CNS INFECTIONS

Dr. Amy YuMay 11, 2011

OUTLINE

Case-based with specific teaching points

ReferenceAAN Continuum for CNS infections from

2006Bradley Chapter 57

CASE 1

58M HCT for myelodysplastic syndromeHCT 3 wks agoOn cyclosporine + mycophenolateH/A & confusion x 3dExam: T 38, disoriented, 0/3 recall, normal

motor, sensory, coordination Next step?

CASE 1

CSF studies720 WBC (92%

lymphocytes)Gluc/Prot normalGram stain

negative

Diagnosis? Treatment?

CASE 1

Patient fails to improve on Acyclovir, day 3Continues to be febrileContinues to be confused

How do you confirm the diagnosis of Herpes encephalitis?8 human herpes virusHerpes group PCR

HHV-6 ENCEPHALITIS

HHV-6 is a common cause of encephalitis in the immunocompromised Population sero-prevalence is >90% (most 1ry

infection before age 2) Predilection for temporal lobes

Dx: viral PCR amplification in CSF & confirm with CSF HHV-6 IgM CSF HHV-6 nucleic acid is not definitive evidence

that it is the etiological organism of the encephalitis Rx: Ganciclovir or Foscarnet IV

Acyclovir is not active against virus Repeat CSF analysis in 14-21 days

D/C therapy when CSF cleared

WHY NOT ACYCLOVIR?

Acyclovir is converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase3000x more effective than cellular

thymidine kinaseFurther phosphorylated into acyclo-GTP

Very potent inhibitor of viral DNA polymerase

Resistance to acyclovir: deficiency or mutation to viral thymidine kinase

HHV-6 lacks thymidine kinase

TRANSPLANT PATIENTS

Expansion of inclusion criteriaIncrease lifespan of transplant

recipientsMore transplant institutionsNeurological complication

42% solid organ transplant (SOT)65% hematopoietic cell transplant

(HCT)

TIMING OF CNS INFECTION S/P TX

EarlyNosocomial: line infections, ventilator-

assocaited pneumoniaDonor-to-recipient viral transmission

MiddleViral and fungal opportunistic infections peak

LateRelated to evidence of graft rejection

(serology, organ failure, biopsy) degree & type immunosuppression

Viral and fungal

Continuum CNS infections 2006

HEMATOPOIETIC CELL TRANSPLANT

Chemotherapy +/- radiation cells or cord blood infusion11% had neurological infection26% death due to CNS infectionMost susceptible immediately after transplant

Risk if donor and recipient are genetically closerAutologous: least immunosuppressedReduced-intensity SCT

Less marrow and immunosuppressionMore GVHD more long-term immune suppression

Travel historyCoccidioides, histoplasmosis, WNV

Risk of zoonosesNeurobrucellosis (cattle)Bartonella, Toxoplasmosis (cats litter, raw

meat)Listeriorisis (unpasteurized dairy)

Immunosuppressant & prophylaxisLevel and degree of immunosuppression

TAKE HOME MESSAGE

Immunocompromised patientsCommon and uncommon infectionsConcurrent multiple infections

Culture +/- biospyBlood, CSF, +/- sputum, urine, skin

lesionsStart with broad-spectrum coverage

BacteriaVirusFungusProtozoal

CASE 2

57F, SLE, Rx chronic prednisone + cyclophosphamide

3 d h/a & confusion Acute seizure today CXR RLL nodule

Ring-enhancing lesions RLL opacification

CASE 2

Which of the following is the least likely pathogenic organism?

a) Nocardiab) Listeriac) Aspergillusd) Tuberculosise) Mucor

CASE 2

Which of the following is the least likely pathogenic organism?

a) Nocardiab) Listeria basal meningitisc) Aspergillusd) Tuberculosise) Mucor Don’t forget

neoplasm!

NOCARDIA

Pleomorphil, acid-fast bacillusOften late infection with chronic immune

suppression90% of CNS Nocardia have associated

pulmonary findingsDx: Culture from BAL or biopsyRx: Sx drainage, high-dose TMP-SMX

for > 6 monthsPx: Fair if dx early!!!

ASPERGILLUS #1 cause of focal CNS infection in

transplant population Angioinvasive fungus CVA! Dx: sputum, BAL, bx culture Galactomannan

Ab immunoassay to detect a polysaccharide marker on Aspergillus cell wall surfaceSerum sensitivity and specificity >80%BAL sensitivity 75%CSF? No data

Fungal culture, Aspergillus PCR Rx: Ampho B, Caspofungin, Voriconazole

CASE 2

Which other organism is angioinvasive?a) CMVb) West Nile virusc) Cryptococcusd) Toxoplasmosise) Mucor

CASE 2

Which other organism is angioinvasive?a) CMVb) West Nile virusc) Cryptococcusd) Toxoplasmosise) Mucor (Zygomycetes class: Rhizopus,

Mucor, Absidia, Cunningbamella)

TAKE HOME MESSAGE

Narrow your differential diagnosisClinical setting (age, degree + type of

immunosuppression)Neurological condition (meningitis, abscess,

encephalitis, ischemia, myelitis) Be alert for associated findings

Respiratory, GI symptomsRash, retinitis, weakness,…E.g. Leukopenia + thrombocytopenia +

petechial rash = ?

CASE 2

Who has prescribed Prednisone for > 1 month?

Who has prescribed PCP prophylaxis? Who needs Septra?

WHO SHOULD RECEIVE PCP PROPHYLAXIS?

Prednisone ≥20 mg QD equivalent ≥ 1 month Immunocompromised state

Alemtuzumab: minimum 2 mths after completion of therapy or until the CD4 count is >200

Temozolomide + Rtx until recovery of lymphopenia ALL & Allo HCT (on immunosupp and/or the CD4 count

is <200), selected autologous HCT recipients SOT (min 6-12 mths + periods of high doses of

immunosuppressive medications eg acute rejection) Certain primary immunodeficiencies

Combination with 2nd immunosuppressive drug E.g. Cyclophosphamide (not MTX) PM/DM + IPF may benefit

PROPHYLAXIS FOR THE MG?

Dr. Chalk says “No.”1 case report

Ruiz-Ruiz, J. Miastenia gravis y neumonia por Pneumocystis carinii. Revista de Neurologia. 25(148):2069-70, 1997 Dec.

PROPHYLAXIS FOR CNS INFECTIONS

AcyclovirHSV 1 and 2

Antifungal (e.g. Fluconazole)Candida

TMP-SMX (Septra)Listeria, nocardia

CASE 3

70M, presents in midsummer Confusion, left LE weakness, diplopia, fever

(39C x 3d) What do you want to know?

CSF: 100 WBC (PMN predominance), glucose normal, protein slightly elevated, Gram stain negative

CASE 3

Altered mental status No clear cranial

neuropathy Left leg flaccid

weakness DTR 0 Kinetic tremor

WEST NILE VIRUS Arboviruses, single-stranded RNA virus Vectors: mosquito and tick Reservoirs: birds, mammals 3 primary families

TogavirusFlaviviruses (e.g. WNV, St Louis encephalitis)Alphaviruses (e.g. Eastern equine encephalomyelitis)

ReovirusBunyavirus (e.g. California encephalitis virus)

WEST NILE VIRUS

#1 cause epidemic meningoencephalitis NA

1st isolated in West Nile province of Uganda in 19371999 1st case in NA (New York state)2002 1st case in Canada (Quebec/Ontario)

Most widely distributed of all arbovirusesWaves of outbreak Identified all parts of the US except Hawaii,

Alaska, Washington

WEST NILE VIRUS

80% remain asymptomatic 20% self-limited flulike illness

Fever, h/a, myalgia, GI sxs, 50% non-specific rash

<1% Neuroinvasive presentationAseptic meningitis, meningoencephalitisEncephalitis age>50 RR 20 folds!Acute flaccid paralysis syndrome Ddx??Brainstem encephalitis, movement disorder, CN

palsies, polyneuropathy, optic neuritisVaries with epidemic season, locale

WEST NILE VIRUS

CSFPleocytosis (PMN or lymphocytic)

Unique: plasmacytoid appearance of lymphocytes

Elevated proteinNormal glucoseCSF for West Nile virus IgM is diagnostic

MRI: usually normal EEG: diffuse irregular slowing in

encephalitisSeizures are rare

WEST NILE VIRUS

Treatment is supportive No person-to-person transmission reported Ongoing studies

Passive immunization, interferon alpha, vaccine development

Mortality: 2-7%12-15% due to encephalitisLong-term fatigue, myalgia, residual tremor &

parkinsonism

RABIES

Should be considered in any rapidly progressive encephalitis

Invariably fatal (1 case of survival reported in 2004)Retrograde axonal transport

1ry carriers in US: bats, raccoons, foxes, coyotes, and skunks, not rodentsCentral & South America: dogs and cattles8000 cases of rabies/yr in wild & domestic

animals in US & Puerto Rico

RABIES

Many cases of confirmed rabies have bat exposure historyOften not evident on history from patient

Diagnosis: ab staining or PCR on nuchal skin bx, corneal smears, serum, buccal mucosaGold standard: brain biopsy with direct

immunofluorescent antibody against rabies Best treatment: Post-exposure prophylaxis

Vaccine and immune globulin

TAKE HOME MESSAGE – ENCEPHALOPATHY

Infectious encephalitisFever, seizures, focal neuro signs,

abnormal CSF Autoimmune encephalopathy

ADEMSteroid-responsiveParaneoplastic

Seizure disorder Metabolic/Toxic disturbances

ENCEPHALITIS ETIOLOGIES

Glaser et al. California Encephalitis Project 1998-2000. Clin Infect Dis 20039% viral3% bacterial1% parasitic10% non-infectious3% non-encephalitic infections

Urgent: treatable life-threatening etiologyBacterial meningitisHerpes encephalitis

ENCEPHALITIS THERAPY

Antiviral agentsAcyclovir, Gancyclovir, etc.

Seizure control Antipyretics Monitor for SIADH Monitor for increased ICP Corticosteroids controversial

SUBACUTE/CHRONIC MENINGITIS

A mimick of encephalitis

Meningitis Encephalitis

Fever Present Very high

CSF WBC 10-1000 100’s or acellular

MRI Normal parenchyma

Abnormal

EEG Normal Diffuse slowing or epileptiform activity

ID OF ORGANISM FROM CSF ESTABLISHES THE DX, BUT…

Organism colony in low numberBound to meninges, in granulomas, in exudates

Fastidious and difficult to isolateSpecial culture media, long incubation time,

may degenerate if sample refrigerated CSF nucleic acid or protein

Detection of IgM ab usually identifies agent (v. large molecule that poorly crosses the BBB)

PCR may detect virus that may not be the causative agent

SUBACUTE/CHRONIC MENINGITIS Infectious

Virus, bacteria, rickettsia, fungus, parasite Suspected infectious

Neurosarcoidosis, Behcet’s, VKH syndrome, Mollaret’s meningitis

Non-infectiousVasculitis (GCA, amphetamine/cocaine)CT disease (SLE)Chemical (dermoid cyst) Iatrogenic (TMP-SMX, IVIG, craniotomy)Neoplastic (Leptomeningeal metastasis)Vascular (Leaky aneurysm)

CSF PROFILE

PMN Mononuclear WBCMost viral infectionsExcept HIV associated CMV radiculitis and West

Nile virus encephalitis Neutrophil predominance

Bacteria, most fungus, non-infectious causes >10% eosinophilia

Certain fungus (Coccidioides immitis)Most parasites (Angiostrongylus, Echinococcus,

Schistosoma, Taenia, Trichinella)Some non-infectious causes (SLE, lymphoma)

NEUROLOGICAL EXAMINATION

CN palsies – basilar meningitis (or ICP)TB, Lyme, fungal, parasitesNeurosarcoidosis, neoplastic meningitis

Focal signs (hemiparesis, aphasia, VF defect)Tuberculoma, abscess, infarction, hemorrhage

Ophthalmological examinationPapilledemaRetinitis (CMV, histoplasmosis) Iritis or uveitis (Behcet’s, sarcoidosis, syphilis,

Sjogren)

DON’T FORGET – GENERAL EXAMINATION

Lungs, joints, and skin Unusual skin lesion or nodule biopsy Swollen, warm joints XRay &

aspirate Pulmonary illness Bronchoscopy &

consider TTNA/open biopsy

MENINGEAL BIOPSY

Yield of the biopsy dependant on MRI scan with gadolinium (Cheng et al, 1994) 80% if focal areas of meningeal enhancement 10% if no enhancement is seen

Open or stereotaxic Yield is slightly higher if posterior fossa Include some underlying brain

Common diagnoses Neurosarcoidosis, hypertrophic pachymeningitis,

leptomeningeal metastasis, vasculitis Candida, Aspergillus, Zygomycetes, and

Acanthamoeba +/- TB, Histoplasma, Blastomyces, Coccidiodes

WHAT IS THE #1 CAUSE OF CHRONIC MENINGITIS WORLD-WIDE?

a) Treponema pallidumb) Borrelia burgdorferic) Mycobacterium tuberculosisd) Human immunodeficiency viruse) Cryptococcus neoformans

WHAT IS THE #1 CAUSE OF CHRONIC MENINGITIS WORLD-WIDE?

a) Treponema pallidumb) Borrelia burgdorferic) Mycobacterium tuberculosisd) Human immunodeficiency viruse) Cryptococcus neoformans

TUBERCULOUS MENINGITIS

>50% active TB meningitis do not have an active pulmonary infectionCXR: look for calcified mediastinal LN (Ghon

complexes) PPD positive in 50% CSF PCR assay available

Sensitivity 56% (same as culture, but result available in days vs. 3-6 weeks), Specificity 98%

Culture still needed for sensitivity profile If high-grade meningitis and RF for TB

treatment is usually recommendedRole of empiric corticosteroids is unclear

THE END: TAKE HOME MESSAGES History is key

Place of origin & recent travelSick contacts or similar symptoms in contactsAnimal exposure (pets and diet habits)Systemic illness (eyes, joints, lungs, liver,…)

Immune statusDegree of suppression, length of time, presence

of prophylaxis medication Neurological and general examination Find something to image, culture, biopsy Be patient and treat for the what could kill

your patient