Amy Gutman MDAmy.Gutman@uc.edu

Between a Rock & a Hard Place: Between a Rock & a Hard Place: A Review of the Neurological Aspects of A Review of the Neurological Aspects of

BioterrorismBioterrorism

Overview

• Epidemiology of Bioterrorism

• Neurological Agents of Bioterrorism & Their Mechanisms of Action

• Response to Bioterrorism– Prehospital – Emergency Department – In-Patient Care– Chronic Care

Thoughts to PonderThoughts to Ponder

• “The American military superiority presents a paradox; potential adversaries know they can’t win a conventional challenge to US forces, so they’re likely to try unconventional methods, such as biologic or chemical weapons.”

W. Cohen, Defense Secretary

Epidemiology of BioterrorismEpidemiology of Bioterrorism

40,000 Metric Ton Russian Chemical Stockpile40,000 Metric Ton Russian Chemical Stockpile (2005 United Nations Report )(2005 United Nations Report )

Consider The Bioterrorism Sources In Consider The Bioterrorism Sources In Hamilton CountyHamilton County

Likelihood of Agent Release

• Vapor / Aerosol Inhalation:– Potentially massive morbidity

& mortality– Immediately affects those in

close proximity – May have large affected area

due to weather conditions

• Liquid Release: – Rapid onset of symptoms

limits potential victims even in a large water source

– Either direct contact or via ingestion

Exposure vs Contamination*

*Credited to Dr Leonard Singer

• ACh released when impulse reaches presynaptic neuron– Ach travels in synaptic cleft to

postsynaptic membrane, binding a muscarinic or nicotinic receptor

– ACh receptor activated generating an action potential

– ACh detaches from receptor & degraded by AChE regenerating the receptor

• Neurotoxins inhibit ACh:– Bind to the active site rendering

it incapable of deactivating ACh

• Undegraded ACh continues to interact with receptors, resulting in persistent & uncontrolled stimulation until fatigued

– Same principle as neuromuscular blocker succinylcholine

Neurotoxin Mechanisms of ActionNeurotoxin Mechanisms of Action

PathophysiologyPathophysiology• Irreversibly inactivate AChE causing toxic accumulation of ACh at

muscarinic, nicotinic, & CNS synapses

• Muscarinic: Miosis, bronchoconstriction, N/V/D, bradycardia, glandular hypersecretion, urinary & fecal

incontinence

• Nicotinic Skin: Sweating

• Nicotinic Muscle: Defasciculation then weakness & flaccid paralysis

• CNS Cholinergic: Irritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures, coma, & respiratory depression

• CNS Delayed: behavioral changes (anxiety, emotional lability), ataxia, insomnia, nightmares, depression, difficulty concentrating, slow recall, confusion, slurred speech

• Adrenal Medulla: Tachycardia & HTN

• GABA & NMDA: Neurotransmission antagonized mediating seizures & CNS neuropathology

Nerve Agent Pharmacologic EffectsNerve Agent Pharmacologic Effects“DUMBELS” or “M T W Th F”*“DUMBELS” or “M T W Th F”*

• Diarrhea• Urination• Miosis• Bronchorrhea / Bronchoconstriction• Emesis• Lacrimation• Salivation

• Alternative is “Days of The Week” – Mydriasis– Tachycardia– Weakness– Hypertension– Fasciculations

*Common mnemonic "SLUDGE" does not include bronchorrhea or bronchoconstriction

Bioterrorism Agents*• Alphaviruses (viral encephalitis)

• Arenaviruses (Lassa, Machupo)

• Bacillus anthracis (anthrax)

• Clostridium botulinum (botulism)

• Clostridium perfringens• Brucella species• Burkholderia mallei (glanders) • Burkholderia mallei (meliodosis)

• Chlamydia psittaci (psittacosis)

• Coxiella burnetii (Q fever)

• Escherichia coli 0157:H7• Filoviruses (Ebola, Marburg)

• G Agents (Sarin, Soman)

• Francisella tularensis (tularemia)• Hantavirus

• Hydrogen Cyanide• Nipah virus (encephalitis)

• Organophosphates• Ricin toxin• Rickettsia prowazekii (typhus)

• Salmonella species (salmonellosis)

• Salmonella Typhi (typhoid fever)

• Shigella (shigellosis)

• Smallpox (variola major)

• Staphylococcal enterotoxin B• V Agents (VX)

• Variola major (smallpox)

• Vibrio cholerae (cholera)

• Yersinia pestis (plague)

*Chemical Weapons Convention of 1997 banned production, stockpiling & use of chemical weapons, & provides for the monitoring of their destruction

V Agents: VX

• Developed by England in 1952– Information traded with US for nuclear weapons technology

• Oily, odorless, amber liquid which does not readily evaporate – Must be aerosolized into tiny droplets

• Degrated products persist on the ground for 2 - 6 days– Continue to have neurotoxic effects

• Enters body via skin or inhaled as a vapor

• V agents ~10X more poisonous than GB (sarin)

G “G “Deutsche Grun DreiDeutsche Grun Drei” Agents” Agents

Agent Base Physical

Property

Odor Color Hazard Degrade

GA

Tabun

Cyanide Oily Fruity Colorless Direct Contact <

Inhalation

1-2 Days

GB

Sarin

Fluorine Watery Odorless Colorless Inhalation

>

Direct Contact

1 Day to stable,

non-toxic product

GD

Soban

Fluorine Watery Fruity or

Camphor

Colorless Inhalation

>

Direct Contact

¼ the rate of water

Other

1st V agent; discovered by Nazis

Released onIranians,Kurds & Japanese

1967 YomKippur War

Botulism:Botulism: Clostridium botulinumClostridium botulinum

• Paralytic illness caused by an anaerobic, gram positive, spore-forming rod

• Lethal dose: one microgram is lethal to humans

• ~110 cases in US annually– 72% are infant botulism– 3% are wound botulism– 25% are food born outbreaks due to home-canning

• The heat-labile toxin blocks ACh release at nerve synapses

Symptoms & DiagnosisSymptoms & Diagnosis

• Symptoms at 12-48 hours: – Dry mouth, double &/or blurred vision, difficulty swallowing, muscle

weakness, ptosis, SOB, slurred speech, vomiting, incontinence, diarrhea then constipation (paralytic ileus)

– Death secondary to respiratory failure (8% case fatality rate)– Long-term effects include: fatigue & SOB (decades)

• DDX:– Guillain-Barré syndrome– CVA– Masthenia gravis

• Diagnostic Testing:– CT, MRI– LP with CSF analysis – EMG– Edrophonium Chloride (Tensilon) – Toxin identification via ELISA or tissue culture in serum, blood, GI

contents, vomit or feces

Botulinum SymptomsBotulinum Symptoms 40 x 10-12g/mL of type A botulinum toxin in serum

• Patient at rest

• Bilateral mild ptosis, mydriasis, disconjugate gaze, & symmetric facial muscles

• Patient smiling

• Absent periorbital smile creases, ptosis, mydriasis, disconjugate gaze, & asymmetric smile

Botulism EvaluationBotulism Evaluation

Botulism TreatmentBotulism Treatment• Supportive, including mechanical

ventilation

• If detected early, passive immunity can be induced via a horse-serum derived antitoxin

• Botulinum Antitoxins: – Trivalent (A,B,E) derived from equine

sources utilizing Fab & Fc antibodies

– Heptavalent (A,B,C,D,E,F,G) derived from "despeciated" equine IgG antibodies which have had the Fc portion cleaved off leaving the F(ab') portions

Anthrax: Anthrax: Bacillus anthracisBacillus anthracis

• Long-lived endospore (centuries) that when inhaled, ingested, or in direct contact with skin reactivates & rapidly multiplies

• Can be grown in vitro

• Does not spread directly from one infected animal or person to another, but spores can be transported by clothing, shoes, or a dead body

• Pasteur developed the first effective vaccine for anthrax in 1881, followed by a century of animal vaccination programs, sterilization of raw animal waste materials & world-wide anthrax eradication programs– 5 US confirmed fatalities in 2006

• Fact: Thought to be the 6th Biblical Plague (shkhin ש��ח�ין) or “boils”

Bacillus AnthracisBacillus Anthracis• Rod-shaped bacterium 1 by 9 um in size,

discovered by R. Koch in 1877, currently with 89 strains

• Once ingested, absorbed or inhaled the bacterium begins multiplying, killing the animal within days to months via an exo-toxin

• Most anthrax bacteria inside the body are destroyed by “normal” anaerobic bacteria The greater danger lies in the bodily fluids that spill from the body into the soil where the anthrax bacteria turn into a dormant protective spore form

• The virulence of a strain of anthrax primarily dependant upon the poly-D-glutamic acid capsule that protects the bacterium from phagocytosis by host neutrophils & its toxins: “edema” toxin & “lethal” toxin

Anthrax TypesAnthrax Types• Pneumonic / “Woolsorter’s Disease”

– Presents with cold or flu-like symptoms for several days, followed by severe & often fatal respiratory collapse (mortality is near 100%)

– This mode of infection is used as a bioweapon

• Gastroenteric / Foodborn– Hematemesis, gastrointestinal difficulty, severe diarrhea, acute GIT

inflammation & anorexia – Spreads through the bloodstream with a fatality rate of 25% to

60%

• Cutaneous– Boil-like skin lesion that eventually forms an ulcer with a large,

painless central eschar – If untreated, 20% of all cutaneous skin infection cases progress to

toxemia & death– 5% fatality rate with treatment

Anthrax: Widened Mediastinum

Anthrax Treatment & PreventionAnthrax Treatment & Prevention

• Direct person-to-person spread unlikely, but patient’s clothing & body may be contaminated with anthrax spores

• Effective decontamination with simple soap & water– Waste water should be treated with bleach – Boil contaminated articles with disinfectants, chlorine or

simply burn in a contained area

• Early antibiotic treatment of anthrax essential with fluoroquinolones (cipro), doxycycline, erythromycin, vancomycin or penicillin

• Anyone working with anthrax in a suspected or confirmed victim should wear a HEPA or P100 filter mask

Treatment & PreventionTreatment & Prevention• If death occurs from anthrax the body should be quarantined

– Burial does not kill anthrax spores

• The most effective form of prevention is vaccination against infection but this must be done well in advance of exposure to the bacillus, and does not protect indefinitely

• Components of black tea, such as polyphenols, have the ability to inhibit the activity of anthrax considerably– The addition of whole milk to a standard cup of tea completely

inhibits its antibacterial activity against anthrax

BioThraxBioThrax• FDA-licensed vaccine,

produced from a non-virulent strain of the bacterium, is called “BioThrax” or “Anthrax Vaccine Adsorbed” (AVA)

• Administered in a six-dose series at 0,2,4 weeks & 6,12,18 months

• Annual boosters required to maintain immunity

– Painful, & causes significant swelling

• Soviets developed a live spore vaccine, known as STI, whose serious side effects restrict use to healthy adults

Anthrax Hemorrhagic Meningitis

Outbreak FeaturesOutbreak Features

• Rapid increase in incidence of a rare disease– Or endemic disease rapidly & uncharacteristically emerging

• Rapid increase in those seeking care for URI / GI illnesses– Systemic symptoms delayed >18 hours if limited dermal exposure– Single location (building, city, stadium)

• Large number of rapidly fatal cases– Respiratory Exposure: death in <15 minutes– Skin bbsorption: death in 1 to 2 minutes

• Uncommon illness with bioterrorism potential– “Sentinel Patients”, i.e. inhalational anthrax

HPIHPI

• Often the first history is the only history available if patients rapidly decompensate

• History of exposure to a nerve agent may be absent

• Always suspect the diagnosis when multiple patients present with symptoms of cholinergic excess

• Occupational history can aid in making the diagnosis in cases of accidental releases – Farmers, military personnel, chemical demilitarization

laborers, & laboratory workers

Physical Exam & DDXPhysical Exam & DDX

• Clinical signs and symptoms related to unopposed stimulation at cholinergic, GABA & NMDA receptors as discussed previously

• Diagnosis is easier in the severely symptomatic patient

• Pathognomonic: – Miosis, copious secretions, & generalized muscular fasciculations in

a gasping, cyanotic, seizing patient

• DDX:– Epilepsy– Gastroenteritis – Upper Respiratory Infection– Heat-Related Illness– Stroke / Head Trauma– Drug overdose

Laboratory Studies: Laboratory Studies: RBC Cholinesterase LevelsRBC Cholinesterase Levels

• Labs do not aid in acute treatment; treat on clinical suspicion– Never withhold treatment while awaiting results

• RBC & plasma cholinesterase (“pseudocholinesterase”) activity can be assayed in blood– Tissue cholinesterase activity cannot be directly measured

• RBC cholinesterase is a sensitive indicator of nerve agent toxicity– Clinical symptoms correlate with 20-25% reduction enzyme activity

• Rising enzyme levels indicate no further absorption occurring– RBC cholinesterase replaced fully every 120 days

• ABG: Decreased PaO2, increased PCO2

• Lactate & CPK: Elevated in seizures (hypoxia, fasciculations)

• Electrolytes: Hypokalemia (G series agents)

• Special Tests: M256A1 or CAM assay, M8, M9 papers

• ECG: Bradycardia, AV blocks (muscarinic) Tachycardia, PVC, VT, VF, (hypoxia)PR interval & QT prolongation, torsades

• EEG: Monitoring for paralyzed patients Nicotinic effects of agents masks seizures

Other StudiesOther Studies

EEG FindingsEEG Findings

• Greater-than-normal variations in potential

• Increased frequency with increased beta waves

• Irregularities in rhythm & intermittent appearance of abnormal high-voltage, slow waves most prominent in the frontal leads

• EEG abnormalities often decreased or reversed by atropine      – EEG abnormalities of a subject poisoned with sarin showed slow

activity with bursts of high-voltage, 5-Hz waves in temporo-frontal leads for 8 days on continuous atropine & benzodiazepine infusion

Imaging: CXR

• Any respiratory distress, dyspnea, or post intubation to evaluate for non-cardiogenic pulmonary edema

ARDS Post Neurotoxin Inhalation

Initial ManagementInitial Management• Goals: rapid termination of exposure, treating life-threatening

emergencies, & administration of antidotes– Safety of patients, EMS, rescuers & hospital workers depends on

early exposure recognition to avoid creating more victims

• Highest level of PPE required:– Fully encapsulated, chemical-resistant, vapor-protective suit via SCBA &

full face shielding, & butyl rubber gloves

• ABCs– Supplemental O2, oximetry & cardiac monitoring, IV access – Early intubation & ventilatory support if severe toxicity – Respiratory failure is leading cause of death

• Medications – Mark I auto-injectors (atropine, pralidoxime chloride 2PAM)

Effective Decontamination

• In a “normal” MCI, priorities are: stabilize patient then decontaminate; In a neurotoxin release priorities are: decontaminate then stabilize patients

• Goal is to prevent further absorption of nerve agents & prevent the spread of nerve agents to others

• Remove all clothing & jewelry

• Cleanse eyes, mucus membranes, wounds & entire skin surface skin with soap & water or 0.5% hypochloride (1:9 ratio of bleach:water) – Breaks neurotoxin ionic bonds

• Clothing & used solution are “contaminated” evidence– Requires double bagging & disposal in a closed container

Basic Decontamination Plan

Shower&

Rinse

HoldingArea

CleanClothing

DryingArea

Cut &

Strip

Hospital Decontamination Hospital Decontamination

• Although prior to EMS transport from a scene, patients undergo initial decontamination, hospital staff must be trained in self-protection, triage, treatment, & decontamination

• In an MCI, patients often self-transport without EMS treatment

• In the Tokyo subway sarin attack, 85% of patients arrived via private car

• This emphasizes the importance of hospital decontamination facilities & training as many victims likely to require initial triage & decontamination at the ED

ED & Hospital Treatment: ABCsED & Hospital Treatment: ABCs

• All personnel must wear PPE until adequate decontamination is assured or the need for decontamination is eliminated

• Any symptomatic patient: O2, pulse ox, cardiac monitor, & IV

• Early ETI & ventilatory support is paramount if severe toxicity– Avoid succinylcholine: metabolized by plasma cholinesterase

leading to markedly prolonged paralysis– Suction is an important adjunct, as secretions may be profuse

• Early consultation with neurology, toxicology, internal medicine, psychiatry, surgery & critical care is essential

• In an MCI, activate the hospital emergency plan (DisasterNet)– DisasterNet automatically starts EOC notifications

• Regional poison center (1-800-222-1222)

• Rapid delivery of critical medical assets to the site of an emergency

• Coordinates agencies in the event of a terrorist attack or natural disaster

• SNS anaged by the CDC as a national repository of:– Antibiotics, antidotes,

antitoxins, life-support meds, IV / airway supplies, & other med-surg items

• “12-hour Push Package” arrives <12 hours after the federal decision to deploy– 2nd phase arrives 24–36 hrs

NIMS, EOP, SNS Federal, State & Local ResponsesNIMS, EOP, SNS Federal, State & Local Responses

• Detailed health histories must be obtained as many patients & families may not be aware of initial exposure

• The key to recognizing neurotoxin exposure is the appearance of multiple patients with similar signs and symptoms

• The route of exposure & the dose of the nerve agent determine the onset & severity of signs & symptoms– Inhaled agents produce a rapid onset of symptoms, potentially

misinterpreted as a URI or allergy symptoms – Patients with only ocular findings following vapor exposure can be

discharged home safely with rapid opthmology referral

• Admit patients with suspected liquid exposures for observation after decontamination– Onset of symptoms may be delayed 18 hours

Initial Patient CareInitial Patient Care

Treatment if Completely Treatment if Completely AsymptomaticAsymptomatic

• For those patients that may have been exposed but are not exhibiting any symptoms

• This may include malingerers or opportunists– Legally prudent to observe

• Reassurance of the rarity of significant health effects

• Place under medical observation in a floor bed:• Vapors: 1 hour• Liquids: 18-24 hours

Inpatient CareInpatient Care

• Patients in respiratory distress may need ventilatory assistance despite aggressive antidotal therapy

• If critically ill with complications such as anoxic brain injury (prolonged seizures or respiratory arrest) may require prolonged intensive care

• Follow RBC cholinesterase and electrolyte levels

• Acute management of & secondary medical or surgical emergencies– Cardiac Arrests– COPD Exacerbations– Blast Injuries

Chronic Neurological & Neuropsychological Effects

• May persist for months if severe cholinergic effects– If discharged without complications or a significant exposure from

the hospital generally no further acute care required

• Subtle behavioral & cognitive changes may persist for weeks

• Permanent neurological sequelae if anoxic brain injury present

• Educate patients on potential long-term complications (>3 years), including:

– Behavioral & cognitive changes difficult to distinguish from PTSD– Impaired memory, difficulty concentrating, anxiety, irritability, depression– Symmetric sensorimotor peripheral neuropathy– Night-time miosis– Postural imbalance – Fatigue– Nausea – Joint stiffness

Medical Errors - InitialMedical Errors - Initial

• Failure of EMS to secure scene, turning themselves into victims

• Failure to decontaminate victims of liquid nerve agent exposure leads to contamination of rescuers & hospital personnel

• Failure to recognize symptoms of cholinergic excess as being caused by nerve agent toxicity leading to delays in care

• Failure to recognize succinylcholine causes prolonged paralysis

• Disposing of evidence collected during triage or treatment

• Poor documentation leading to confusion at hospital

Medical Errors - DelayedMedical Errors - Delayed

• Failure to recognize symptoms of cholinergic excess may not appear for 18 hours in low-level exposures

• Solely using presence or absence of miosis to guide atropine therapy

• Over-reliance on pseudocholinesterase levels to guide treatment

• Failure to suspect occult seizures in paralyzed patients & order EEG to prevent hypoxic brain injury

AntidotesAntidotes

Atropine Pralidoxime Chloride (2 PAM)

Antidotes

• Even with rapid administration respiratory failure may occur due to bronchoconstriction, increased airway secretions, & increased airway resistance– Prepare to provide intubation & mechanical ventilation

• Supplemental oxygen, suctioning, & careful monitoring of vital signs, electrolyte levels, & cardiac rhythm are essential

• Symptoms often improve after antidote administration, though the duration of the symptoms depends on the route & degree of exposure to the nerve agent

Antidotes Two-Tiered Antidotes Two-Tiered Mechanisms of ActionMechanisms of Action

• Atropine (Anticholinergic):– Counteracts muscarinic effects resulting from excess ACh in the

absence of functional AChE– Dries respiratory secretions; does not relieve diaphragm paralysis– Continue dosing until symptoms improve (“atropinization”) – Adverse effects include: flushing, warmth, tachycardia, urinary

hesitancy, blurred vision, & drowsiness

• 2-PAM (Oxime / Cholinesterase Reactivator)– Removes organophosphate from AChE which then deactivates ACh– Restores normal skeletal muscle function (including diaphragm) – Adverse effects include malignant HTN, tachycardia, diplopia, N/V &

dizziness

Mark I Auto-InjectorsMark I Auto-Injectors

• 2mg atropine auto-injector contains glycerin, phenol, citrate buffer, & water

• 600mg 2-PAM auto-injector contains benzyl alcohol, glycine, & water

• Do not administer to patient with hypersensitivity to any component solution

Pyridostigmine Pyridostigmine (Mestinon, Regonol)(Mestinon, Regonol) ChemoprophylaxisChemoprophylaxis

• Temporarily binds to AChE theoretically blocking binding of nerve agents to AChE

• Effective: GA, GD, GF• Ineffective: GB, VX

• Orally available cholinesterase inhibitor

• Only effective in preventing peripheral effects – Ionized form does not pass into CNS

• 50% of the Gulf War military taking chemoprophylaxis experienced flatus, diarrhea, & abdominal cramping

• 5-30% had urinary frequency & urgency, headaches, rhinorrhea, diaphoresis, & / or paresthesias

Common Treatment Problems

• Not adding benzodiazepine as adjuncts to antidote treatment:– Necessary for seizure prophylaxis & / or control– Treat manifestations from fasciculation to paralysis

• Underdosage– Administering too little antidote to relieve symptoms– Failing to administer atropine when needed (late

recognition)

• Overdosage– Administering antidote to un-exposed patients

Management Steps US Army, Biologic Casualties Handbook, 2001

1. Maintain an index of suspicion

2. Protect thyself

3. Assess the patient

4. Decontaminate as appropriate

5. Establish a diagnosis

6. Render prompt therapy

7. Practice good infection control

8. Alert the proper authorities

9. Assist in the epidemiologic investigation

10. Maintain proficiency & spread the gospel

SummarySummary

• Recognizing the various presentations of neurotoxin bioterrorism

• Review of the mechanism of action of organophosphates and antidotes

• Evaluation of prehospital, emergency, and in-patient patient management of the patient with neurotoxicity

References

• BioChem 1st Responder ER• National Incident Management System (NIMS)• www.CNSForum.com• Ohio Emergency Operations Committee (OEOC)• Ohio Emergency Response Plan (OERC)• Ohio Outbreak Response & Bioterrorism Team (ORBIT)• Kentucky Emergency Response Plan (KERP)• DHS Chemical Stockpile Emergency Preparedness Program (CSEPP) • Centers for Disease Control (CDC) • Center for Infections Disease Research & Policy Bioterrorism Prepardness• Institutes of Medicine Committee on R&D Needs for Improving Civilian Medical

Response to Chemical & Biological Terrorism Incidents• Food and Drug Administration (FDA)• NC Statewide Program for Infection Control & Epidemiology Bioterrorism Agents • UAB at Birmingham Bioterrorism & Emerging Infections Education• www.cbwinfo.com