Meningitis, Encephalitis & Rabies

Overview

• Meningitis– The most board relevant topic

• Encephalitis

• A few brief words about Rabies

Definitions

• Meningitis is an inflammation of the membranes that cover the brain and spinal cord.

• Encephalitis is an inflammation of the brain

Meningitis

• Typical pathogens depend on the age of the host and the presence of comorbidities

• Impaired cellular immunity (HIV, steroid use, transplant, cytotoxic chemotherapy) increases risk of Listeria monocytogenes

• Impaired humoral immunity (splenectomy, hypogammaglobulinemia, multiple myeloma) increase risk of S. pneumoniae

• Differential diagnosis of acute meningitis includes infectious and noninfectious causes

Differential Diagnosis of Infectious Causes of Acute Meningitis

VirusesNonpolio enterovirusesArbovirusesHerpesviruses (HSV, VZV, CMV,

EBV and HHV-6)Lymphocytic choriomeningitis virusHIVAdenovirusParainfluenza virus type 3Influenza virusMeasles virus

RickettsiaeRickettsia rickettsiiRickettsia conoriiRickettsia prowazekiiRickettsia typhiOrientia tsutsugamushiEhrlichia and Anaplasma spp.

BacteriaHaemophilus influenzaeNeisseria meningitidisStreptococcus pneumoniaeListeria monocytogenesEscherichia coliStreptococcus agalactiaePropionibacterium acnesStaphylococcus aureusStaphylococcus epidermidis

Bacteria continuedCoxiella burnetiiMycoplasma pneumoniaeEnterococcus spp.Klebsiella pneumoniaePseudomonas aeruginosaSalmonellaAcinetobacterViridans streptococciFusobacterium necrophorumStenotrophomonas maltophiliaStreptococcus pyogenesPasteurella multocidaBacillus anthracisCapnocytophaga canimorsusNocardia spp.Mycobacterium tuberculosis

SpirochetesTreponema pallidumBorrelia burgdorferiLeptospira

Protozoa and helminths

Naegleria fowleriAngiostrongylus cantonensisBaylisascaris procynonisStrongyloides stercoralis

Expanded from PPID 7th ed.

Noninfectious Etiologies of Acute Meningitis

Other infectious syndromes

Parameningeal foci of infection

Infective endocarditis

Viral postinfectious syndromes

Postvaccination (mumps, measles, polio, pertussis,

rabies, vaccinia)

Noninfectious etiologies and diseases of unknown etiology

Intracranial tumors and cysts

Craniopharyngioma

Dermoid/epidermoid cyst

Teratoma

Systemic illness

Systemic lupus erythematosus

Vogt-Koyanagi-Harada syndrome

Procedure-related

Postneurosurgery

Spinal anesthesia

Intrathecal injections

Chymopapain injection

Medications

AntimicrobialsTrimethoprimSulfamethoxazoleCiprofloxacinPenicillinIsoniazidMetronidazoleCephalosporinsPyrazinamide

NSAIDsMuromonab-CD3 (OKT3)AzathioprineCytosine arabinoside (high dose)CarbamazepineImmune globulinRanitidinePhenazopyridine

Miscellaneous

SeizuresMigraine or migraine-like syndromesMollaret’s meningitis

PPID 7th ed

Acute Bacterial Meningitis

PPID 7th edition

Clinical Presentation

• Headache (>90%)• Fever (>90%)• Meningismus (>85%)• Altered sensorium (>80%)• Vomiting (35%)• Seizures (30%)• Focal neurologic findings (10-20%)• Papilledema (<5%)

PPID 7th ed Chapter 84

ABM can be excluded in a patient with none of these symptoms

JAMA 282 (2): 175-181, 1999

Clinical Presentation

• Kernig’s sign and Brudzinski’s sign both classically described but poor diagnostic sensitivity

JAMA 282 (2): 175-181, 1999

Pop Quiz

• Which physical exam maneuver has the highest sensitivity for meningitis?

Jolt Accentuation of Headache

• Asking the patient to move their head side to side at a rate of 2-3x/min

• Sensitivity of 97% and Specificity of 60%

• Very High negative predictive value

Uchihara, T. Headache. 1991

Clinical Presentation

• N. meningitidis is present in 73% of patients with ABM who have a rash (petechial)

• Differential diagnosis includes RMSF, echovirus type 9, S. pneumoniae, H. influenzae, Acinetobacter and Staphylococcus aureus meningitis with sepsis

Diagnosis & Treatment

Who needs a head CT prior to lumbar puncture?

Characteristics of Cerebrospinal Fluid Analysis in Meningitis

Normal CSF Bloody Tap Viral Meningitis Bacterial meningitis

Opening pressure (cm H2O) 5-20 Normal Normal to mildly elevated >18

WBC count (cells/mm3) <10 monocytes WBC:RBC 1:700 10-1000 lymphocyte 1000-5000 PMN

< 1 PMN predominance predominance

RBC count (cells/mm3) < 2 WBC:RBC 1:700 Normal Normal

Protein (mg/dl) <45 15-45 Normal 100-500

Glucose (mg/dl) >50% serum levels Normal Normal <40

Modified from Bartlett JG, Pocket book of infectious disease therapy, 10 th ed, Baltimore, 1999

10% of ABM presents with lymphocyte predominance

Up to 50% of West Nile virus patients have neutrophil predominance

CSF Gram staining

• Sensitivity correlates with bacterial load– 25% of pts with < 103 CFUs/ml have + gs– 97% of pts with > 105 CFUs/ml have + gs

• Sensitivity also correlates with pathogen– S. pneumoniae 90%– H. flu 86%– N. meningitidis 75%– GNR 50%– Listeria 30%

PPID 7th ed. Ch 84

Gram positive lancet-shaped diplococci of Streptococcus pneumoniae

Listeria monocytogenes Infections. Cerebrospinal fluid shows characteristic gram-positive rods (Gram stain). Listeriosis is much more common among patients with human immunodeficiency virus infection or acquired immunodeficiency syndrome compared with the general population.

Neisseria meningitidis: Gram negative diplococci on CSF Gram stain

CSF culture

• Positive in 70-85% of patients who have not received prior antimicrobial therapy

• Cultures may take up to 48 hrs for identification

Steroids in Adults with Bacterial Meningitis

• Routine use of dexamethasone is warranted in most adults with suspected pneumococcal meningitis

• If the meningitis is found not to be caused by S. pneumoniae, dexamethasone should be discontinued

• Should be given before or with first dose of abx• If the strain is highly resistant to PCN or

cephalosporins “careful observation and follow-up are critical”

MKSAP 14 Item 16 Gram Positive Diplococci

MKSAP 14 Item 14

Viral Meningitis/EncephalitisNonpolio enteroviruses

EchovirusesCoxsackievirusesEnterovirus-71

HerpesvirusesHSV, VZV, CMV,

EBV and HHV-6Lymphocytic choriomeningitis virusMumps virusHIVAdenovirusParainfluenza virus type 3Influenza virusMeasles virus

Arboviruses

Mosquito-borneCaliforniaSt. LouisEastern equineWestern equineVenezuelan equineWest Nile virus

Tick-borneColorado tick feverPowassan

Enteroviruses

• Leading recognizable cause of aseptic meningitis

• 30,000 – 75,000 U.S. meningitis cases/yr• Marked summer/fall seasonality in temperate

climates• Periods of warm weather and wearing sparse

clothing facilitate fecal-oral spread• PCR on CSF and supportive therapy• Newly described Enterovirus-71 can cause

anterior myelitis

Arboviruses

• California (La Crosse)

• St. Louis

• Eastern Equine -- 50-70% mortality

• Western Equine

• Venezuelan Equine

• West Nile

• Colorado tick fever

West Nile Neuroinvasive Disease

• WNV is now the most common cause of epidemic viral encephalitis in U.S.

• WNV infection– Asymptomatic 80%– West Nile Fever 20%– Neuroinvasive disease <1%

• Meningitis 40%• Encephalitis 60%• Acute flaccid paralysis/poliomyelitis

– 5-10% of all patients with neuroinvasive disease– 4 cases/100,000 population during a WNV epidemic

Ann Neurol 2006; 60:286-300

www.cdc.gov

www.cdc.gov

West Nile Virus Screening of Blood Donations and Transfusion-Associated Transmission --- United

States, 2003

• In 2002, transfusion-associated transmission of WNV recognized

• In June 2003, nucleic acid amplification tests (NATs) for WNV applied to screen all blood donations

• 6 million units screened– 818 positive viremia– 6 cases negative screen by NAT that transmitted

WNV

MMWR April 9, 2004 / 53(13);281-2

Distinguishing WNV, Enterovirus-71, Poliomyelitis and Guillain-Barre Syndrome

Coastal marshes

June, July, August

Age <10, >55 yrs

Unique clinical features CSF WBC >1000

Mortality 50-70%

Sequelae 80% (esp children <10yrs)

West, midwest

Infants and adults >50 years old

5-15% mortality

Sequelae: moderate in infants and low in others

Mostly LaCrosse Virus

Woodlands; June-September

Children <20

Unique clinical feature: seizures

Mortality <1%

Sequelae rare <2%

US, Canada, Caribbean (urban and rural)

June, July, August

Unique clinical feature: dysuria

Mortality 2 – 20%

Sequelae 25%

HSV meningitis

• Can be complication of primary genital infection (more common with HSV-2)– 36% of women and 13% of women with primary genital HSV-2

infection had stiff neck, headache and photophobia– Hospitalization was required in 6.4% of women and 1.6% of men

for aseptic meningitis in association with primary HSV-2 infections

• Meningeal symptoms start 3-12 days after onset of genital lesions

• Use of antiviral therapy early for genital lesions decreases subsequent development of aseptic meningitis

• Association with recurrent aseptic meningitis

HSV Encephalitis

• Biphasic age distribution

• Temporal lobe disease

• Focal neurologic findings

• Diagnosis CSF PCR (culture) and MRI

• Therapy IV Acyclovir

• Outcome– Mortality 15%– Morbidity 50%

MKSAP 14 Item 120

Diseases which mimic HSE

• St. Louis encephalitis• Western equine encephalitis• California encephalitis• Eastern equine encephalitis• EBV• CMV• Echovirus• PML• SSPE

West Nile Encephalitis does not appear to mimic Herpes Simplex Encephalitis

HHV-6

• Infects nearly all humans by age 2 years• Exanthem subitum (roseola, Sixth dz)• Immunocompromised hosts

– Reactivation in 1/3 of solid organ transplant pts and 1/2 of BMT pts by 4 weeks posttransplant

– GVHD, delayed bone marrow engraftment, encephalitis, hepatitis, interstitial pneumonitis

– Epiphenomen of immunocompromise?– Promotes CMV or other pathogens?– Quantitative PCR needed on CSF to invoke as etiologic

agent of meningitis/encephalitis

Eosinophilic Meningitis

Nematodes• Angiostrongylus

cantonensis • Gnathostoma

spinigerum• Baylisascaris

procyonis• Toxocara canis

Cestodes• Taenia solium

Trematodes• Paragonimus

westermani• Schistosomiasis• Fascioliasis

Eosinophilic Meningitis

Nonparasitic• Coccidiomycosis• Cryptococcosis• Myiasis

Noninfectious• Idiopathic

hypereosinophilic syndrome

• Leukemia/lymphoma• Cipro/Bactrim• Intraventricular

gentamicin/vanc• NSAIDS• Myelography contrast

Angiostrongylus cantonensis

• Adults reside in pulmonary arteries of rats

• Eggs hatch in the lungs, the larvae are swallowed, expelled in feces and seek an appropriate molluscan intermediate host

• Develops into infective larvae in:– Slugs, land snails– Freshwater prawns,

land and coconut crabs, frogs

Angiostrongylus cantonensis

• Epidemics and sporadic infections reported in– South Pacific– Southeast Asia– Tawain– Jamaica, Cuba, Egypt

• Recognized sources of human infection– Raw or undercooked snails, prawns, crabs– Contamination of leafy vegetables by larvae

deposited by slugs or snails– Caesar salad recognized in one epidemic

Angiostrongylus infection

• Disease self-limited• Rare fatal cases (massive inoculum)• Incubation period 1-6 days after ingestion

of infected snails• HA, stiff neck, fever, rash, pruritus,

abdominal pain, nausea, vomiting• Paresthesias – chest wall, face, limbs• Cranial nerve palsies (fourth and sixth

most common)

Angiostrongylus treatment

• Supportive care

• Killing larvae in and around the brain may be detrimental

• Repeated lumbar punctures helpful in treating headaches

• Recovery usually complete by 2 months

• Corticosteroids decrease duration of headaches CID 2000; 31: 660-2

Baylisascaris procyonis

• Ascarid of raccoons• Visceral larval migrans in humans• Severe and commonly fatal eosinophilic

meningoencephalitis occurs in more than half the cases

• Eye involvement is common• Diagnosed by detecting larvae in tissue• Experimental serology• Albendazole and steroids are commonly tried

Bayliscariasis

• Severity of disease– Number of eggs ingested– Extent/location of larval migration– Severity of ensuing inflammation and necrosis

Treatment

• Laser photocoagulation in ocular dz• No cure for clinical disease• Albendazole and dexamethasone used with

good CNS and ocular penetration• Prophylaxis with albendazole on days 1-10 or

days 3-10 after exposure offers 95-100% protection

• No children receiving albendazole after eating raccoon feces have developed baylisascariasis

CID 2004: 39 (15 November)

Rabies

• Highest case fatality rate of any infectious disease

• Let me say it again…

• 2-3 cases annually in USA

• Recent death in a returned OEF soldier

• Transmitted most often by bite from rabid animal

• Transmission from tissue donors has also been described

Source: Centers for Disease Control and Prevention, November 2010

Rabies

• Virus amplifies at inoculation site and reaches CNS via motor/sensory nerves

• Moves centrally at a rate of 5-10cm/day

• Clinical Latency period 3-6 mos (7d-1yr)

• Nonspecific prodrome– “flu like symptoms”– Paresthesia or pain at site

Rabies

• Encephalitic Rabies (80%)– Hydrophobia, aerophobia, pharyngeal spasms

• Paralytic Rabies (20%)• Clinically similar to Guillan-Barre Syndrome

• Coma, paralysis and cardio/pulmonary collapse with 2 weeks

Diagnosis/Treatment

• Sample of saliva, skin for PCR

• Antibody from serum or CSF

• Treatment is RIG and Vaccine after exposure

• 1 patient has survived (17 yo F from Wisconsin)

• The “Milwaukee Protocol”– Ketamine, Ribavirin, Amantadine

• Has not been successful in subsequent patients

Pre/Post Exposure

• Prior to exposure in high risk individuals

Questions/Comments?