle vesicle and then a pustule which becomes crusted scabbed This leads to permanent scarring usually extensive on the face Classically the lesions are at stage of deveLopment at a given point and can affelt1 palms and sales Chickenpox (varicella) the disease frequently confused with smallpox differs in that are In middotarious stages of development at a given Varicella lesions are more superficial rarely fou nd on palms and soles and the distribution is centripetal the trunk affected more than the (ace and extremitiesw

Nearly one-third of patients with smaUpox will usually during the second week of illness This most

results from the toxemia and C~d~io~vla~s~CU~~Ia~~i~~~ associated with circulating immune variola antigens t3 PneumOn ia encephalitis o rchitis sepsis and overwhelming hemorrhage into skin and mucous membranes can complicate infection 41 Variola mino r the less severe form of pox results in milder symplOms 1th only a sparse and less than 1 mortaUty 13

Patients are most infectious during the first week iUness however some risk of transmission is all scabs have fallen Off4~ It is thought that Ismallpoxcaru~

I

transmitted until the onset of the rash Z~ so diagnosis the prodromal stage with subsequent quarantine

be essential to limit additional exposure

lp~~~~I~~~ manifestations In led to blindness in 2 to 5 of students in blind

of developing countries in Africa 48-30 Typically a conjunctivitis appears around the fifth day of illness subconju nctival hemo rrhage in some cases Actual

whIch resemble phlyctenules may form on the or tarsal conjunctiva and even involve the limbus~l lesions are very inflamed and painful and can lead I and ulceration of the cornea Less frequently

imerSlitial 01 disciform keratitis evolves (Fig 1042) Lid and punctal stenosis may result when pustules

the cUla and punda respectively Ankyloblepharon also been reported due to severe eyelid adhesions

the upper and lower canthiY Secondary infectious can ocCur late and lead to significant morbid ity

~me antibiotic prophylaxis is warranted Dense comeaJ can leave patient s phthiSical and blind

beatorv diagnosis of smallpox can be confi rmed with microscopy of vesicular o r pustular nuld or

~~sect~Guamieri bodies can be visualized under lightVirus culture of skin lesions oropharynx

and urine is definitive peR techniques ca n ~ between strains and offer a more rapid

rne and vaccination is no specific systemic or ocular treatment for smallshy

although cidofovir has In vitro and In vivo activity

External Eye Mlfestatlons of Chemical and Blologkal Warfare

against Poxviridae P 1n 1796 Edwardjenner demonstrated that an Lniection caused by cowpox protected against smallshypox wh ich led to the worldwide practice of vacdnatiooS3

Curremly smallpox vaccine is prepared from live vaccinia virus using cell culture techniquesl4

The interval between an aerosol release of variola and diagnosis of the first cases is as much as 2 weeksH Fortushynately the virus is Inactivated after 2 days eliminating further exposure Individuals in whom infection is suspected should be vaccinat ed within 4 days o f exposure and placed under surveillance Vaccination programs ended in 1972 in the United States and it Is presumed that few people who wefe vaccinated have lasting protective levels of immunity

Complications of vaccination Vaccination is not without risk Life-threatening encephalshyitis occurs at a rate of 1 case per 300 OOOH ProgreSSive vaccinia or vaccinia gangrenosum results from neaogtls of the skin at the vacd nation site with advanced cases involving underlying bone and viscera Patient s wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites (Fig 1043) In some vaccine recipients blood-bome dissemimiddot nation of virus leads to a self-limiting generalized vactinial rash TransmISSion of vaccinia froro the site of vaccination to close contacts or autoinoculatjon to sites such as face mouth eyelid aod genitalia can take place Vaccinia immune globulin is used to treat these complications with variable success

Vaccinia ophthalmic manifestations Inadvertent autoinoculation of vaccinia from the deltoid site accounts for the ophthalmic co mpUcations of vaccishynation The majority of patients have vaccinia of the eyelidgt or conjunctiva but a smaller percenlage have comeal involvement ss Typically patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and

Ag 1042 ilfiol (smallpox) This patient demonstmtes a centrlll Fig 1043 Eczema vaCtinllll)nl Vaccinial skin leJioru extending (Ver the not scar from a sm~lIpox or variola infection area currently afflicted with eczema (Courtl$) of Rkhard K Forster MD)

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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2 Gfoiraquolf E 8ioogual and fI)~ill _pam rodily ~ York NY 1986 Oxford Unlvenlry Preraquo

3 HrTU S Japa~ blologllta1 warlue re~arch on humans a CiCie $rultI) of mlcroblology and ethio tirln N Y Acad So 66621-5Z 1992

4 Slnu NA n~ diplomacy of biological d1samamal New York NY 1983 Plenum Pteraquo

5 Meseuon M Guillemln J HughmiddotJones M et i l The Sverdlovs~ anthux OUibreu of 197J Sdmct 266 I lQZ-l 208 1994

6 ZllJns~ RA lqmiddot~ biological up0n5 thf past as fulUl1 JAt4 278(S)laquo I8-424 1997

7 WHO Group of ConmltaJl lJ Ht(llh r15pertl 0 rllmlical iUld biologicill wapon Geneva SwlUerland 1970 World HeMth Organization pp72-99

8 McGovern TW Chrlnophcr CW Eitzen EM Culolneou~ mallifesIilTioJ) at biologiCiI mace am t tltlted lhlUt Jgen l$ An-I Dmnmoi 1353 11-3U 1999

9 American Colleg~ of PhysKin~middotAmtIiClUl Soot) 0( Inlemal Medldn~ AC pmiddotASJMmiddot Guide 10 8)Otenorhm ldoen t l-ticotlon 2002

]0 Cenltrs for OiseltlSl Control and Prev~ntlon BIOlogical DI5e~IAgent5 UsC Available at http wwwbICdcgovIAgemagentlhl llp laM updlted 10040Z

I I lttn ten for Oi$eaSl Conn-ol and Prevention Chemical Agent~ Ult aoa Infomudon Avillabl at httpwwwIxcdcgovAgUltfagen UiSKhemasp lAS t updated 1009OZ

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13 Youton 0 Fmter A CUUIlKlUS anthrax leadlng to Ul rneai scarrtng from deatrldal ectropion Sr f Oplllllalmol 73809-8 11 1989

H 8rouswd iJ Biological agenu wapon of warfase and bio~rTOtJsm

)lt) DIltun 6(4)1Z3-1J1 ZOOI 15 Q-Iebl S Ayun U AiagOt G et Ill Palpebral antJuax W OphlJlalmol

11 (2) ]71- 174 ZOO I 16 5oysl HG Kirntli H Rlaquo-ep O f Anth rax as ure ca~ 01 prewptal

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17 A~lan G nmoglu A SUfgJcaJ management 01 Ntaneous anthraX Arm PlIlJI SUrf 415)468-470 1998

la Glovet M Ducam M Nfgn1AD f al jL1te a5pKU 0 1 palpebral antiultu authors lansl)I MtJ Trop 39(1)91_96 197J

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22 Ba~by 0 8(gtIlllelt M Geny B- Human cowpox 1969- 91 a (vif W b ued on S ot ~ 8J I OtmratoI 111(5)598-607 1994

II OConnol GM Thim AA Caul Opound Orulu cowpox rransml1Q hom the domtsti ca t to Ilan 8r I Ophrhalmol 74(4)245-246 1990

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25 Inglesoy lV OJboie T Hendenon OA et il Anlhrlx as a bloIogtca l eapon 2002 upd3ted rKOmmf nWtlonli Of management lAMA 287(1 7)2136-m2 2002

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34 lttn ters for DlseilSf COnno) and Prevention BoruJi~n in hi US 1899-19 Iadboolaquo ot tpJemJoiogisll d id4lm QOO l~borafQry lO-orkt7 AUa Olil GA 1998 CDC

35 C hcrington M Laghmari M Kaonaoyen A el al Clinical sJlK1rum of botulism Musc~ N~ 2 1701-7 10 1998

36 Hughes 1M Blumenthal JR Mergtan MH e al Clinical leatun1 of WS A and B foodmiddotbomf lXItu lls m Ann [ntern Mal 95442-445 )981

17 Ehttn~lch H Gamer CG Wi tt 1N Complete bilateral llltemal ophthalmoplegia as so lt c1lnlcal sign of borulism oonJirmation of diagnmis by single fibre d~om)-ography J Nnuvl2J624-J-HS 1981

38 Fried Dian 01 Fonanu(e VN Sldun AA Tonie pupi ls ~ a r~l of botlJ lislJl Am JOpllalmoll09(Z)236-2)7 1990

39 Monaco S Freddi N Francavi lla pound ~t u Tralslem Ionic pupll~ In botulism type S I N~ro Sd IS696-98 1998

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43 Fenner F Henderson OA M ta et aI SmoJpox Ilm its eradICatorl Gel)~va Switzerland 196-8 Wor ld Hulth Organiza lion p 1460

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76 Klbad K Mupapa K Kuvula K t l al La te ophthalmolagk mmifes~oons in mrviVOB of the I99S poundbola vlrw tpidemic in Ki lcwit [)emornuic Repub lic of the Co~ J In(ta Dis 179 (Stlppl 1)5 13-51-4 1999

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80 Saa ri KM Acute glaucoma In h emorrhagic fevff ith renal s~ndlome (nephropalhia ~ pldemlC3) Am JOphwmol S (4)4~61 1976

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85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

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87 Thbbara kF Al-KaWmi H Orulat bruc eUo$b j t I Ophrhillmal i4(4) 249- lS0 1990

88 Woolth AC NUIJDub r )era liUs anO ocular brocellogtls Aidgt Ophlhalmol l 549(l 1946

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93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

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1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

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IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 4: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

THie 1042 CDC recommendations for anlimicrolXitl thtrapy 19Iinn anthrax

PO~lexpowre

CutaneoUl ~ nthru

Inhalational anthrax

OR

PLUS (tor either drug)

middotCiplollooClCn dmt It (fIIJdrrn 001 10 excffii I gldcry

mg by mouth twice a day

Doxycycline 100 mg by mouth twice a day

mg

Doxycycline 100 mg by mOUlh twice a day

mg every 12 hrs

DOxycycline 100 mg intravenously every 12 hli

One or two additional antibiotics (eg rifampin vilncomycin penlcillin ampicillin chloramphenicol imipenem clindamycin clarimomycin)

by mouth every OR Doxycycline 8 yrs and gt45 kg 100 mg by mouth every 12 hn gt8 yli and $45 kg 22 mglkg by mouth every 12 hrs ~8 yli 22 mgkg by mouth every 12 hrs

mgkg by mouth every t2 hrs OR DoKycycline 8 yJ$ and gt45 kg 100 mg by mouth every 12 hrs XI yr~ and ~5 kg 22 mgkg by mOuth fNfry 12 hIS s8 yrs 22 mgkg by mouth every 12 hrs

10-15 mgkg lntravenomfy every 12 hIS

Ooxyltyltline 8 yrs and gt45 kg 100 mg intravenou~ly every 12 hrs 8 yrs and ~5 kg 22 mgkg intraveou~1y every 12 hn s8 yli 22 mgkg intravenously every 12 hrs PLUS (for either dNg) One or two addit ional antibiotiCS

rom~ 19 ~ 1008 1~ 1 Hod~ TP BioIogl(OJotKIchemi(Ol~iJtn t(0gn4ion lNldrnonogtmtnl Cleve Ctin I Med 611(11J IQOI-IOI6 1001

ciprofloxacin or dOlCcycline alone Treatment should be continued for 60 days because of the possibility o( delayed germination of spores2S Direct contact with wound or wound drainage should be avoided when caring for a patient with cutaneous anthrax

Despite aggressive supportive therapy and antibiotics fatality is very high In the 2Oth-century series of 18 patients in the Uni ted States the mortality rate of occupationally acquired inhalational anthrax was 89 but the malority of these cases occurred before the development of critical care units and antibiotics2S After Ihe September 2001 terrorist attacks on the United Stales anthrax spores were sent to various locations via the postal service resultlng In 11 cases of inhalatlon al anthrax with five deaths25

Prevention Since there aTe no data to support personmiddot la-person transshymission of anthrax patient contacts do not need immushynization or prophylactic treatment unless they were exposed 10 the aerosol or surface contamination al the liJne o f attack

A vaccine derived fTOm an attenuated stra in of anthrax is available and studies in rhesus monkejs indicate that it is protective (or inhalational anthrax29 Should an anack occur those exposed must be vaccinated and receive

chemoprophylaxis with either dlofloxaon m dCIIctinlt orally until a l least three doses of vaccine have administeredu The safety of the vaccine was studied ill military personnel and 1 of inocul ations were associated with one or more systemiC events (ie headache blurred vis ion nausea) Interestingly two cases of bullbull Optic neuritis have been reported after anthrax

YIvacctnation One patient resolved without nmn~ the other had bilateral involvement that reqUired immunosuppression to maintain vision Retinal and nerve autoanlibodies were presenl in this patient 0 of unilateral optic neuropathy bilateral anter10r bIlateral posterior scleritis bilateral sensorineural loss and focal segmental giomerulosclerosis has also reported likely due to an Immune-mediated eaction the vaccine l l

Botulism

Borulism is a serious paralytic illness caused by a toxln produced by the bacterium Clostridium be It poses a major bioweapons threat because of its

potency and lethality its ease of production IPDtatloo and misuse and the need for prolonged intensive among affected personsll

298

~~~~Ibo~ruinum is a rod-shaped spore-formioamp obli shyanaerobe commo nly fouod jn soil There are seven of toxin designated A th rough G wh ich are defined

their absence of cross-neutralization (Le anti-A antlshydoes not neutralize toxin types S-G)32 Types A B

E account for greater than 9m of human botulisrn ll A toxJ o is the most potent poison known to humans

times more toxic than sarin nerve gasY Once the toxin is catred via the blood to peripheral synapses It irreversibly binds to the presynapUc

junction where it is internalized and blocks release causing paralysis Interestingly a vlal Botoxreg (Allerga n Irvine CA USA) contains

about 0301 the estimated human le thal inhaJationaJ and 0005 of the estimated lethal ora~ dosel]

fcnns o f narurally OCCUrring botulism exist foodshywound and intestinal The o ldest and most commiddot

form observed on a worldwide basis is foodmiddotbome occurs after ingestion of food that contains premiddot neurotoxin 33 Typical cases result from ingestion

improperly prepared hOme-canned food The m ost ro~~ form of botulism reponed in the United States is in intestinal botulism14 Unlike the foodmiddot borne rype

infant form is a combination of iniection and intoximiddot resulting from ingestion of C botulinum spores germinate within the gastrointestinal tract and

produgt toxin locally Honey consumption is a significant factor and Is not reltommended fot children under age of 1 year35 Wound infection with C botlliinum

can occur under conditions of tissue necrosis and

~~~~~ Spores can germinate in vivo and produce n which leads to the same chnica features as

seen In Cood-bome botulism except for the acute gaonn symptoms l3

CIiic1 manifestations an attack botulinum toxin would likely be used as

inhalal lonal agent or 10 deliberately contaminate food since it does not penetrate lntact skin and is n ot t ransmiddot mitted from person to perso n12 Symptoms generally begin 12 to 72 hours after ingeStion The time of onset after an inhalational exposure is not known but experimentally is Millar to foodmiddotborne exposureY

Botutism classically presents as an acute afebrile symmiddot merrie descending flaccid paralysis that always begins in the bulbar musculature (Box 1042)3ZmiddotlJ Patients have a dear sensorium because the toxin does not penetrate the brain tissue The prominent bulbar palsies (4 Os) include diplopia dysarthria dysphonia and dysphagia If the origin is foodmiddotborne the neurologic signs may be preceded by alxlominal cramps nausea vontiting or diarrheaYgt Sensory changes are not present As the disease progresses weakshyness extends below the neck with loss of deep tendon retlexes constipation and unsteady gait Severe cases lead to respi ratory collapse (rom diaphragm and intercostal muscle involvement and a irway obsrructlon fro m pharyn-

External Eye Manifestations of Chemical and BJoiogical Warfare

Box 1042

Signs and lYptoms of food-bome and wound botulllm

Signs Ventilatory (rlspiratory) problems Extraocular muscle paresis or paralysis (including eyelids) Muscle paresis or paralysis Dry mucous membranes in mouth throat Dilated fixed pupils Ataxia Somnolence Hypotlnsion (including postural) Nystagmus ~crNsed to absectent deep tendon reflexes Fever (more common for wound botulism) 5ensoty deficits (very rare)

Symptoms Visual disturbances (blurred vision diplopla photophobia) Dy~phagia Dry mouth Generalired weakness (tnUally bilateral) Nau~a or vomiting Dizziness or vertigo Abdominal pain cramps discomfort Oiantlea Urinary retention or incontinence Sore throat Constipation ParlISthesias

Adapted from ~ference )3 pampge 28 Table$ 1 and 2 Caya IG Clostridium IgtoMirom and the ophthal~ a ~ of boWIiirn including bIoIogIuI warfom ramifiutions of botulinum toxirI SuN OphhoIrno( 62~)ltI 2001

geal musde paralysis32 Autonomic nervous system lnvolvemiddot ment can lead to cardiovascular lability

Ophthalmic manifestations Visual symptoms of diplopia photophobia and blurred vision are present early (fable 1043)33 Accommodative paresis and mydriaSiS account for the blurred vision and photophObia respectively Blepharoptosis gaze paralysis pupillary dilation and nystagmus are common ophthalmic signs Dry eye and dry mouth trom parasympathetic cholinergic blockade can also be proQlinent

Uncommon neuro-ophthalmic manifestations include complete bilateral inlemal ophthalmop legia)] whIch can indude both permanent18 and transienrl9 tonic pupilS A dilated and poorly reactive pupil wi th loss of accommoshydation are typical findings Lightmiddotnea r dissociation ~ctoral iris COntractions and supersensitivity of the iris sphincter muscle to weak mimics (pilocarpine 01) are also hallshymark findings of a tonic pupil

Diagnosis Early diagnosis of botu lism is made by the history and physical exam The differential diagnosis includes GuHlainmiddot Barre and the Miller-Fisher variant myasthenia gravis Lambert-Eaton syndrqme tick paraliS stroke and various central nervous system disorders 19 1 80tulism differs from other causes of flacCid paralyses in that there is the presence

1299

T 1041 Ophthalmic signs and symptoms of botulism

S9n 1iJ- -6u~ vision PloJojs 0 Diplopia 59

Abnormal pupil re~dion to light 9

Impaired accommodation 9 Nystagmus MydriasiJ 2

poundXtraocvlar muscle dysfunction on eltAm 3

Mopsrd hom rtf~renCpound 33 pOgf 31 Table 8 Coyo jG Clostridium boIulinum and tilfI ophlhtllmoiogiIl a fevtW of bolu~Jm ilduding bigkal worfall ramiflcolon 01 botulinum I~n SIIV Clphlhalmol 4615-34 1001

of symmetry absence of sensory nerve damage and disprOshyportionate involvement of cranial nerves compared to muscles below the neck l 2

Demonstration of toxin by mouse bioassay is diagnostic in samples of serum stool gastric aspirate and suspect food 32 Studies suggest that aerosolized toxin is usually not identifiable in serum or stOol but may be present on nasal mucous membranes and detected by ELISA for up to 24 hours after exposure 27 Fecal wound and gastric sped mens can be cultured anaerobica lly if a food-borne or wound source of C botulinum is suspected An electroshymyogram can show characteristic findings which include normal nerve conduction velocity normal sensory nerve function a pattern of brief sma llmiddotampLitude motor potenshytials and most distinctiveLy an incremental response to repetitive stimulation often seen only at SO HZ40

Treatment Management is primarily supportive with ventilatory assistance essential in advanced cases Ea rly ad ministration with equlne-deTived trivalent (types A B E) antitoxin can minlmile subsequent nerve damage and severity of d isease but Will not reverse existing paralysis which can last from weeks to monthsH Wound-relat ed botulism reqUires debridement and antibiotics for secondary infections In a large outbreak of botulism the need for mechanical ventishylators critical care beds and sldlJed personnel might quickly exceed capacity Research directed at recombinant vaccines and human antibody may eventually minimize the threat of borulinum toxin as a weapon of mass destruction

Smallpox SmatJpox is one of the most dreaded diseases in the history

1300 of humankind It raged in epidemic and endemic forms fOr more than 3000 years killing hundreds of millions of

people In 1966 the World Health Organization established a middotvaccination program with extensive educational and surveillance programs for global eradication Smallpox was successfully eradicated in 1977 with the last case docushymented in Somalia42

Microbiology Variola is a large double-SlJanded DNA virus and member of the genus orthopoxVirus The viruses are complex and the virion is brick-shaped with a diameter of about 200 nmj

Three other members of this genus (monkeypox vaccinia and cowpox) can infect humans but are not high1y contagiousiJ

Epidemiology There are two clini cal forms of smallpox variola major and a much milder form variola minor TypicaL varl ola major epidemics resulted ill mortaLity rates of greater than 30 among unvaconated persons H Smallpox spreads from person to person primarily in droplet form or aerosols expelled from the oropharynx of infected persons Conshytaminated bedding and clothing can also spread the virus via direct contact44 Smallpox would likely be used in aerosol form during a biologica l assault given bolh iU small iruectious dose and sign ificant stabili ty

Clinical manifestations After an incubation period of about 12 days patients febole and often develop severe constitutional symptoms Headache backache vomiting abdominal pa in and malaise afe common The clinical presentation ofsmaUpox is heralded by a diffu se maculopapular rash begtnn lng to 3 days after this prodroma l phase~ Lesions first on the mucous memb ranes of the oropharynx Skin appear mostly o n the head torso and extremities in centrifugal pattern evolving from a flat rash to a papUle vesicle and then a pustule which becomes crusted scabbed This leads to permanent scarring usually extensive on the face Classically the lesions are at stage of deveLopment at a given point and can affelt1 palms and sales Chickenpox (varicella) the disease frequently confused with smallpox differs in that are In middotarious stages of development at a given Varicella lesions are more superficial rarely fou nd on palms and soles and the distribution is centripetal the trunk affected more than the (ace and extremitiesw

Nearly one-third of patients with smaUpox will usually during the second week of illness This most

results from the toxemia and C~d~io~vla~s~CU~~Ia~~i~~~ associated with circulating immune variola antigens t3 PneumOn ia encephalitis o rchitis sepsis and overwhelming hemorrhage into skin and mucous membranes can complicate infection 41 Variola mino r the less severe form of pox results in milder symplOms 1th only a sparse and less than 1 mortaUty 13

Patients are most infectious during the first week iUness however some risk of transmission is all scabs have fallen Off4~ It is thought that Ismallpoxcaru~

I

transmitted until the onset of the rash Z~ so diagnosis the prodromal stage with subsequent quarantine

be essential to limit additional exposure

lp~~~~I~~~ manifestations In led to blindness in 2 to 5 of students in blind

of developing countries in Africa 48-30 Typically a conjunctivitis appears around the fifth day of illness subconju nctival hemo rrhage in some cases Actual

whIch resemble phlyctenules may form on the or tarsal conjunctiva and even involve the limbus~l lesions are very inflamed and painful and can lead I and ulceration of the cornea Less frequently

imerSlitial 01 disciform keratitis evolves (Fig 1042) Lid and punctal stenosis may result when pustules

the cUla and punda respectively Ankyloblepharon also been reported due to severe eyelid adhesions

the upper and lower canthiY Secondary infectious can ocCur late and lead to significant morbid ity

~me antibiotic prophylaxis is warranted Dense comeaJ can leave patient s phthiSical and blind

beatorv diagnosis of smallpox can be confi rmed with microscopy of vesicular o r pustular nuld or

~~sect~Guamieri bodies can be visualized under lightVirus culture of skin lesions oropharynx

and urine is definitive peR techniques ca n ~ between strains and offer a more rapid

rne and vaccination is no specific systemic or ocular treatment for smallshy

although cidofovir has In vitro and In vivo activity

External Eye Mlfestatlons of Chemical and Blologkal Warfare

against Poxviridae P 1n 1796 Edwardjenner demonstrated that an Lniection caused by cowpox protected against smallshypox wh ich led to the worldwide practice of vacdnatiooS3

Curremly smallpox vaccine is prepared from live vaccinia virus using cell culture techniquesl4

The interval between an aerosol release of variola and diagnosis of the first cases is as much as 2 weeksH Fortushynately the virus is Inactivated after 2 days eliminating further exposure Individuals in whom infection is suspected should be vaccinat ed within 4 days o f exposure and placed under surveillance Vaccination programs ended in 1972 in the United States and it Is presumed that few people who wefe vaccinated have lasting protective levels of immunity

Complications of vaccination Vaccination is not without risk Life-threatening encephalshyitis occurs at a rate of 1 case per 300 OOOH ProgreSSive vaccinia or vaccinia gangrenosum results from neaogtls of the skin at the vacd nation site with advanced cases involving underlying bone and viscera Patient s wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites (Fig 1043) In some vaccine recipients blood-bome dissemimiddot nation of virus leads to a self-limiting generalized vactinial rash TransmISSion of vaccinia froro the site of vaccination to close contacts or autoinoculatjon to sites such as face mouth eyelid aod genitalia can take place Vaccinia immune globulin is used to treat these complications with variable success

Vaccinia ophthalmic manifestations Inadvertent autoinoculation of vaccinia from the deltoid site accounts for the ophthalmic co mpUcations of vaccishynation The majority of patients have vaccinia of the eyelidgt or conjunctiva but a smaller percenlage have comeal involvement ss Typically patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and

Ag 1042 ilfiol (smallpox) This patient demonstmtes a centrlll Fig 1043 Eczema vaCtinllll)nl Vaccinial skin leJioru extending (Ver the not scar from a sm~lIpox or variola infection area currently afflicted with eczema (Courtl$) of Rkhard K Forster MD)

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

I Ou$Iophtr GW Ci~l1k T) P~v1111 JA el Oll 81eloglcotl wariall l hIsIotlcal pmpeGive lAMA 273(S)412-11 7 1991

2 Gfoiraquolf E 8ioogual and fI)~ill _pam rodily ~ York NY 1986 Oxford Unlvenlry Preraquo

3 HrTU S Japa~ blologllta1 warlue re~arch on humans a CiCie $rultI) of mlcroblology and ethio tirln N Y Acad So 66621-5Z 1992

4 Slnu NA n~ diplomacy of biological d1samamal New York NY 1983 Plenum Pteraquo

5 Meseuon M Guillemln J HughmiddotJones M et i l The Sverdlovs~ anthux OUibreu of 197J Sdmct 266 I lQZ-l 208 1994

6 ZllJns~ RA lqmiddot~ biological up0n5 thf past as fulUl1 JAt4 278(S)laquo I8-424 1997

7 WHO Group of ConmltaJl lJ Ht(llh r15pertl 0 rllmlical iUld biologicill wapon Geneva SwlUerland 1970 World HeMth Organization pp72-99

8 McGovern TW Chrlnophcr CW Eitzen EM Culolneou~ mallifesIilTioJ) at biologiCiI mace am t tltlted lhlUt Jgen l$ An-I Dmnmoi 1353 11-3U 1999

9 American Colleg~ of PhysKin~middotAmtIiClUl Soot) 0( Inlemal Medldn~ AC pmiddotASJMmiddot Guide 10 8)Otenorhm ldoen t l-ticotlon 2002

]0 Cenltrs for OiseltlSl Control and Prev~ntlon BIOlogical DI5e~IAgent5 UsC Available at http wwwbICdcgovIAgemagentlhl llp laM updlted 10040Z

I I lttn ten for Oi$eaSl Conn-ol and Prevention Chemical Agent~ Ult aoa Infomudon Avillabl at httpwwwIxcdcgovAgUltfagen UiSKhemasp lAS t updated 1009OZ

12 K10t SA An thrax In GOlbach 5 Banlom J Bbcklow N editon In(WIow diJ~ltlJ(S PhilMelptUa PA 1992 WB ~undm pp 1291- I29J

13 Youton 0 Fmter A CUUIlKlUS anthrax leadlng to Ul rneai scarrtng from deatrldal ectropion Sr f Oplllllalmol 73809-8 11 1989

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25 Inglesoy lV OJboie T Hendenon OA et il Anlhrlx as a bloIogtca l eapon 2002 upd3ted rKOmmf nWtlonli Of management lAMA 287(1 7)2136-m2 2002

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34 lttn ters for DlseilSf COnno) and Prevention BoruJi~n in hi US 1899-19 Iadboolaquo ot tpJemJoiogisll d id4lm QOO l~borafQry lO-orkt7 AUa Olil GA 1998 CDC

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Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

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dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

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1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

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102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

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109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

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Page 5: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

~~~~Ibo~ruinum is a rod-shaped spore-formioamp obli shyanaerobe commo nly fouod jn soil There are seven of toxin designated A th rough G wh ich are defined

their absence of cross-neutralization (Le anti-A antlshydoes not neutralize toxin types S-G)32 Types A B

E account for greater than 9m of human botulisrn ll A toxJ o is the most potent poison known to humans

times more toxic than sarin nerve gasY Once the toxin is catred via the blood to peripheral synapses It irreversibly binds to the presynapUc

junction where it is internalized and blocks release causing paralysis Interestingly a vlal Botoxreg (Allerga n Irvine CA USA) contains

about 0301 the estimated human le thal inhaJationaJ and 0005 of the estimated lethal ora~ dosel]

fcnns o f narurally OCCUrring botulism exist foodshywound and intestinal The o ldest and most commiddot

form observed on a worldwide basis is foodmiddotbome occurs after ingestion of food that contains premiddot neurotoxin 33 Typical cases result from ingestion

improperly prepared hOme-canned food The m ost ro~~ form of botulism reponed in the United States is in intestinal botulism14 Unlike the foodmiddot borne rype

infant form is a combination of iniection and intoximiddot resulting from ingestion of C botulinum spores germinate within the gastrointestinal tract and

produgt toxin locally Honey consumption is a significant factor and Is not reltommended fot children under age of 1 year35 Wound infection with C botlliinum

can occur under conditions of tissue necrosis and

~~~~~ Spores can germinate in vivo and produce n which leads to the same chnica features as

seen In Cood-bome botulism except for the acute gaonn symptoms l3

CIiic1 manifestations an attack botulinum toxin would likely be used as

inhalal lonal agent or 10 deliberately contaminate food since it does not penetrate lntact skin and is n ot t ransmiddot mitted from person to perso n12 Symptoms generally begin 12 to 72 hours after ingeStion The time of onset after an inhalational exposure is not known but experimentally is Millar to foodmiddotborne exposureY

Botutism classically presents as an acute afebrile symmiddot merrie descending flaccid paralysis that always begins in the bulbar musculature (Box 1042)3ZmiddotlJ Patients have a dear sensorium because the toxin does not penetrate the brain tissue The prominent bulbar palsies (4 Os) include diplopia dysarthria dysphonia and dysphagia If the origin is foodmiddotborne the neurologic signs may be preceded by alxlominal cramps nausea vontiting or diarrheaYgt Sensory changes are not present As the disease progresses weakshyness extends below the neck with loss of deep tendon retlexes constipation and unsteady gait Severe cases lead to respi ratory collapse (rom diaphragm and intercostal muscle involvement and a irway obsrructlon fro m pharyn-

External Eye Manifestations of Chemical and BJoiogical Warfare

Box 1042

Signs and lYptoms of food-bome and wound botulllm

Signs Ventilatory (rlspiratory) problems Extraocular muscle paresis or paralysis (including eyelids) Muscle paresis or paralysis Dry mucous membranes in mouth throat Dilated fixed pupils Ataxia Somnolence Hypotlnsion (including postural) Nystagmus ~crNsed to absectent deep tendon reflexes Fever (more common for wound botulism) 5ensoty deficits (very rare)

Symptoms Visual disturbances (blurred vision diplopla photophobia) Dy~phagia Dry mouth Generalired weakness (tnUally bilateral) Nau~a or vomiting Dizziness or vertigo Abdominal pain cramps discomfort Oiantlea Urinary retention or incontinence Sore throat Constipation ParlISthesias

Adapted from ~ference )3 pampge 28 Table$ 1 and 2 Caya IG Clostridium IgtoMirom and the ophthal~ a ~ of boWIiirn including bIoIogIuI warfom ramifiutions of botulinum toxirI SuN OphhoIrno( 62~)ltI 2001

geal musde paralysis32 Autonomic nervous system lnvolvemiddot ment can lead to cardiovascular lability

Ophthalmic manifestations Visual symptoms of diplopia photophobia and blurred vision are present early (fable 1043)33 Accommodative paresis and mydriaSiS account for the blurred vision and photophObia respectively Blepharoptosis gaze paralysis pupillary dilation and nystagmus are common ophthalmic signs Dry eye and dry mouth trom parasympathetic cholinergic blockade can also be proQlinent

Uncommon neuro-ophthalmic manifestations include complete bilateral inlemal ophthalmop legia)] whIch can indude both permanent18 and transienrl9 tonic pupilS A dilated and poorly reactive pupil wi th loss of accommoshydation are typical findings Lightmiddotnea r dissociation ~ctoral iris COntractions and supersensitivity of the iris sphincter muscle to weak mimics (pilocarpine 01) are also hallshymark findings of a tonic pupil

Diagnosis Early diagnosis of botu lism is made by the history and physical exam The differential diagnosis includes GuHlainmiddot Barre and the Miller-Fisher variant myasthenia gravis Lambert-Eaton syndrqme tick paraliS stroke and various central nervous system disorders 19 1 80tulism differs from other causes of flacCid paralyses in that there is the presence

1299

T 1041 Ophthalmic signs and symptoms of botulism

S9n 1iJ- -6u~ vision PloJojs 0 Diplopia 59

Abnormal pupil re~dion to light 9

Impaired accommodation 9 Nystagmus MydriasiJ 2

poundXtraocvlar muscle dysfunction on eltAm 3

Mopsrd hom rtf~renCpound 33 pOgf 31 Table 8 Coyo jG Clostridium boIulinum and tilfI ophlhtllmoiogiIl a fevtW of bolu~Jm ilduding bigkal worfall ramiflcolon 01 botulinum I~n SIIV Clphlhalmol 4615-34 1001

of symmetry absence of sensory nerve damage and disprOshyportionate involvement of cranial nerves compared to muscles below the neck l 2

Demonstration of toxin by mouse bioassay is diagnostic in samples of serum stool gastric aspirate and suspect food 32 Studies suggest that aerosolized toxin is usually not identifiable in serum or stOol but may be present on nasal mucous membranes and detected by ELISA for up to 24 hours after exposure 27 Fecal wound and gastric sped mens can be cultured anaerobica lly if a food-borne or wound source of C botulinum is suspected An electroshymyogram can show characteristic findings which include normal nerve conduction velocity normal sensory nerve function a pattern of brief sma llmiddotampLitude motor potenshytials and most distinctiveLy an incremental response to repetitive stimulation often seen only at SO HZ40

Treatment Management is primarily supportive with ventilatory assistance essential in advanced cases Ea rly ad ministration with equlne-deTived trivalent (types A B E) antitoxin can minlmile subsequent nerve damage and severity of d isease but Will not reverse existing paralysis which can last from weeks to monthsH Wound-relat ed botulism reqUires debridement and antibiotics for secondary infections In a large outbreak of botulism the need for mechanical ventishylators critical care beds and sldlJed personnel might quickly exceed capacity Research directed at recombinant vaccines and human antibody may eventually minimize the threat of borulinum toxin as a weapon of mass destruction

Smallpox SmatJpox is one of the most dreaded diseases in the history

1300 of humankind It raged in epidemic and endemic forms fOr more than 3000 years killing hundreds of millions of

people In 1966 the World Health Organization established a middotvaccination program with extensive educational and surveillance programs for global eradication Smallpox was successfully eradicated in 1977 with the last case docushymented in Somalia42

Microbiology Variola is a large double-SlJanded DNA virus and member of the genus orthopoxVirus The viruses are complex and the virion is brick-shaped with a diameter of about 200 nmj

Three other members of this genus (monkeypox vaccinia and cowpox) can infect humans but are not high1y contagiousiJ

Epidemiology There are two clini cal forms of smallpox variola major and a much milder form variola minor TypicaL varl ola major epidemics resulted ill mortaLity rates of greater than 30 among unvaconated persons H Smallpox spreads from person to person primarily in droplet form or aerosols expelled from the oropharynx of infected persons Conshytaminated bedding and clothing can also spread the virus via direct contact44 Smallpox would likely be used in aerosol form during a biologica l assault given bolh iU small iruectious dose and sign ificant stabili ty

Clinical manifestations After an incubation period of about 12 days patients febole and often develop severe constitutional symptoms Headache backache vomiting abdominal pa in and malaise afe common The clinical presentation ofsmaUpox is heralded by a diffu se maculopapular rash begtnn lng to 3 days after this prodroma l phase~ Lesions first on the mucous memb ranes of the oropharynx Skin appear mostly o n the head torso and extremities in centrifugal pattern evolving from a flat rash to a papUle vesicle and then a pustule which becomes crusted scabbed This leads to permanent scarring usually extensive on the face Classically the lesions are at stage of deveLopment at a given point and can affelt1 palms and sales Chickenpox (varicella) the disease frequently confused with smallpox differs in that are In middotarious stages of development at a given Varicella lesions are more superficial rarely fou nd on palms and soles and the distribution is centripetal the trunk affected more than the (ace and extremitiesw

Nearly one-third of patients with smaUpox will usually during the second week of illness This most

results from the toxemia and C~d~io~vla~s~CU~~Ia~~i~~~ associated with circulating immune variola antigens t3 PneumOn ia encephalitis o rchitis sepsis and overwhelming hemorrhage into skin and mucous membranes can complicate infection 41 Variola mino r the less severe form of pox results in milder symplOms 1th only a sparse and less than 1 mortaUty 13

Patients are most infectious during the first week iUness however some risk of transmission is all scabs have fallen Off4~ It is thought that Ismallpoxcaru~

I

transmitted until the onset of the rash Z~ so diagnosis the prodromal stage with subsequent quarantine

be essential to limit additional exposure

lp~~~~I~~~ manifestations In led to blindness in 2 to 5 of students in blind

of developing countries in Africa 48-30 Typically a conjunctivitis appears around the fifth day of illness subconju nctival hemo rrhage in some cases Actual

whIch resemble phlyctenules may form on the or tarsal conjunctiva and even involve the limbus~l lesions are very inflamed and painful and can lead I and ulceration of the cornea Less frequently

imerSlitial 01 disciform keratitis evolves (Fig 1042) Lid and punctal stenosis may result when pustules

the cUla and punda respectively Ankyloblepharon also been reported due to severe eyelid adhesions

the upper and lower canthiY Secondary infectious can ocCur late and lead to significant morbid ity

~me antibiotic prophylaxis is warranted Dense comeaJ can leave patient s phthiSical and blind

beatorv diagnosis of smallpox can be confi rmed with microscopy of vesicular o r pustular nuld or

~~sect~Guamieri bodies can be visualized under lightVirus culture of skin lesions oropharynx

and urine is definitive peR techniques ca n ~ between strains and offer a more rapid

rne and vaccination is no specific systemic or ocular treatment for smallshy

although cidofovir has In vitro and In vivo activity

External Eye Mlfestatlons of Chemical and Blologkal Warfare

against Poxviridae P 1n 1796 Edwardjenner demonstrated that an Lniection caused by cowpox protected against smallshypox wh ich led to the worldwide practice of vacdnatiooS3

Curremly smallpox vaccine is prepared from live vaccinia virus using cell culture techniquesl4

The interval between an aerosol release of variola and diagnosis of the first cases is as much as 2 weeksH Fortushynately the virus is Inactivated after 2 days eliminating further exposure Individuals in whom infection is suspected should be vaccinat ed within 4 days o f exposure and placed under surveillance Vaccination programs ended in 1972 in the United States and it Is presumed that few people who wefe vaccinated have lasting protective levels of immunity

Complications of vaccination Vaccination is not without risk Life-threatening encephalshyitis occurs at a rate of 1 case per 300 OOOH ProgreSSive vaccinia or vaccinia gangrenosum results from neaogtls of the skin at the vacd nation site with advanced cases involving underlying bone and viscera Patient s wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites (Fig 1043) In some vaccine recipients blood-bome dissemimiddot nation of virus leads to a self-limiting generalized vactinial rash TransmISSion of vaccinia froro the site of vaccination to close contacts or autoinoculatjon to sites such as face mouth eyelid aod genitalia can take place Vaccinia immune globulin is used to treat these complications with variable success

Vaccinia ophthalmic manifestations Inadvertent autoinoculation of vaccinia from the deltoid site accounts for the ophthalmic co mpUcations of vaccishynation The majority of patients have vaccinia of the eyelidgt or conjunctiva but a smaller percenlage have comeal involvement ss Typically patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and

Ag 1042 ilfiol (smallpox) This patient demonstmtes a centrlll Fig 1043 Eczema vaCtinllll)nl Vaccinial skin leJioru extending (Ver the not scar from a sm~lIpox or variola infection area currently afflicted with eczema (Courtl$) of Rkhard K Forster MD)

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

I Ou$Iophtr GW Ci~l1k T) P~v1111 JA el Oll 81eloglcotl wariall l hIsIotlcal pmpeGive lAMA 273(S)412-11 7 1991

2 Gfoiraquolf E 8ioogual and fI)~ill _pam rodily ~ York NY 1986 Oxford Unlvenlry Preraquo

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25 Inglesoy lV OJboie T Hendenon OA et il Anlhrlx as a bloIogtca l eapon 2002 upd3ted rKOmmf nWtlonli Of management lAMA 287(1 7)2136-m2 2002

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34 lttn ters for DlseilSf COnno) and Prevention BoruJi~n in hi US 1899-19 Iadboolaquo ot tpJemJoiogisll d id4lm QOO l~borafQry lO-orkt7 AUa Olil GA 1998 CDC

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76 Klbad K Mupapa K Kuvula K t l al La te ophthalmolagk mmifes~oons in mrviVOB of the I99S poundbola vlrw tpidemic in Ki lcwit [)emornuic Repub lic of the Co~ J In(ta Dis 179 (Stlppl 1)5 13-51-4 1999

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80 Saa ri KM Acute glaucoma In h emorrhagic fevff ith renal s~ndlome (nephropalhia ~ pldemlC3) Am JOphwmol S (4)4~61 1976

8L Saari )(M iuolo S Oph thalroologlcal W lngs In nephropathia epidernia ln I3pl4nd A Cla Ophlhalmo6Z235-243 198lt1

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8l Llaquo tY Ch o SO Choi GB et ill lsoblelt abd ucens n erve pa~y IS a complia tion o f haemon hagic fever Wi lh renll syndrome Ntphrol DI TIansprmI1 321 13-21141 998 YOle SL Forster DJ Rao NA Systellll c viral Infections and their retinal ltld OlOloidal manlJestalions Surv OphlhQ lmo 37(S)313-352 1993

85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

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93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

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102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

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l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

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117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

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Page 6: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

T 1041 Ophthalmic signs and symptoms of botulism

S9n 1iJ- -6u~ vision PloJojs 0 Diplopia 59

Abnormal pupil re~dion to light 9

Impaired accommodation 9 Nystagmus MydriasiJ 2

poundXtraocvlar muscle dysfunction on eltAm 3

Mopsrd hom rtf~renCpound 33 pOgf 31 Table 8 Coyo jG Clostridium boIulinum and tilfI ophlhtllmoiogiIl a fevtW of bolu~Jm ilduding bigkal worfall ramiflcolon 01 botulinum I~n SIIV Clphlhalmol 4615-34 1001

of symmetry absence of sensory nerve damage and disprOshyportionate involvement of cranial nerves compared to muscles below the neck l 2

Demonstration of toxin by mouse bioassay is diagnostic in samples of serum stool gastric aspirate and suspect food 32 Studies suggest that aerosolized toxin is usually not identifiable in serum or stOol but may be present on nasal mucous membranes and detected by ELISA for up to 24 hours after exposure 27 Fecal wound and gastric sped mens can be cultured anaerobica lly if a food-borne or wound source of C botulinum is suspected An electroshymyogram can show characteristic findings which include normal nerve conduction velocity normal sensory nerve function a pattern of brief sma llmiddotampLitude motor potenshytials and most distinctiveLy an incremental response to repetitive stimulation often seen only at SO HZ40

Treatment Management is primarily supportive with ventilatory assistance essential in advanced cases Ea rly ad ministration with equlne-deTived trivalent (types A B E) antitoxin can minlmile subsequent nerve damage and severity of d isease but Will not reverse existing paralysis which can last from weeks to monthsH Wound-relat ed botulism reqUires debridement and antibiotics for secondary infections In a large outbreak of botulism the need for mechanical ventishylators critical care beds and sldlJed personnel might quickly exceed capacity Research directed at recombinant vaccines and human antibody may eventually minimize the threat of borulinum toxin as a weapon of mass destruction

Smallpox SmatJpox is one of the most dreaded diseases in the history

1300 of humankind It raged in epidemic and endemic forms fOr more than 3000 years killing hundreds of millions of

people In 1966 the World Health Organization established a middotvaccination program with extensive educational and surveillance programs for global eradication Smallpox was successfully eradicated in 1977 with the last case docushymented in Somalia42

Microbiology Variola is a large double-SlJanded DNA virus and member of the genus orthopoxVirus The viruses are complex and the virion is brick-shaped with a diameter of about 200 nmj

Three other members of this genus (monkeypox vaccinia and cowpox) can infect humans but are not high1y contagiousiJ

Epidemiology There are two clini cal forms of smallpox variola major and a much milder form variola minor TypicaL varl ola major epidemics resulted ill mortaLity rates of greater than 30 among unvaconated persons H Smallpox spreads from person to person primarily in droplet form or aerosols expelled from the oropharynx of infected persons Conshytaminated bedding and clothing can also spread the virus via direct contact44 Smallpox would likely be used in aerosol form during a biologica l assault given bolh iU small iruectious dose and sign ificant stabili ty

Clinical manifestations After an incubation period of about 12 days patients febole and often develop severe constitutional symptoms Headache backache vomiting abdominal pa in and malaise afe common The clinical presentation ofsmaUpox is heralded by a diffu se maculopapular rash begtnn lng to 3 days after this prodroma l phase~ Lesions first on the mucous memb ranes of the oropharynx Skin appear mostly o n the head torso and extremities in centrifugal pattern evolving from a flat rash to a papUle vesicle and then a pustule which becomes crusted scabbed This leads to permanent scarring usually extensive on the face Classically the lesions are at stage of deveLopment at a given point and can affelt1 palms and sales Chickenpox (varicella) the disease frequently confused with smallpox differs in that are In middotarious stages of development at a given Varicella lesions are more superficial rarely fou nd on palms and soles and the distribution is centripetal the trunk affected more than the (ace and extremitiesw

Nearly one-third of patients with smaUpox will usually during the second week of illness This most

results from the toxemia and C~d~io~vla~s~CU~~Ia~~i~~~ associated with circulating immune variola antigens t3 PneumOn ia encephalitis o rchitis sepsis and overwhelming hemorrhage into skin and mucous membranes can complicate infection 41 Variola mino r the less severe form of pox results in milder symplOms 1th only a sparse and less than 1 mortaUty 13

Patients are most infectious during the first week iUness however some risk of transmission is all scabs have fallen Off4~ It is thought that Ismallpoxcaru~

I

transmitted until the onset of the rash Z~ so diagnosis the prodromal stage with subsequent quarantine

be essential to limit additional exposure

lp~~~~I~~~ manifestations In led to blindness in 2 to 5 of students in blind

of developing countries in Africa 48-30 Typically a conjunctivitis appears around the fifth day of illness subconju nctival hemo rrhage in some cases Actual

whIch resemble phlyctenules may form on the or tarsal conjunctiva and even involve the limbus~l lesions are very inflamed and painful and can lead I and ulceration of the cornea Less frequently

imerSlitial 01 disciform keratitis evolves (Fig 1042) Lid and punctal stenosis may result when pustules

the cUla and punda respectively Ankyloblepharon also been reported due to severe eyelid adhesions

the upper and lower canthiY Secondary infectious can ocCur late and lead to significant morbid ity

~me antibiotic prophylaxis is warranted Dense comeaJ can leave patient s phthiSical and blind

beatorv diagnosis of smallpox can be confi rmed with microscopy of vesicular o r pustular nuld or

~~sect~Guamieri bodies can be visualized under lightVirus culture of skin lesions oropharynx

and urine is definitive peR techniques ca n ~ between strains and offer a more rapid

rne and vaccination is no specific systemic or ocular treatment for smallshy

although cidofovir has In vitro and In vivo activity

External Eye Mlfestatlons of Chemical and Blologkal Warfare

against Poxviridae P 1n 1796 Edwardjenner demonstrated that an Lniection caused by cowpox protected against smallshypox wh ich led to the worldwide practice of vacdnatiooS3

Curremly smallpox vaccine is prepared from live vaccinia virus using cell culture techniquesl4

The interval between an aerosol release of variola and diagnosis of the first cases is as much as 2 weeksH Fortushynately the virus is Inactivated after 2 days eliminating further exposure Individuals in whom infection is suspected should be vaccinat ed within 4 days o f exposure and placed under surveillance Vaccination programs ended in 1972 in the United States and it Is presumed that few people who wefe vaccinated have lasting protective levels of immunity

Complications of vaccination Vaccination is not without risk Life-threatening encephalshyitis occurs at a rate of 1 case per 300 OOOH ProgreSSive vaccinia or vaccinia gangrenosum results from neaogtls of the skin at the vacd nation site with advanced cases involving underlying bone and viscera Patient s wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites (Fig 1043) In some vaccine recipients blood-bome dissemimiddot nation of virus leads to a self-limiting generalized vactinial rash TransmISSion of vaccinia froro the site of vaccination to close contacts or autoinoculatjon to sites such as face mouth eyelid aod genitalia can take place Vaccinia immune globulin is used to treat these complications with variable success

Vaccinia ophthalmic manifestations Inadvertent autoinoculation of vaccinia from the deltoid site accounts for the ophthalmic co mpUcations of vaccishynation The majority of patients have vaccinia of the eyelidgt or conjunctiva but a smaller percenlage have comeal involvement ss Typically patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and

Ag 1042 ilfiol (smallpox) This patient demonstmtes a centrlll Fig 1043 Eczema vaCtinllll)nl Vaccinial skin leJioru extending (Ver the not scar from a sm~lIpox or variola infection area currently afflicted with eczema (Courtl$) of Rkhard K Forster MD)

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

I Ou$Iophtr GW Ci~l1k T) P~v1111 JA el Oll 81eloglcotl wariall l hIsIotlcal pmpeGive lAMA 273(S)412-11 7 1991

2 Gfoiraquolf E 8ioogual and fI)~ill _pam rodily ~ York NY 1986 Oxford Unlvenlry Preraquo

3 HrTU S Japa~ blologllta1 warlue re~arch on humans a CiCie $rultI) of mlcroblology and ethio tirln N Y Acad So 66621-5Z 1992

4 Slnu NA n~ diplomacy of biological d1samamal New York NY 1983 Plenum Pteraquo

5 Meseuon M Guillemln J HughmiddotJones M et i l The Sverdlovs~ anthux OUibreu of 197J Sdmct 266 I lQZ-l 208 1994

6 ZllJns~ RA lqmiddot~ biological up0n5 thf past as fulUl1 JAt4 278(S)laquo I8-424 1997

7 WHO Group of ConmltaJl lJ Ht(llh r15pertl 0 rllmlical iUld biologicill wapon Geneva SwlUerland 1970 World HeMth Organization pp72-99

8 McGovern TW Chrlnophcr CW Eitzen EM Culolneou~ mallifesIilTioJ) at biologiCiI mace am t tltlted lhlUt Jgen l$ An-I Dmnmoi 1353 11-3U 1999

9 American Colleg~ of PhysKin~middotAmtIiClUl Soot) 0( Inlemal Medldn~ AC pmiddotASJMmiddot Guide 10 8)Otenorhm ldoen t l-ticotlon 2002

]0 Cenltrs for OiseltlSl Control and Prev~ntlon BIOlogical DI5e~IAgent5 UsC Available at http wwwbICdcgovIAgemagentlhl llp laM updlted 10040Z

I I lttn ten for Oi$eaSl Conn-ol and Prevention Chemical Agent~ Ult aoa Infomudon Avillabl at httpwwwIxcdcgovAgUltfagen UiSKhemasp lAS t updated 1009OZ

12 K10t SA An thrax In GOlbach 5 Banlom J Bbcklow N editon In(WIow diJ~ltlJ(S PhilMelptUa PA 1992 WB ~undm pp 1291- I29J

13 Youton 0 Fmter A CUUIlKlUS anthrax leadlng to Ul rneai scarrtng from deatrldal ectropion Sr f Oplllllalmol 73809-8 11 1989

H 8rouswd iJ Biological agenu wapon of warfase and bio~rTOtJsm

)lt) DIltun 6(4)1Z3-1J1 ZOOI 15 Q-Iebl S Ayun U AiagOt G et Ill Palpebral antJuax W OphlJlalmol

11 (2) ]71- 174 ZOO I 16 5oysl HG Kirntli H Rlaquo-ep O f Anth rax as ure ca~ 01 prewptal

cclIulJtJs and cicatricial ectropion Ada OplhalmtJl SeaId 79(2) 208-209 ZOOI

17 A~lan G nmoglu A SUfgJcaJ management 01 Ntaneous anthraX Arm PlIlJI SUrf 415)468-470 1998

la Glovet M Ducam M Nfgn1AD f al jL1te a5pKU 0 1 palpebral antiultu authors lansl)I MtJ Trop 39(1)91_96 197J

19 NutUer T1 BkIJoglcal and chemic1 teu o n $m reltllgrlilion and m~33f1Uem ClITe e liul M~d 68( 12)1001- 10162001

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25 Inglesoy lV OJboie T Hendenon OA et il Anlhrlx as a bloIogtca l eapon 2002 upd3ted rKOmmf nWtlonli Of management lAMA 287(1 7)2136-m2 2002

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4 Hendenon OA logle1by TV 8lrtlfit JG t t al SmallpolltU a blologUI weapon medical and public oealth mOUlagoment JAMA 2-8 1(22)2 127- 2 117 1999

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62 Hyndiul ItA Okumolo M DamiAno RAt l al Trt atmem of vacrinial kem llraquo wilh viduabtne An-h OpIJUoalmltJl9( 136J--IlM 1976

61 DtnnIIDT In gltSby lV Hendmon VA el al 1ul ar~a as it biological weapon mWIcal m d public health management lAMA 285(2 1)2763--27732001

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6 D n1n rand S Ringcrtt 0 leltedlefg 6 Arboml IUl3 remiI in 5 Iln 5(anJ nKf Ds 3( 1)7-1 6 19 71

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PtuJadelph PA 1996 LipplncOttmiddotRwen Pilrulttt n 0 Rummublntn M Arule glaucoma and acute co rneal oedtma i n UOdalkln wirh tularem Ia AC1a OpllJmlmol Sum~

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199s 75 Jau Nllt Davu K] Gelsba 1J el at lelha l experimental infectiom o f

rhesus monkey with poundbola-Zaire (Maylnga) vinu by the oral and conjunCTIval rou te of eposure Arci1 P~lh(1 L~b M(~ 12014()1 55 1 9~6

76 Klbad K Mupapa K Kuvula K t l al La te ophthalmolagk mmifes~oons in mrviVOB of the I99S poundbola vlrw tpidemic in Ki lcwit [)emornuic Repub lic of the Co~ J In(ta Dis 179 (Stlppl 1)5 13-51-4 1999

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78 Kont lwlen M luustj1rvt T Kluppi P Ocular chU~ClfrtStlCS In nephropathl l eplderuka or puumuJa viN~ Ittllaquotlon Aaa Ophthilimol 5(lIl1d 74621-625 1996 Komkanen MI PuUStjltlrvllJ LlhdevLtta JK IntTaocular pressure changes In neptuopathia epideuiC3 a prospective ~rudy of 37 patients wuh aevte systemic puumula vlTU$ infect ion OphthalmOlOgy 102181 3-1817 1995

80 Saa ri KM Acute glaucoma In h emorrhagic fevff ith renal s~ndlome (nephropalhia ~ pldemlC3) Am JOphwmol S (4)4~61 1976

8L Saari )(M iuolo S Oph thalroologlcal W lngs In nephropathia epidernia ln I3pl4nd A Cla Ophlhalmo6Z235-243 198lt1

8gt Pamlntn O Kwooer 1 Tonk pupWary runton alief epidlmic nephlopathy and rramlem myopla Am J0pIthalmol I0l(2)20I-202 1989

8l Llaquo tY Ch o SO Choi GB et ill lsoblelt abd ucens n erve pa~y IS a complia tion o f haemon hagic fever Wi lh renll syndrome Ntphrol DI TIansprmI1 321 13-21141 998 YOle SL Forster DJ Rao NA Systellll c viral Infections and their retinal ltld OlOloidal manlJestalions Surv OphlhQ lmo 37(S)313-352 1993

85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

86 Walke J Sharma Of Ra o NA BrureUo~ ls a nd uvei1~ Am IOphllullmo 114(3 )]14-]75 1992_

87 Thbbara kF Al-KaWmi H Orulat bruc eUo$b j t I Ophrhillmal i4(4) 249- lS0 1990

88 Woolth AC NUIJDub r )era liUs anO ocular brocellogtls Aidgt Ophlhalmol l 549(l 1946

89 G(ingor K Beki NA Namldwv M Re(I~n l episdetlds asoctal ld wlIh bruoelCKI Aaa OplltJwJmoI sca lld 19 76-78 2001

90 Putg Sollnes M Heatley J mnilS F el al Orolar com plicati ons In brulaquolIoill Am I Ophrhalmol 3667s-QS9 1953

9 Btki l NA GungJ K Si d lClal dacryoaderU lj woclated Wllh bru~Uosh A a OpirrJQmoJi Scnd 77(3)357-358 1999

92 al fa ran Mf BnK~lIa mfiUn$u ( ndogenogtn rndophltulmlUS OpIhalmologicn ZOl i l )19- ZZ 1990

93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

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Page 7: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

transmitted until the onset of the rash Z~ so diagnosis the prodromal stage with subsequent quarantine

be essential to limit additional exposure

lp~~~~I~~~ manifestations In led to blindness in 2 to 5 of students in blind

of developing countries in Africa 48-30 Typically a conjunctivitis appears around the fifth day of illness subconju nctival hemo rrhage in some cases Actual

whIch resemble phlyctenules may form on the or tarsal conjunctiva and even involve the limbus~l lesions are very inflamed and painful and can lead I and ulceration of the cornea Less frequently

imerSlitial 01 disciform keratitis evolves (Fig 1042) Lid and punctal stenosis may result when pustules

the cUla and punda respectively Ankyloblepharon also been reported due to severe eyelid adhesions

the upper and lower canthiY Secondary infectious can ocCur late and lead to significant morbid ity

~me antibiotic prophylaxis is warranted Dense comeaJ can leave patient s phthiSical and blind

beatorv diagnosis of smallpox can be confi rmed with microscopy of vesicular o r pustular nuld or

~~sect~Guamieri bodies can be visualized under lightVirus culture of skin lesions oropharynx

and urine is definitive peR techniques ca n ~ between strains and offer a more rapid

rne and vaccination is no specific systemic or ocular treatment for smallshy

although cidofovir has In vitro and In vivo activity

External Eye Mlfestatlons of Chemical and Blologkal Warfare

against Poxviridae P 1n 1796 Edwardjenner demonstrated that an Lniection caused by cowpox protected against smallshypox wh ich led to the worldwide practice of vacdnatiooS3

Curremly smallpox vaccine is prepared from live vaccinia virus using cell culture techniquesl4

The interval between an aerosol release of variola and diagnosis of the first cases is as much as 2 weeksH Fortushynately the virus is Inactivated after 2 days eliminating further exposure Individuals in whom infection is suspected should be vaccinat ed within 4 days o f exposure and placed under surveillance Vaccination programs ended in 1972 in the United States and it Is presumed that few people who wefe vaccinated have lasting protective levels of immunity

Complications of vaccination Vaccination is not without risk Life-threatening encephalshyitis occurs at a rate of 1 case per 300 OOOH ProgreSSive vaccinia or vaccinia gangrenosum results from neaogtls of the skin at the vacd nation site with advanced cases involving underlying bone and viscera Patient s wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites (Fig 1043) In some vaccine recipients blood-bome dissemimiddot nation of virus leads to a self-limiting generalized vactinial rash TransmISSion of vaccinia froro the site of vaccination to close contacts or autoinoculatjon to sites such as face mouth eyelid aod genitalia can take place Vaccinia immune globulin is used to treat these complications with variable success

Vaccinia ophthalmic manifestations Inadvertent autoinoculation of vaccinia from the deltoid site accounts for the ophthalmic co mpUcations of vaccishynation The majority of patients have vaccinia of the eyelidgt or conjunctiva but a smaller percenlage have comeal involvement ss Typically patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and

Ag 1042 ilfiol (smallpox) This patient demonstmtes a centrlll Fig 1043 Eczema vaCtinllll)nl Vaccinial skin leJioru extending (Ver the not scar from a sm~lIpox or variola infection area currently afflicted with eczema (Courtl$) of Rkhard K Forster MD)

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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54 tane jM Ruben fL NeffJM et I Compllcattons 0 mullpox vacctnatlon 1968 n~f1onal surveillance In the United Staes Npoundngf I Me 2SU201-1208 1969

S5 Ruben FL LaneIM Orular valtonla an eptdernkllogk analysis oj 348 ca l-tS Arc OpMhaImcl84 45-t8 1970

56 Je llf) 8R AlmiddotH~raquolni MK Therapeuuc com~ratoom In ocular v~laquotnla Trans Ophllial Soc UK 8361J63 1 1961

57 Litis pP WiFlOgrad 1) Ocu~ r valaquoirua spedhlt lIeatmelll Aft Oplllhal68 600-609 1962

58 Ryd~rg M Pandolfi M Tr~atment of ~acctnla keratitis with postmiddot vaccinial gamma globulin Ada Opllllu1141 71 3-718 1963

59 Ja Ck MK Soreruon lW Vaccinial keraOtillIn ted with IOU Alaquoh noOphlhalmoJ 69710-732 1961

60 Kaufmltl HE N~bl)fn AB Mlonty ED Cure 01 vaCCinia in feCTIon by smiddotlodo-2ooxyurldlne Virolog 1856 7- 569 1962

L Fulgin iti VA W1tJoOgrl1d lA jactson M I 1 Thflap y of CJltperlmt1l tal v(ci nl~1 kelaril l efleer of idoxur1dlnt a nd VIG AlCh Ophl almQl 74S39-$44 1965

62 Hyndiul ItA Okumolo M DamiAno RAt l al Trt atmem of vacrinial kem llraquo wilh viduabtne An-h OpIJUoalmltJl9( 136J--IlM 1976

61 DtnnIIDT In gltSby lV Hendmon VA el al 1ul ar~a as it biological weapon mWIcal m d public health management lAMA 285(2 1)2763--27732001

6 Oo JT Pmn RL Francisd la ru ll1rtruis (1U Il l emia) In Mandel GL BeM t ltJE Dolin R oollon Principles orld P(i(1ct oinfeaiow diflttiltj ed 5 Philadelphi a PA 2000 Ch urchJ lI Uv1ngslo n e pp 2393--2-402

6S h ans Mt Gregory DW ~haffn er W et al TU laremia a 30-ytar

txpt rienc~ 11h 88 rasa l_diel 60125 1- 269 1985 Amu ian Colleg~ of Physidampns-Amer1 can Soc fI) of Int em~1 Mlaquo1Icine 8lott n orlsrn Quid h CLS ~ bOII t TlJIMtmlii Avaiiable 1I h ttp wwwKpOTlinlorampfbiotcrro rulart miahrm I~ acceSfd I l fQSfQ2

6 D n1n rand S Ringcrtt 0 leltedlefg 6 Arboml IUl3 remiI in 5 Iln 5(anJ nKf Ds 3( 1)7-1 6 19 71

OS fI n c1 ~ t Oruloglandu l~ r tulampJlm1 a AlO OpIlrJoa lmol 287 1l 1942 69 Steln eml nn TL Sh~lkhalcilaml MR Brown HH el al Oculogla ndu b r

tuln eml bull Arch Ophrhalmol11 7 132-1 33 1999 Chin GN P-inaud oculaglilndula r conlunctl vitls In fuman W

Jaeger EA SchWilb fR edJtou Dulln~s rlinral ophtlullmology voL 4

PtuJadelph PA 1996 LipplncOttmiddotRwen Pilrulttt n 0 Rummublntn M Arule glaucoma and acute co rneal oedtma i n UOdalkln wirh tularem Ia AC1a OpllJmlmol Sum~

7S732-734 1997 n Marcus OM Fredtgtrkk AR II HodamptS 1 et al TyphOldigtllIla~mla

Arch 0pJ11haImol l08118-- 19 1990 73 Bono L inglesby T igtellors CI et aJ HemOl1 hagic fever virus aJ

biOlogica l wea pons medicl l and publiC h ealth mmag-ement fA MA

281( 81239 1-24052002 7lt jOM son E lnx N White J et al U lh al txpe rtroental infection~ 0(

rh e$U~ moflkly by aerosolized Ebltlb vj ru ~ 1m I up P~lhol76 227-236

199s 75 Jau Nllt Davu K] Gelsba 1J el at lelha l experimental infectiom o f

rhesus monkey with poundbola-Zaire (Maylnga) vinu by the oral and conjunCTIval rou te of eposure Arci1 P~lh(1 L~b M(~ 12014()1 55 1 9~6

76 Klbad K Mupapa K Kuvula K t l al La te ophthalmolagk mmifes~oons in mrviVOB of the I99S poundbola vlrw tpidemic in Ki lcwit [)emornuic Repub lic of the Co~ J In(ta Dis 179 (Stlppl 1)5 13-51-4 1999

n Kurn ln US KokoriJ N UilI iJw olvemenl in Muburg ~illJS dl~ Br I OphZhnlmo 6 1265_266 1971

78 Kont lwlen M luustj1rvt T Kluppi P Ocular chU~ClfrtStlCS In nephropathl l eplderuka or puumuJa viN~ Ittllaquotlon Aaa Ophthilimol 5(lIl1d 74621-625 1996 Komkanen MI PuUStjltlrvllJ LlhdevLtta JK IntTaocular pressure changes In neptuopathia epideuiC3 a prospective ~rudy of 37 patients wuh aevte systemic puumula vlTU$ infect ion OphthalmOlOgy 102181 3-1817 1995

80 Saa ri KM Acute glaucoma In h emorrhagic fevff ith renal s~ndlome (nephropalhia ~ pldemlC3) Am JOphwmol S (4)4~61 1976

8L Saari )(M iuolo S Oph thalroologlcal W lngs In nephropathia epidernia ln I3pl4nd A Cla Ophlhalmo6Z235-243 198lt1

8gt Pamlntn O Kwooer 1 Tonk pupWary runton alief epidlmic nephlopathy and rramlem myopla Am J0pIthalmol I0l(2)20I-202 1989

8l Llaquo tY Ch o SO Choi GB et ill lsoblelt abd ucens n erve pa~y IS a complia tion o f haemon hagic fever Wi lh renll syndrome Ntphrol DI TIansprmI1 321 13-21141 998 YOle SL Forster DJ Rao NA Systellll c viral Infections and their retinal ltld OlOloidal manlJestalions Surv OphlhQ lmo 37(S)313-352 1993

85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

86 Walke J Sharma Of Ra o NA BrureUo~ ls a nd uvei1~ Am IOphllullmo 114(3 )]14-]75 1992_

87 Thbbara kF Al-KaWmi H Orulat bruc eUo$b j t I Ophrhillmal i4(4) 249- lS0 1990

88 Woolth AC NUIJDub r )era liUs anO ocular brocellogtls Aidgt Ophlhalmol l 549(l 1946

89 G(ingor K Beki NA Namldwv M Re(I~n l episdetlds asoctal ld wlIh bruoelCKI Aaa OplltJwJmoI sca lld 19 76-78 2001

90 Putg Sollnes M Heatley J mnilS F el al Orolar com plicati ons In brulaquolIoill Am I Ophrhalmol 3667s-QS9 1953

9 Btki l NA GungJ K Si d lClal dacryoaderU lj woclated Wllh bru~Uosh A a OpirrJQmoJi Scnd 77(3)357-358 1999

92 al fa ran Mf BnK~lIa mfiUn$u ( ndogenogtn rndophltulmlUS OpIhalmologicn ZOl i l )19- ZZ 1990

93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 8: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

fig 1044 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pustules (Courte~y 01 Richard K Forster MO)

pustules commonly affecting both lids (Fig 1044) The conjunctivit is is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular lymphadenopathy~ Severe cases present with periorbital edema mimicking orbital cellulitis56

Vaccinial keratitis is the most feared ophthalntic complishycation Corneal involvemen t develops in 20 to 37 of cases of ocular vaccinia~ When virus inlects the corneal epithelium it produces a grayish 6ne granula r opacity with mild epi theJial edema~ Diseased cells stain with rose bengal and dendritic lesions are occasionally present Subepithelial infiltrates may form and lead to peripheral neovascularlza ti on and ulceration Some patients develop a disciform or necrotizing stromal keratitis with possible perforation ~)s6 The diseased epithelium is less opaque and swollen than that In herpes simplex and a conjunctival follicular reaction is usually absent The ulceration is more rapid extensive and Irregular than In herpesS6 Permanent sequelae indude corneal scarring punctal stenosis eyelid scarring and loss of lashes

freamenl

Topical steroids are effective for stromal opaCities neashyvascularization and uveitis however treatment of the acute infection reqUires viral inactivation and steroids are contraindicated Topical and parenteral vaccinia immune globulin is effective for ocular vaCCinia ~1sa especially with orbital inflammation$6 Idoxuridine an antiviral used for herpes simplex cao be used to trea t early vaccinial keratitis ~U9 Idoxuridine was found effective in a rabbit model by Kauhnan et al60 but Fulginiti et al61 fo und no sign1ficant difference when idoxuridine or vaccinla immune globulin was used compared to rabbit contTols without treatshyment Vidarabine (aden ine arabinoside) h as been proven more effective than idoxuridine in a rabbit model62 It is

Ukely that n ewer antivirals (triOuridine) would be at least as effective as idoxuridine as both inhibit viral DNA synthesis by thymidine kinase phosphorylation

Tularemia

Microbiology and epidemiology The causative bacterial agent o f tularem ia Frandsella tularensis is a highly infectious aerobic Gram-negative coccobaci llus found in widely diverse animal hosts and habita ts throughout the world Tularem ia has epiderolc potential but typically occu rs in isolated cases in rural areas The natural reservoirS fo r infection ate va rious small animals including rabbits squir rels voles mice and watt ra ts that become infected through bites from ticks rues and mosqu itoes and through contact with con taminated soil wat er and vegetation6J Humans become infected by various modes including bites by arthropods handllng infectious animal tissues or fluids direct contact with or ingestion of contaminated water food or soil and inhamiddot lation of infective aerosols

Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation Disease presentations include ukeroglandular glandular oculGshyglandular oropharyngeal pneumonic typhOidal and septic forms 8636-I Alter an incubation of 2 to 10 days there js

rapid onset of fever chill s rigors headache myalglas coryza and sore throat Frequently there is a dry or slightly productive cough mth substernal pain63 Nausea vomiting and diarrhea can occur and nearly half of patients demonmiddot stra te a pulse-temperature dissoc iatio nM

Inten tiona l aerosol release of F ruarensis would lead 10

the generalized iUness wi th a significant number of patients developing pJeuropneumonitis Hematogenous spread may occur with death resulting from sepsis disseminated intrashyvascular coagulation adult respiratory distress syndrome and multiple organ failure M 66 The largest recorded airborne outbreak of tularemia occurred in a fanning community In Sweden in 1966-1967 The stra in was a less virulent form but sHU led to 140 serolOgically confirmed cases Pulmonary sympto ms were present in 10 conjunctivitis in 26 skin ulcera tion in 12 pharyngitis in 31 o ral ulcers in 9 and 32 had various exanthemas such as erythema multHorrne and erythema o odosum67 Personmiddot to-person transmission is not known to occur1raquo

Ophthalmic manifestations Tularem ia Is one of the causes of Parinauds oculoglandular synd ro me68 Direct contaminatio n of the eye leads to COf) junctival ulceration chemosiS and of the preauricular submandi bular and cervical The conjunctivitis is unila teral (90) and typically With multiple yellow nodules involving or bulbar surface 69 Rare ocular effects include ulceratlon68M dacryocystiti S1O acute glaucoma lI genous retinitis n and optic neuritis 70 The differential nosis Includes bacterial conjunctivitis adenoviral bill

2

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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102 Ron en S Rorenmuill Y R tI aI 1

103

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06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 9: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

External Eye Manifestations of Chemical and Blologfcal Warfare

disease herpes simplex infection and other causes of PaMnauds oculoglandular syndrome~middot7o

Diagnosis F tularensis can be identified by examlnation of secretions or biopsy specimens using direct fluorescent antibody or immunohistochemi ca l srans 63 Cultures are definitive but

be performed with cyste ine-enriched medla636-

Serological testing can be diagnostic however it can take longer than 10 days after the onset of illness for a signifishycant change In titers proving less useful in an outbreak63

Several peR assays have been developed that would give faster results H

Treatment Treatment is with streptomycin 1 g 1M bid for to days with gentamitin (S mglkg 1M o r IV) as an alternative Ruoroqulnolones are probably as effective6J

middotJ 1 In a mass

exposu re situation or for postexposure prophylaxis oral doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can be used for 14 days6l Treatment for ocular disease should include frequent topica l gentamicin~ 70

Viral hemorrhagic fever

Microbiology and epidemiology Viral hemorrhagic fever is a clinical illness associated with

one of four familie~ Filoviridae Arenaviridae Bunyaviridae and Flaviviridae (Table 1044) 13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors Humans are Infected by the bile of an Infected arthropod via aerosol generated from Infected rodent excreta or by direct contact with Infected animal carcasses Some viruses can lead to human-to-human transmission via direct conshytact wtth blood secretions or tissues of lnfected patients or needlestick injurtes 73 Successful infection of rhesus monkeys with Ebola virus has been shown with aerosol preparatlom4 Via oral and conju nctival exposure 7S Thereshyfore a biological attack would Illost likely utilize an aerosol release of virus

Clinical manifestations The vascular system is primarily targeted by these viruses Microvascular damage with changes in vascular permeshyability lead to a coagulopa thy and Signs o f bleeding which include conjunctival hemorrhage mild hypotension flushshying and pelechiae 71 Symptoms of fatigue dizziness and myalgjas are present during the first week of illness Nausea and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 daysn Disseminated intravascular coagulation with hematuria hematemesis and melena occurs as a late ominous sign In severe cases shock and generalized mucous membrane hemorrhage results with end-organ damage and death

fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks

Table 104A HelTlOflhagic f~er virusesshy

- VI

filoviridae Filovirus poundbola Marburg

Aremwiridae ArenlVirus La New World A~narldM

8unyaviridae Nairovirus

Phlebovirus Hano)virus

Crimean-Coogo hemorrhagic lever Rift Vall~ (ever Agenu of hemorrhagic f~ with renal l)ndrome

Aaviviridae ~Javivirv s Dengue

Yellow (ever Omd hflmormaglc (ever Kyaanur Forest disease

DI

Ebola hemorrhagic fever Marburg hemorrhagic lever

Lassa f~er New World hemorrhagic fever

Crimean-Congo hemorrhagic fever Rift Valley lever HelTlOfTflagic f~ with rellal syndrome

Dengue leve Dengue hemon1ugic lever and Dengue shock syndrome Yellow fever Omsk hemorrhagic fever Kyasanur Forest disease

Bold indi(I1~~ tllmrgtrrh9k fever vftlJe1tlot post url$ fisk aI bioJogkol weapons 1T~re art lovr wbrypt of fbolo loire Sudon Ivory Cool ond Rtfon

-M shyUnknown Unknown

Rodent- nCk

Mosquito RodMt

Mosquito

MosquIto n (k Tick

shy-Africa Afria

West Africa Americas-

Atria central Alia Eastern Europe Middle Ean Africa Saudi Arabia Yemen Asia Balkans Europe Eurasiai

AsIa Africa Pacific America~

Africa tropical Americas Centramp1 Asia India

The New World Arem1Viridot Include M(J(vpo the alUSt of amplIMon hemonhogic fever Ivnin Iht alll~e of Aitntint htmorrlclgl f~ GlJllncmto IfIt aJU~ of V~llielon hemorrhOiic fever ond Sabia thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf n additional OffflaviflJ$ hell bein isolOled followlnQ Ih~ leJla ru~ 01 hemorroogic fevN In Califomfo 1999-2000 AkWona1y the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt how btfn jolt11OO In NOfItl Anlfrl(o rom refeflnct fJ page 2392 rllblfl I Bolio to Ingifllit r PeltfS q fl 01 Hemorrhogic fever virvl OJ b~oglrol OPO mMiclI ond public hlaquoJkh 9mfnt )lIMA 287(18)2391-240$ 2002 Copyrighl C) (2002) Americoo Medical Aaooolion AI1 righl~ rfltfVfd 1

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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62 Hyndiul ItA Okumolo M DamiAno RAt l al Trt atmem of vacrinial kem llraquo wilh viduabtne An-h OpIJUoalmltJl9( 136J--IlM 1976

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PtuJadelph PA 1996 LipplncOttmiddotRwen Pilrulttt n 0 Rummublntn M Arule glaucoma and acute co rneal oedtma i n UOdalkln wirh tularem Ia AC1a OpllJmlmol Sum~

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199s 75 Jau Nllt Davu K] Gelsba 1J el at lelha l experimental infectiom o f

rhesus monkey with poundbola-Zaire (Maylnga) vinu by the oral and conjunCTIval rou te of eposure Arci1 P~lh(1 L~b M(~ 12014()1 55 1 9~6

76 Klbad K Mupapa K Kuvula K t l al La te ophthalmolagk mmifes~oons in mrviVOB of the I99S poundbola vlrw tpidemic in Ki lcwit [)emornuic Repub lic of the Co~ J In(ta Dis 179 (Stlppl 1)5 13-51-4 1999

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78 Kont lwlen M luustj1rvt T Kluppi P Ocular chU~ClfrtStlCS In nephropathl l eplderuka or puumuJa viN~ Ittllaquotlon Aaa Ophthilimol 5(lIl1d 74621-625 1996 Komkanen MI PuUStjltlrvllJ LlhdevLtta JK IntTaocular pressure changes In neptuopathia epideuiC3 a prospective ~rudy of 37 patients wuh aevte systemic puumula vlTU$ infect ion OphthalmOlOgy 102181 3-1817 1995

80 Saa ri KM Acute glaucoma In h emorrhagic fevff ith renal s~ndlome (nephropalhia ~ pldemlC3) Am JOphwmol S (4)4~61 1976

8L Saari )(M iuolo S Oph thalroologlcal W lngs In nephropathia epidernia ln I3pl4nd A Cla Ophlhalmo6Z235-243 198lt1

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85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

86 Walke J Sharma Of Ra o NA BrureUo~ ls a nd uvei1~ Am IOphllullmo 114(3 )]14-]75 1992_

87 Thbbara kF Al-KaWmi H Orulat bruc eUo$b j t I Ophrhillmal i4(4) 249- lS0 1990

88 Woolth AC NUIJDub r )era liUs anO ocular brocellogtls Aidgt Ophlhalmol l 549(l 1946

89 G(ingor K Beki NA Namldwv M Re(I~n l episdetlds asoctal ld wlIh bruoelCKI Aaa OplltJwJmoI sca lld 19 76-78 2001

90 Putg Sollnes M Heatley J mnilS F el al Orolar com plicati ons In brulaquolIoill Am I Ophrhalmol 3667s-QS9 1953

9 Btki l NA GungJ K Si d lClal dacryoaderU lj woclated Wllh bru~Uosh A a OpirrJQmoJi Scnd 77(3)357-358 1999

92 al fa ran Mf BnK~lIa mfiUn$u ( ndogenogtn rndophltulmlUS OpIhalmologicn ZOl i l )19- ZZ 1990

93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 10: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

Some viral hemorrhagtc feve rs present with suggestive dlJl icaJ features]) Ebola and Marburg (FiloviTidae genus) are especially virulent and can cause necrosis o f visceral o rga ns (liver spleen kidneys) Adult respiratory distress syndrome is a sequela of Onl species 01 Hantavirus Nephropathia epidemica is caused by Puwnala virus and leads to an acute hemorrhagic tubular and Interstitial nephritis

Ophthalmic manifestations Fllovlridae

Due to high mortality rates Ebola and Marburg hemorrhagic feve r are two of the most feared illnesses Eye involvement presents wit h sympto ms of pain photophobia tearing and blurred vision 6 Conjunctival injection is seen in at least onemiddothaJj of patients during the acute phase and may present with subconjunctival hemorrhage Fifteen percent (320) of patients who survived the 1995 poundbola outbreak in the Democratic RepubU c of the Congo developed acut e anterjor uveitis with vitreous opacities in one patient 76 The onset of uveitis was 1 to 2 months after initial infecmiddot tion Treatment with topica l cycloplegics and steroids was effective in all patients A case of recurren t anterio r uveitis with elevated intraocular pressure occu rred after a small outbreak of Malburg virus in Jo hannesburg South Mrica in 1975 Virus was cultured fro m the amerio r chamber aspirate at presentation SO days after initial infedion 71

Nephropathia epldemkll Some of the other less virulent causes of viral hemorrhagic fever also have ophthalmIc Signs Patients affected with nephropathia epidemica can present with eye pain blurred vision and photophobia The most prominent eye fi nding is transient myopi a due to forward movement of the ante rior diaphragm and thickening of the aystaUine lens78

Usually the intraocular pressure is s lightly lowered19 howmiddot ever acute glauco ma has been observedso Other Ilnd ings include conjunctiva l injeCtion and hemorrhage iritis and retinal edema with hemo rrh age 81 Neuromiddotophthalmlc findings include toniC pupils82 and Isolated abducens palsy81

Rift Valley fever Rift Valley lever presents predomina ntly with retinal findmiddot ings although conjunctival injection wich pho tophobia and ret roorbital pain is present initially Fundus exam typica ll y reve3Js cottonmiddotwool exuda tes and hemo rrhage in the macu la and paramacula r area vascular occlusions and sheathing macular edema and optic pallor tw Vitreous hemorrhage retinal detachmen t and epiretinal mem shybranes may also develop UveltJs with occasional anterior chamber reaction occurs in Jess than one-third of patients

Diagnosis Travel history and clini cal presentation can aid in the diagshynosis and help determine the type of hemorrhagic fe ver virus OccaSionally thrombocytopenia or leukopenia may be present Viral cultures rapid enzyme immunoassays (EUSA reverse transcription-PCR) and electron microscopy can identify the speci5c subtYPe of virus 2

Treatment Treatment is supportive but ribavirin may be beneficial in Arenavjruses or Bunyaviruses71 With the exception of yellow fever there is no licensed vaco ne for an) of the viral hemorrhagie feve rs

Others The CDC has listed additional biological agents that pose Significant but less ri sk to public health than the agents already described The known ophthalmic associations of Ihmiddotese a re listed in Box 104 3)08gt-108

Chemical Agents C hemical attacks can easily overwhelm medical ~ especially in urban areas Materials to manufactuIe I weapons are inexpensive and easy to obtain The nve classes of chemica warfare agents are nerve (h()I1~ esterase) vesicant s (blister) pulmonary toxicants (cyanogens) and incapacitating agents (Box 1044)109 can be found as solids Uquids gases vapors and The state of an agent is chosen depending on its

Box 1043

Biological agenU of ~econd highest priority and ohth~ manifestations

Brucellosis (Bruulla spp ) _ uveitlsuu with iridocyclitis chronic granulomatous or nongranulomatous) and mltl choroiditis (nodulllr Of geographic) nummular keratitisa (KUrTent eplscleritis optic nuriti5~ dacryoadenili5l endogenous endophthalmjris9~

Epsilon toxin or Closlridium perfringem _ corneal ulcerI endogenous endophthalmitis

Solmonefo spp - Reiterl $)ndromen peripheral uktfatM keratitis6 steUtlite milculopathy and chorioretinitist1 endophthalmitis

Escherichia coli 0157H7 - keratitis99 endogenoo~t Shcentla spp _ Reiters syndrome keratitisQ 0

Glanders (Burhokferia mtJllet) - none

Melioidosis (Burfloldtfia pseudomalleJ) - anophthltllmk socbt infection0J keralilis with endophthaJmitislOt

Psittacosis (ChomyfJio psittocJ) - coojunctMtis uveitis middot keratitis106

Q fever (CoxielJo bumetii) _ choroidal n~ascularilation1111

neuritis101

Ricin toxin from RicnilS communis (castor beans) - none

Staphylococcal enterotoxin B _ none Trichothecene mycotoxiru _ none Typhus fever (Rickettsia prowoukllJ - none Vibrio cholerae - none keratitis In other Vibrio species Viral encephalilb (alphavlruses Ie Venezuelan eastern equine enuphalitis western equine

list from reference 10 MedlIM seudgt fur lot 01_ COI1rQ1 1d Pf~Iion 8101oglal 1 httpftwww~cdcgoyAgentlagentlisu$p 1104

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

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pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

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102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

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l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

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118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

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Page 11: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

Cyltlohexyl sarin (GF)

G Silon (GB) SorNtl (GO) TAbun (GA) VE YO

VX

Outjlled mUltard (HO) lewisite (l) Mustard gu (H) NitrogM mustard (HN-2) PIIosgMe ~me (eX) Ethytdict1loroarsloe (EO) ltwilite 1 (L- l ) lewisite 1 (l-2) lewisite 1 (l-) MethydichloroalSine (MD) MustardLewisectite (HL) MustardfT Nitrogen mustard (HN-l) Nitrogen musurd (HN-l) Phe1Iodichloroarsine (PO) Sesqui mustard

toltiants

_(Of) Cyanide Nittogen oxide (NO) ~u(orisobuty1ene (PfIB) Phosgene (CG) Red phosphorus (RP)

External Eye Manifestations of Chemlul mel BlDlogkal Warf~

Box 1045

N~ ~ent dgns

Muscarinic Smooth muscle B(Ofl(h()(orutriction Increased gtitrk

motJllty Miosis Glands LKrftNltion Rhinorrhea Salivation lncrellstro gntroin testinal

secrelions Bronchorrhea Diaphoresis

Oth Bradyardla Heart bkgtck Hypotension

Nicotinic Muscle Fasclculalions Twitching Fatigue Flaccid paralysis

Tachyc~

Hypertension

Centnll nervous system Heidaches Venigo ~Itation

Anxiety Slurred speelth Delirium Com s

Urinary Incontinence Cent ~ory dlpmsion

Adapted from reffteK 110 AIMrbrI College at~ ~ of Inwnal M~ 8iotaJOri)m SummatiH from MnuI SetsQrl 20021w1IbIe - htlpJfwwwiKpOrlIine~eJTOI4uumlhlmIISl ac(~~ 11 0502

choline neurotransmitter at I1 s post-synaptic receptor sites 80th muscarinic and nicotinic relteptors are affected cawing cholinergiC crisis (Box 1045) 110 Muscarinic effects involve the smooth muscles (bronchoconstrtcnon increased gastriC mo tility miosiS) the glands (lacrimation rhinorrhea saJlmiddot vaUon increased secretion - gastrOintestinal and airway) and the heart (bradycardia) Nicotinic effects include faslcushylations twttching fa tigue tachyca rdia hypertension and paralysis Nerve agents cross Ule blood-brain barMer and can lead to confusion aJtered consciousness seimres apnea coma and death Small exposures are associated with Janshysient effects such as poor concentration and disturbances of viSion steep and emotions

Nerve agents tnat have been used as chemical weapons include tabun (GA) sarin (GB) soman (GO) cyclohexyl sarin (GF) and VX At room temperature all except VX are volatile VX has an oily conSistency and becomes volatile only at high ambient temperaturesll l The vapor or gas form would likely be utiUzed In an overt attaCk with variable onset and severity depending on the agent and duration of ex posu re

Ophthalmic manifestations On March 20 J995 the Aum Shinrikyo cult released sari n (isopropyl methyiphosphonofluoridate) gas at several pointS in Ihe Tokyo Japan subway systemIII A simUar incident occurred on June 27 1994 in Matsumoto Japan1IJ Pure sarin is colorless and odorless and when vaporiZed Is absorbed through the respiratory tract and conjunctiva Wlthln minutes of exposure victims noted a sensaUon of darkness related to miosis Many had conjwlCllva l lnjec shytion with pain and impalred accommodation related to

nos

SuKur u ioxidelthlorosulfonic add (FS)

Tetton nd perfIurorisobutylene (PFIB)

TItanium tetl1lChloride (FM) Zinc oxide (HC)

8kxgtd Arsine (SA) cyanogen chloride (CIC) Hydrogen chloride Hydroglfl cyanide (AQ

Incapacitating Agent IS BZ CaMiboids Fentanyls l50 Phenohiazines

Riot cOfltroltear 8romobenzylcyanide (CA) Chlotoacetophenone (eN) Chloropicrin (PS) CNB - (CN in benzene and

carbon tetrilchlotide) CNC - (eN in chloroform) CNS - (CN and chloroplcrin

in chloroform) CR C5

Vomiting Adamsite (DM) OIpheflykhloroarsine (DA) Diphenylcyanoal1ine (DC)

Centeo for ~se Control bull Available at

IItt updiltfd 10092002

and desired duration of exposure or persistence Uquids solids persist the longesl wUh variables that include

peral wind conditions agent-surface interactions the agents volatility

The efficacy of a chemical agent is determined by its ~middotn(absorption and its toxJdty Chemicals penetrate pldermD surfaces due to their IipophiJic natute and are

mixed with additional substances to enhance diffusion 1Iu protective clothing and other barriers no Toxicity

determined by the dose or concentration (gas or vapor) length of exposure Most chem1cal agents produce at mUd eye irrttation but nerve agents and vesicants particular interest to ophthalmologists

Nerve agents Nerve agents are potent organophosphate compounds that inhibit acetylchoUnesterase leading to excessive acetylshy

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

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in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

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102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

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107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 12: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

dliary spasm In nearly one-third of patients there was an approximate 3 mm lowering of intraocu lar pressure Ocular signs and symptoms resolved within severaJ days to several weeks after treatment with topical cydoplegics

Treatment Management includes basic life resuscit ation deconta mishynation drug therapy and supportive ca re Removal of clothing and jewelry and forceful soap and water washing of the skin is recommended Hypochlorite (05 solution) can be used instead of water as it inactivates nerve agents 1

Despite decontamination the effects may worsen with time because these agents can accumu late in at and release slow ly no Atropine is a competit ive inhibitor of acetylmiddot choline at muscarinic recepto rs and thus reverses the hypersecreto ty bro nchoconst riCti ve bradycardic and gastrointestinal effects of nerve agen ts 1 Pralidoxime (Protopam ~PAM) can counteract nicotinic (primarily muscle weakness) effects by binding to the nerve agent and reactivating acetylcholinesterase Ea rly use is critical since pralidoXime is only effective when administered before the nerve agent- acetylcholinesterase bond has become pennanent (~ages) The time it takes for half of the nerve agent to age ranges from about 2 minutes (soman) to 48 hOurs (VX) Use of benzod iazepines (ie diazepam) may prevent brain damage from seiZures In advanced cases

Vesicants Vesican ts are oily liquids that becom e aerosolized when dispersed by an explosive blast from a bomb or when released under high ambient temperatures Sulfur mustard is the most common vesicant used in chemical weapons It is lipophilic and readily penetrates skin most textiles and rubber II I Skin penetration occu rs in less than 2 minutes but there is a delay of min utes to hours in the onset of a burning sensation In contragtt lewisite causes almost immeshydiate burning Once absorbed It aJyJates and denatures DNA RNA and proteins leading to cell death

Clinical manifestations Clinical effects usually appear vithin 4 to 8 hours after exposure to musta rd Dermal exposure produces superficial (erythema pajn) to pa nial-thickness (buUae) burns with uncommon ful l-thickness (deep buUae uJcer) involvement I II Inhalation o f mu stard vapor can cause bronchospasm mucosal sloughing and hemorrhagiC pulmonary edema in severe cases Large exposure can lead to bone marrow suppreSSion and gastrointestinal effects which may lead to secondary infection sepsis and death

Ophthalmic manifestations Ocular effects range from a mild coniunctivitis to corneal bums and blindness The eye is very susceptible to damage due to the Enhanc~d absorption by the aqueous-mucous surface and the tendency for concentration in the oily layer of the tear fi lm due to mustards lipophllic qua lity1IS The cornea is thus ~posed for a prolonged period of time leadshying to loosening of the epithelial layer from the stroma

exposing the free unmyelinated nerve endings and inducing ocu lar pain

Symptoms begin with eye pain photophobia lacrimation and blurred vision A mild conjunctivitis is commonJy seen within an hou r of exposure a nd is one of the earliest clinical signs lIS Mild iJliury causes blepharospasm eyelid erythema and lacrimation Moderate injury leads to perimiddot orbital edema corneal epitheUal edema and punC1ate comeal erosions Vesication of th e cornea can lead to complete sloughing of the eplthelium Microscopically there Is loss of conjunctival mucus with occlusion of blood vesse ls due to goblet and endothelial cell injury respectively) Recovery typically occurs without significant adverse sequelae however about 90 of mildly affeltted pltltieJlts are visually d isabled fOr approKimately 10 days1l1

Severe injury (about 10 o f patients) can result in conshyiunctival chemosis and blanching due to destruction of conjunctival and limbaJ blood vessels There is corneal stromal edema with diminished or absent sensation which can lead to ulceration secondary microbial keratitis and perforation Deeper penetration may result in anterior uveitis the formation of posterior synechiae a transienl elevation of intraocular pressu re and lens opacification COlnea l pannus (ormat ion begi ns wi thin a few w~ks due to persistent innammario n and limbal stem cell Corneal scarring and coniu nctivali zation lead to vision in the months that follow the acute injury tival scrape cytology in soldiers with chronic eye after exposure to mustard gas duri ng the Iraq-Iran war shown dysplaSia in 4 1 (9 of 22) studied but none squamous cell carcinoma 118 Chronic angle closure glu and phthisis can lead to blindness

An unusual delayed type of kela topathy develops in of patients up to 40 years after severe exposure to m1U gas lIS After an inactive period the patient experien a rerunent attack of stroma l keratitis starting near limbus and advanCing cen trally There is a porcelain-white epi scleral area adjacent corneal ulceration H~ Areas of stromal overlying epithelial breakdown are in the lower and central comea 120 Aneurysmatic and tortuosity of conjunctival and corneal vessels wit h inlTacomeal hemo rrhage Advanced cases lead corneal o pacification with crysta l and cholesterol

The pathogenesis is unknown but maY~Er~~rp~~~~=proces~es that accompany the deposition o f as well as immunological reaction to comea l were structurally modified by the mustard

Treatment Managemen t of acute exposu re should include mno con taminated dotheS and nushing of the skin with and water Absorbent powders such as calcium and magnesium oKide are also effective iI voUble The eyes o f both symptomatic and asymptomatiC sho uld be irriga ted with tap wa ter as soon as Topical antibiotia an d cycloplegics should be p~CJibe but the use of topical ste roids is con troversial use within 7 to 10 days can lintit polymorphonuclear 1306

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

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trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 13: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

Extemal Eye Manifestations of Chemical and BkJloglca Warfare

inhibit colla genolysis and quell chemica l uveitis The disadvantage is Impai red epithelial

healing with the pOSSibility or subsequent corneal ~laatjor and perforation Vitamin C (ascorbate) titrate

N-acetylcysteine (Mucornyst) may be beneficial adj uncshytherapies Frequent lubrication bandage contact lenses tarsorrhaphy aid in management Penetrating keratomiddot

lunbal stem celilTansplantation may be required fu ll visual rehabilitation

I Ou$Iophtr GW Ci~l1k T) P~v1111 JA el Oll 81eloglcotl wariall l hIsIotlcal pmpeGive lAMA 273(S)412-11 7 1991

2 Gfoiraquolf E 8ioogual and fI)~ill _pam rodily ~ York NY 1986 Oxford Unlvenlry Preraquo

3 HrTU S Japa~ blologllta1 warlue re~arch on humans a CiCie $rultI) of mlcroblology and ethio tirln N Y Acad So 66621-5Z 1992

4 Slnu NA n~ diplomacy of biological d1samamal New York NY 1983 Plenum Pteraquo

5 Meseuon M Guillemln J HughmiddotJones M et i l The Sverdlovs~ anthux OUibreu of 197J Sdmct 266 I lQZ-l 208 1994

6 ZllJns~ RA lqmiddot~ biological up0n5 thf past as fulUl1 JAt4 278(S)laquo I8-424 1997

7 WHO Group of ConmltaJl lJ Ht(llh r15pertl 0 rllmlical iUld biologicill wapon Geneva SwlUerland 1970 World HeMth Organization pp72-99

8 McGovern TW Chrlnophcr CW Eitzen EM Culolneou~ mallifesIilTioJ) at biologiCiI mace am t tltlted lhlUt Jgen l$ An-I Dmnmoi 1353 11-3U 1999

9 American Colleg~ of PhysKin~middotAmtIiClUl Soot) 0( Inlemal Medldn~ AC pmiddotASJMmiddot Guide 10 8)Otenorhm ldoen t l-ticotlon 2002

]0 Cenltrs for OiseltlSl Control and Prev~ntlon BIOlogical DI5e~IAgent5 UsC Available at http wwwbICdcgovIAgemagentlhl llp laM updlted 10040Z

I I lttn ten for Oi$eaSl Conn-ol and Prevention Chemical Agent~ Ult aoa Infomudon Avillabl at httpwwwIxcdcgovAgUltfagen UiSKhemasp lAS t updated 1009OZ

12 K10t SA An thrax In GOlbach 5 Banlom J Bbcklow N editon In(WIow diJ~ltlJ(S PhilMelptUa PA 1992 WB ~undm pp 1291- I29J

13 Youton 0 Fmter A CUUIlKlUS anthrax leadlng to Ul rneai scarrtng from deatrldal ectropion Sr f Oplllllalmol 73809-8 11 1989

H 8rouswd iJ Biological agenu wapon of warfase and bio~rTOtJsm

)lt) DIltun 6(4)1Z3-1J1 ZOOI 15 Q-Iebl S Ayun U AiagOt G et Ill Palpebral antJuax W OphlJlalmol

11 (2) ]71- 174 ZOO I 16 5oysl HG Kirntli H Rlaquo-ep O f Anth rax as ure ca~ 01 prewptal

cclIulJtJs and cicatricial ectropion Ada OplhalmtJl SeaId 79(2) 208-209 ZOOI

17 A~lan G nmoglu A SUfgJcaJ management 01 Ntaneous anthraX Arm PlIlJI SUrf 415)468-470 1998

la Glovet M Ducam M Nfgn1AD f al jL1te a5pKU 0 1 palpebral antiultu authors lansl)I MtJ Trop 39(1)91_96 197J

19 NutUer T1 BkIJoglcal and chemic1 teu o n $m reltllgrlilion and m~33f1Uem ClITe e liul M~d 68( 12)1001- 10162001

20 Dogany M Aygen B Inan M el ill Temporal arte ry Inf1amm~tion as a romplltltlon of ltlmhrax I Infect 28(3)31l-3H 1994

21 Trylnd M Mynn~1 H Hohet L et al Clinica l cowpox cases in Norway 5cltgtnd f ref [(s 30(1)101-303 L998

22 Ba~by 0 8(gtIlllelt M Geny B- Human cowpox 1969- 91 a (vif W b ued on S ot ~ 8J I OtmratoI 111(5)598-607 1994

II OConnol GM Thim AA Caul Opound Orulu cowpox rransml1Q hom the domtsti ca t to Ilan 8r I Ophrhalmol 74(4)245-246 1990

24 unlers klr Di5lt~se ComTol a nd Prevention Anwax Lab ~d H~atth Profelonals Tr3ltllng Material AvlU3ble 11 hnpIWWbtcOCgovl AgpntanthraxSlldeSelAnth raxpdl 1031Z001

25 Inglesoy lV OJboie T Hendenon OA et il Anlhrlx as a bloIogtca l eapon 2002 upd3ted rKOmmf nWtlonli Of management lAMA 287(1 7)2136-m2 2002

26 AbrlllllOva FA Grinbe rg LoI Ympoluy~ 0 t l al Pathology of lnhalat lonalanthrout In 42 cases from the Sverdluvsk OJtbrea in 19 79 Prof Nal Mad Scj USA 9OZ291-2Z94 1993

27 Funz OR j ahrllng PS Frltdlandr r AM et al ClinKal rKogrurion Ind mal1llgement 0( patien ts C)( posd 10 bialog1cal wa rflIe agent ~ IAMA

278(5)39911 1997

Z8 Brltl t hman P Fnedlandfl A Inhalatlon mlhrU Ann NY Acad ScI 35383-93 1980

29 Friedland~ AM Welkes SL Pin ML Postexposure proptoylub againll expertmf nta1 nhalilllon _JlUirilll I nflXl Dis 167 1219- 1242 1993

30 Kerrlson JB lounsbury 0 ThlrkUl CE e Opttt murltll ahef anthrM VlIccinatJon Ophmalmology 109 99-10lt1 2002

31 Syed NA GlarermiddotHoc~te in C l(olaslmki SI SUMeral anterior uveitiS posterior scleritis and opUC IlfwopaUly foll oWing nthru vaccination AmPrfcan Academy of Ophthalmoiogy scipnnlic poster Olando Florilla 2002

n Amon SS Scheaer R Inglesby TV e aI 80rulln um toxin as ~ biological weapon medical and public hfalth Dar)Ogfment IA14 2-8S(8)1059-I0702001

33 caya j C CI(mridillm bolllllnm and the ophthalmologist a reView o f botu lism including biolOgical warfare rilmllkltiOns of botuUnum toxJn S OphlhalmaJ 1625-34 20(H

34 lttn ters for DlseilSf COnno) and Prevention BoruJi~n in hi US 1899-19 Iadboolaquo ot tpJemJoiogisll d id4lm QOO l~borafQry lO-orkt7 AUa Olil GA 1998 CDC

35 C hcrington M Laghmari M Kaonaoyen A el al Clinical sJlK1rum of botulism Musc~ N~ 2 1701-7 10 1998

36 Hughes 1M Blumenthal JR Mergtan MH e al Clinical leatun1 of WS A and B foodmiddotbomf lXItu lls m Ann [ntern Mal 95442-445 )981

17 Ehttn~lch H Gamer CG Wi tt 1N Complete bilateral llltemal ophthalmoplegia as so lt c1lnlcal sign of borulism oonJirmation of diagnmis by single fibre d~om)-ography J Nnuvl2J624-J-HS 1981

38 Fried Dian 01 Fonanu(e VN Sldun AA Tonie pupi ls ~ a r~l of botlJ lislJl Am JOpllalmoll09(Z)236-2)7 1990

39 Monaco S Freddi N Francavi lla pound ~t u Tralslem Ionic pupll~ In botulism type S I N~ro Sd IS696-98 1998

40 ManllJ RA 8akshl N Amtrlcan AwxiatJon 0 1 poundJectrodiagTIostlc Me-dlclne case report 16 botulism M~lt NtrW 231 137-1 44 2000

41 Tadel CO Shanden WK MannjM el 1J Equille antltoidn uw and o toe ractors that predict outcome in lypf A foodborrw borulhm Am I Mtd 7679 198 1 98~

12 World Heotlth Orgutilatlon 1M gloOltll eliminaoon of 5nlltllIpox fi ~t ftpJrta(thegloba lcommiJJlon f()( the certifica tion of smailflO tr~d(rQriM Geneva Switzerland World Health Organization 1980

43 Fenner F Henderson OA M ta et aI SmoJpox Ilm its eradICatorl Gel)~va Switzerland 196-8 Wor ld Hulth Organiza lion p 1460

4 Hendenon OA logle1by TV 8lrtlfit JG t t al SmallpolltU a blologUI weapon medical and public oealth mOUlagoment JAMA 2-8 1(22)2 127- 2 117 1999

45 Nob le) Smutpox 1(1 Gorbach S Banll J BlaUlow N ~ dllol5

nftrN0U5 dlJlaS~ PhUaltlflphla PA 1992 VB Saunders pp lll Z- I1i3

i6 Wold Heal th Organiulion Available al hlrp1 Wwhointelllcldscmiddotvsmailpoxilid e-setfpages~poxOI ~hun

Iccewlt ll 08OZ 47 Amtrican Collegf o f Physldlos-Amencan SocIety of Imtmal

MedlClnr BiotelJOtism Quick Facn aboUl Smotllpo)( Available at httpwwwacponUne orglbloterro~lOallpo)(_f8CUhfm last aCreMtd IIIOSOZ

48 OlUM 0 Etiology of b lindness in Nigerian chlldren Am I OpthalmQi 70(4)533-540 1970

49 C hlrambo MC ikneua 0 Causelt at tgtllndness among uud~ms In blind poundtoool lnsttlUtiom In a developing counny 8t JOphrJramol 6O66~68 1976

SO WOIOe-Gebric l Z Gebru H West Ci Causes of bllndnlSS In c1k1rm in the bUnd ~ch() I of Ethlopi~ Trap Gtogr MiJ 4413S-141 1992

51 DukemiddotElder S DieQSe1 of thf ourer err IlIlleraro-ltOlljuncrlvills London 1965 Henry Kingston pp 359-360

52 S-axena RC Gug KC Ramchand $ Ankyloblepharoo followin g ~fDaIlpo)( Am f Ophthalm() 6 1169-171 1966

53 SutcllHf J Ollln N A lIuttlry 0(medicine london 1992 Morgan Samutl Uillions p 40

54 tane jM Ruben fL NeffJM et I Compllcattons 0 mullpox vacctnatlon 1968 n~f1onal surveillance In the United Staes Npoundngf I Me 2SU201-1208 1969

S5 Ruben FL LaneIM Orular valtonla an eptdernkllogk analysis oj 348 ca l-tS Arc OpMhaImcl84 45-t8 1970

56 Je llf) 8R AlmiddotH~raquolni MK Therapeuuc com~ratoom In ocular v~laquotnla Trans Ophllial Soc UK 8361J63 1 1961

57 Litis pP WiFlOgrad 1) Ocu~ r valaquoirua spedhlt lIeatmelll Aft Oplllhal68 600-609 1962

58 Ryd~rg M Pandolfi M Tr~atment of ~acctnla keratitis with postmiddot vaccinial gamma globulin Ada Opllllu1141 71 3-718 1963

59 Ja Ck MK Soreruon lW Vaccinial keraOtillIn ted with IOU Alaquoh noOphlhalmoJ 69710-732 1961

60 Kaufmltl HE N~bl)fn AB Mlonty ED Cure 01 vaCCinia in feCTIon by smiddotlodo-2ooxyurldlne Virolog 1856 7- 569 1962

L Fulgin iti VA W1tJoOgrl1d lA jactson M I 1 Thflap y of CJltperlmt1l tal v(ci nl~1 kelaril l efleer of idoxur1dlnt a nd VIG AlCh Ophl almQl 74S39-$44 1965

62 Hyndiul ItA Okumolo M DamiAno RAt l al Trt atmem of vacrinial kem llraquo wilh viduabtne An-h OpIJUoalmltJl9( 136J--IlM 1976

61 DtnnIIDT In gltSby lV Hendmon VA el al 1ul ar~a as it biological weapon mWIcal m d public health management lAMA 285(2 1)2763--27732001

6 Oo JT Pmn RL Francisd la ru ll1rtruis (1U Il l emia) In Mandel GL BeM t ltJE Dolin R oollon Principles orld P(i(1ct oinfeaiow diflttiltj ed 5 Philadelphi a PA 2000 Ch urchJ lI Uv1ngslo n e pp 2393--2-402

6S h ans Mt Gregory DW ~haffn er W et al TU laremia a 30-ytar

txpt rienc~ 11h 88 rasa l_diel 60125 1- 269 1985 Amu ian Colleg~ of Physidampns-Amer1 can Soc fI) of Int em~1 Mlaquo1Icine 8lott n orlsrn Quid h CLS ~ bOII t TlJIMtmlii Avaiiable 1I h ttp wwwKpOTlinlorampfbiotcrro rulart miahrm I~ acceSfd I l fQSfQ2

6 D n1n rand S Ringcrtt 0 leltedlefg 6 Arboml IUl3 remiI in 5 Iln 5(anJ nKf Ds 3( 1)7-1 6 19 71

OS fI n c1 ~ t Oruloglandu l~ r tulampJlm1 a AlO OpIlrJoa lmol 287 1l 1942 69 Steln eml nn TL Sh~lkhalcilaml MR Brown HH el al Oculogla ndu b r

tuln eml bull Arch Ophrhalmol11 7 132-1 33 1999 Chin GN P-inaud oculaglilndula r conlunctl vitls In fuman W

Jaeger EA SchWilb fR edJtou Dulln~s rlinral ophtlullmology voL 4

PtuJadelph PA 1996 LipplncOttmiddotRwen Pilrulttt n 0 Rummublntn M Arule glaucoma and acute co rneal oedtma i n UOdalkln wirh tularem Ia AC1a OpllJmlmol Sum~

7S732-734 1997 n Marcus OM Fredtgtrkk AR II HodamptS 1 et al TyphOldigtllIla~mla

Arch 0pJ11haImol l08118-- 19 1990 73 Bono L inglesby T igtellors CI et aJ HemOl1 hagic fever virus aJ

biOlogica l wea pons medicl l and publiC h ealth mmag-ement fA MA

281( 81239 1-24052002 7lt jOM son E lnx N White J et al U lh al txpe rtroental infection~ 0(

rh e$U~ moflkly by aerosolized Ebltlb vj ru ~ 1m I up P~lhol76 227-236

199s 75 Jau Nllt Davu K] Gelsba 1J el at lelha l experimental infectiom o f

rhesus monkey with poundbola-Zaire (Maylnga) vinu by the oral and conjunCTIval rou te of eposure Arci1 P~lh(1 L~b M(~ 12014()1 55 1 9~6

76 Klbad K Mupapa K Kuvula K t l al La te ophthalmolagk mmifes~oons in mrviVOB of the I99S poundbola vlrw tpidemic in Ki lcwit [)emornuic Repub lic of the Co~ J In(ta Dis 179 (Stlppl 1)5 13-51-4 1999

n Kurn ln US KokoriJ N UilI iJw olvemenl in Muburg ~illJS dl~ Br I OphZhnlmo 6 1265_266 1971

78 Kont lwlen M luustj1rvt T Kluppi P Ocular chU~ClfrtStlCS In nephropathl l eplderuka or puumuJa viN~ Ittllaquotlon Aaa Ophthilimol 5(lIl1d 74621-625 1996 Komkanen MI PuUStjltlrvllJ LlhdevLtta JK IntTaocular pressure changes In neptuopathia epideuiC3 a prospective ~rudy of 37 patients wuh aevte systemic puumula vlTU$ infect ion OphthalmOlOgy 102181 3-1817 1995

80 Saa ri KM Acute glaucoma In h emorrhagic fevff ith renal s~ndlome (nephropalhia ~ pldemlC3) Am JOphwmol S (4)4~61 1976

8L Saari )(M iuolo S Oph thalroologlcal W lngs In nephropathia epidernia ln I3pl4nd A Cla Ophlhalmo6Z235-243 198lt1

8gt Pamlntn O Kwooer 1 Tonk pupWary runton alief epidlmic nephlopathy and rramlem myopla Am J0pIthalmol I0l(2)20I-202 1989

8l Llaquo tY Ch o SO Choi GB et ill lsoblelt abd ucens n erve pa~y IS a complia tion o f haemon hagic fever Wi lh renll syndrome Ntphrol DI TIansprmI1 321 13-21141 998 YOle SL Forster DJ Rao NA Systellll c viral Infections and their retinal ltld OlOloidal manlJestalions Surv OphlhQ lmo 37(S)313-352 1993

85 Al middotKaff AS OculilI bruceUosls Jnt OphlhQlmoI Clln 35(3)139-145 99S

86 Walke J Sharma Of Ra o NA BrureUo~ ls a nd uvei1~ Am IOphllullmo 114(3 )]14-]75 1992_

87 Thbbara kF Al-KaWmi H Orulat bruc eUo$b j t I Ophrhillmal i4(4) 249- lS0 1990

88 Woolth AC NUIJDub r )era liUs anO ocular brocellogtls Aidgt Ophlhalmol l 549(l 1946

89 G(ingor K Beki NA Namldwv M Re(I~n l episdetlds asoctal ld wlIh bruoelCKI Aaa OplltJwJmoI sca lld 19 76-78 2001

90 Putg Sollnes M Heatley J mnilS F el al Orolar com plicati ons In brulaquolIoill Am I Ophrhalmol 3667s-QS9 1953

9 Btki l NA GungJ K Si d lClal dacryoaderU lj woclated Wllh bru~Uosh A a OpirrJQmoJi Scnd 77(3)357-358 1999

92 al fa ran Mf BnK~lIa mfiUn$u ( ndogenogtn rndophltulmlUS OpIhalmologicn ZOl i l )19- ZZ 1990

93 Sle m GA Hodelgt liL Stock El Closlridilm perfiingmrcomeal uI~

Atdr OphlhmoI97( 4)66 1 ~3 1979 94 Nan gja V Hutchin SOn C Metolu llc endophthalmli$ OImtd bp

Clos tridium perfringllll 8 I Ophlhalmol 76( )252- 253 1992 95 Saart KM Vilppula A Lassus A et al Ocular Inflammation In fI~ten

dJsern after Salmonfl lQ t nl erirts Am J OplJtilaImo 9O(l)63-68 1980 96 Ya ng J Baltatti ~ S Fom~r CS PerIpheral ul cerarive leu titis 1I1tl

SQlmondla gastroen teri TI S Come 17(6)672-674 1998 97 Fusco 11 Magll A GUlcd P 5tc ll~ r ~ maculopalhy due 10 Sa lmotlila

trPi A C~~ rcpon OphllwmoIogica 192(3) 154---158 19S6 98 Senft SH Awad A Balh olomew L 5ltl lmontlo endophthalntl tU In w

in fanl with pre5umed rWnopalhy of prtmaruri ry Err(PI 1 ~ 1 90- 191

1993 99 ltahe~ AB A1 Rl Oo ldraquoD 11 al Su ture alNbses afie

pentU llng keJalo pluly Comta 12(6)489-92 1993 100 T~ng CY I-Iu PY Sh l rY f l aI Endo8ef1degU~ endophlhllmltl ~ dllf to

poundschtrich j~ coli case repon an d review CIlIl Inoct Dis 22(6)1107- 1103 1996

10 1 KeUnske M Polrer 11 Corneal ulrerittlQ n due 10 ShIgella fItJNrl I Pe~latr Ophthalmol STIbirmUS 17(1)-18-5 1 1980

102 Ron en S Rorenmuill Y R tI aI 1

103

10 5 T Wlinabf Y f l ill (A ca~ of psiU4OSb wi th uveiTIs ) k lI5hoShinkeigaku 29(1)1 22- 124 1989

06 Oarou gar 5 Joh n AC V~waJlngam M ~t OI L lwla lion of Clllamyd4 psittaci from a pa tleQt Wllh in rf tS fl tiai keratitis and uveltb m oc1u ed wi th Dlological and cardlovucul31 lesions 8T I Ophthalmol 62(10)709-7141978

107 Ruiz-MorenoIM Ch ololdJ l neovwuurila tkln In th e coulltolQ RulUl1 7(6)553-5SS 1997

lOS Schuil J RI(hardu~ JH ampatsma GS tf I Q feveru a posIjbl ~ caWt of b113tt ral opTic ncurins Bt I OpIhtllmol 69 (8)560-583 1985

109 CtmeB for 01 Con lTo l and IrfYenJio n C hmlkal Agent ~I aIId InlolnatiOn _ Available at hnpllwww_hrucgovAgentJ agentUstchema3p last updated 10092002

110 American CoUtge of Ph ysiciln smiddotAmeflcan Society of Inlf mal Medicine Biotenortlm Swnlllules from Annual Seuion 2002 Available al h ttpJlwwwar ponlneOlgJbiotenoM_sumlhllrtllSl ~cc=oo 11 05 02_

11) rrev~ntion and matment of In jury from ~hemical wrtne ~1loo Medical Letter 44 issue 112 1 1- J~n-ry 7 W(ll_

112 Kato T Hamanaka T OC1JI~r slgru and symptOJfl5 caused by ~ to ann ga5 Am I OphlNlimol 121(2)209-210 1996

113 Nohara M Segawil K tXulaf symptom~ due to organophosphorW p (sarin) polwnlng In Ma~lIlotO 811 Ophthdmltgtl801023 1996

114 Maclnt)le AG Chrlstopllt r GW _n~EJ(Un E Wfapon P du truction egtiIlIS Wilh COntaminaled cagtUaIUes ~ ht ill ih GUe facilities_ l AMA 283(Z)242- 2-I9 2000

l IS Solberg Y Akalay M 8e1kin M OcuIM In jury by m Wla4 JiI) SIn OplJha rmol4l(6)~6 1 -466 1997

116 Mauroen te AE Slthol~ RO The hUulpl1hology 01 oculat lesIoiu plOduced by sulfur and nltlogen mUifards Sull ohn Ht2pIiru Imp 82 ]21- )471 948_

117 Safarinejad MR Moosavi SA Momazerl S Ckular lnjuric-s call1ld by mu~tard gu diagno51~ n eauneot and medIcal defen~ MIl MttI 166(1)67-70 ZOOI

118 Sarael A Salmi R Kumar PV Co njuncrival dysplasia In loO ldltn eqgtosed to musta rd gas dwing th ~ Iraq-I ran war SCTape o~~ C)10145(6)909-9 13 2OO1

11 9 Pltye U Sherif Z SMtz H e l al De ll yed mU5lilfd gaJ UraloPfIhy d lnlcal bndlngs and confocal rn lCr()j(op y Am Ophlh rnol 128506-S07 1999_

IZO 8kKh FC Mustard gu keratopalh y Inl Ophdullmol Clln 2(3)1- 1l 197 1

IZI Aaned A Darr~ E Wulf He Mu~l~ rd sas d lnlcal mxlcologlaJ iIld mutagen icupeltU ba5ed o n modem experl(flce Ann Plan Surf 19330-333 19B7_ 1308

Page 14: txt:ernal Eye Manifestations of Chemical d Biological Warfare AND... · External Eye Manifestations of ClM!mkal and Biotogkal Warfare . ential diagnosis of cutaneous anth.ra-x also

60 Kaufmltl HE N~bl)fn AB Mlonty ED Cure 01 vaCCinia in feCTIon by smiddotlodo-2ooxyurldlne Virolog 1856 7- 569 1962

L Fulgin iti VA W1tJoOgrl1d lA jactson M I 1 Thflap y of CJltperlmt1l tal v(ci nl~1 kelaril l efleer of idoxur1dlnt a nd VIG AlCh Ophl almQl 74S39-$44 1965

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