CNS

INFECTIONS

Dr. Amy Yu May 11, 2011

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UTLINE  Case-based with specific teaching points  Reference   AAN Continuum for CNS infections from 2006 Bradley Chapter 57

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ASE

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 58M HCT for myelodysplastic syndrome  HCT 3 wks ago    On cyclosporine + mycophenolate H/A & confusion x 3d Exam: T 38, disoriented, 0/3 recall, normal motor, sensory, coordination  Next step?

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 CSF studies   720 WBC (92% lymphocytes) Gluc/Prot normal  Gram stain negative  Diagnosis?

 Treatment?

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 Patient fails to improve on Acyclovir, day 3   Continues to be febrile Continues to be confused  How do you confirm the diagnosis of Herpes encephalitis?

  8 human herpes virus Herpes 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

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HY NOT ACYCLOVIR

?

 Acyclovir is converted into acyclo guanosine monophosphate (acyclo-GMP) by

viral thymidine kinase

  3000x more effective than cellular thymidine kinase Further phosphorylated into acyclo-GTP  Very potent inhibitor of viral DNA polymerase  Resistance to acyclovir:

mutation deficiency

to viral thymidine kinase or  HHV-6 lacks thymidine kinase

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RANSPLANT PATIENTS  Expansion of inclusion criteria  Increase lifespan of transplant recipients  More transplant institutions  Neurological complication   42% solid organ transplant (SOT) 65% hematopoietic cell transplant (HCT)

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IMING OF

CNS

INFECTION S

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P TX  Early   Nosocomial: line infections, ventilator-assocaited pneumonia Donor-to-recipient viral transmission  Middle  Viral and fungal opportunistic infections peak  Late   Related to evidence of graft rejection (serology, organ failure, biopsy)  degree & type immunosuppression Viral and fungal

Continuum CNS infections 2006

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EMATOPOIETIC CELL TRANSPLANT   Chemotherapy +/- radiation  blood infusion   11% had neurological infection 26% death due to CNS infection cells or cord  Most susceptible immediately after transplant  Risk if donor and recipient are genetically closer   Autologous: least immunosuppressed Reduced-intensity SCT  Less marrow and immunosuppression  More GVHD  suppression more long-term immune

 Travel history  Coccidioides, histoplasmosis, WNV  Risk of zoonoses   Neurobrucellosis (cattle) Bartonella, Toxoplasmosis (cats litter, raw meat)  Listeriorisis (unpasteurized dairy)  Immunosuppressant & prophylaxis  Level and degree of immunosuppression

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AKE HOME MESSAGE  Immunocompromised patients  Common and uncommon infections  Concurrent multiple infections  Culture +/- biospy  Blood, CSF, +/- sputum, urine, skin lesions  Start with broad-spectrum coverage  Bacteria    Virus Fungus Protozoal

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    57F, SLE, Rx chronic prednisone + cyclophosphamide 3 d h/a & confusion Acute seizure today CXR RLL nodule   Ring-enhancing lesions RLL opacification

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Which of the following is the least likely pathogenic organism?

a) b) c) d) e) Nocardia Listeria Aspergillus Tuberculosis Mucor

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Which of the following is the least likely pathogenic organism?

a) b) c) d) e) Nocardia Listeria  Aspergillus basal meningitis Tuberculosis Mucor

Don’t forget neoplasm!

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OCARDIA  Pleomorphil, acid-fast bacillus  Often late infection with chronic immune suppression  90% of CNS Nocardia have associated pulmonary findings  Dx: Culture from BAL or biopsy  Rx: Sx drainage, high-dose TMP-SMX for > 6 months  Px: Fair if dx early!!!

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SPERGILLUS      #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 surface  Serum sensitivity and specificity >80%  BAL sensitivity 75%  CSF? No data  Fungal culture, Aspergillus PCR Rx: Ampho B, Caspofungin, Voriconazole

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Which other organism is angioinvasive?

a) b) c) d) e) CMV West Nile virus Cryptococcus Toxoplasmosis Mucor

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Which other organism is angioinvasive?

a) b) c) d) e) CMV West Nile virus Cryptococcus Toxoplasmosis Mucor (Zygomycetes class: Rhizopus, Mucor, Absidia, Cunningbamella)

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AKE HOME MESSAGE  Narrow your differential diagnosis   Clinical setting (age, degree + type of immunosuppression) Neurological condition (meningitis, abscess, encephalitis, ischemia, myelitis)  Be alert for associated findings    Respiratory, GI symptoms Rash, retinitis, weakness,… E.g. Leukopenia + thrombocytopenia + petechial rash = ?

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 Who has prescribed Prednisone for > 1 month?

  Who has prescribed PCP prophylaxis?

Who needs Septra?

W HO 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 2 nd   immunosuppressive drug E.g. Cyclophosphamide (not MTX) PM/DM + IPF may benefit

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ROPHYLAXIS 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.

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ROPHYLAXIS FOR

CNS

INFECTIONS  Acyclovir  HSV 1 and 2  Antifungal (e.g. Fluconazole)  Candida  TMP-SMX (Septra)  Listeria, nocardia

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ASE

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 70M, presents in midsummer   Confusion, left LE weakness, diplopia, fever (39  C x 3d) What do you want to know?

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

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 Altered mental status  No clear cranial neuropathy  Left leg flaccid weakness  DTR 0  Kinetic tremor

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EST

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ILE VIRUS  Arboviruses, single-stranded RNA virus    Vectors: mosquito and tick Reservoirs: birds, mammals 3 primary families  Togavirus    Flaviviruses (e.g. WNV , St Louis encephalitis)  Alphaviruses (e.g. Eastern equine encephalomyelitis) Reovirus Bunyavirus (e.g. California encephalitis virus)

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EST

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ILE VIRUS  #1 cause epidemic meningoencephalitis NA  1st isolated in West Nile province of Uganda in 1937   1999 1 st 2002 1 st case in NA (New York state) case in Canada (Quebec/Ontario)  Most widely distributed of all arboviruses   Waves of outbreak Identified all parts of the US except Hawaii, Alaska, Washington

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EST

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ILE VIRUS  80% remain asymptomatic  20% self-limited flulike illness  Fever, h/a, myalgia, GI sxs, 50% non-specific rash  <1% Neuroinvasive presentation      Aseptic meningitis, meningoencephalitis Encephalitis age>50 RR 20 folds!

Acute flaccid paralysis syndrome  Ddx??

Brainstem encephalitis, movement disorder, CN palsies, polyneuropathy, optic neuritis Varies with epidemic season, locale

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EST

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ILE VIRUS    CSF     Pleocytosis (PMN or lymphocytic)  Unique: plasmacytoid appearance of lymphocytes Elevated protein Normal glucose CSF for West Nile virus IgM is diagnostic MRI: usually normal EEG: diffuse irregular slowing in encephalitis  Seizures are rare

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EST

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ILE 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 encephalitis Long-term fatigue, myalgia, residual tremor & parkinsonism

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ABIES  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 rodents   Central & South America: dogs and cattles 8000 cases of rabies/yr in wild & domestic animals in US & Puerto Rico

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ABIES  Many cases of confirmed rabies have bat exposure history  Often not evident on history from patient  Diagnosis: ab staining or PCR on nuchal skin bx, corneal smears, serum, buccal mucosa  Gold standard: brain biopsy with direct immunofluorescent antibody against rabies  Best treatment: Post-exposure prophylaxis  Vaccine and immune globulin

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AKE HOME MESSAGE

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NCEPHALOPATHY

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 Infectious encephalitis  Fever, seizures, focal neuro signs, abnormal CSF  Autoimmune encephalopathy    ADEM Steroid-responsive Paraneoplastic  Seizure disorder  Metabolic/Toxic disturbances

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NCEPHALITIS ETIOLOGIES  Glaser et al. California Encephalitis Project 1998-2000. Clin Infect Dis 2003      9% viral 3% bacterial 1% parasitic 10% non-infectious 3% non-encephalitic infections  Urgent: treatable life-threatening etiology   Bacterial meningitis Herpes encephalitis

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NCEPHALITIS THERAPY  Antiviral agents  Acyclovir, Gancyclovir, etc.

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

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UBACUTE

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HRONIC MENINGITIS  A mimick of encephalitis Fever CSF WBC Meningitis Present 10-1000 Encephalitis Very high 100’s or acellular MRI EEG Normal parenchyma Normal Abnormal Diffuse slowing or epileptiform activity

ID OF ORGANISM FROM CSF ESTABLISHES THE DX , BUT …  Organism colony in low number  Bound to meninges, in granulomas, in exudates  Fastidious and difficult to isolate  Special 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

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UBACUTE

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HRONIC MENINGITIS    Infectious  Virus, bacteria, rickettsia, fungus, parasite Suspected infectious  Neurosarcoidosis, Behcet’s, VKH syndrome, Mollaret’s meningitis Non-infectious       Vasculitis (GCA, amphetamine/cocaine) CT disease (SLE) Chemical (dermoid cyst) Iatrogenic (TMP-SMX, IVIG, craniotomy) Neoplastic (Leptomeningeal metastasis) Vascular (Leaky aneurysm)

CSF

PROFILE  PMN    Mononuclear WBC Most viral infections Except 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)

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EUROLOGICAL EXAMINATION  CN palsies – basilar meningitis (or   TB, Lyme, fungal, parasites  Neurosarcoidosis, neoplastic meningitis ICP)  Focal signs (hemiparesis, aphasia, VF defect)  Tuberculoma, abscess, infarction, hemorrhage  Ophthalmological examination    Papilledema Retinitis (CMV, histoplasmosis) Iritis or uveitis (Behcet’s, sarcoidosis, syphilis, Sjogren)

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ON

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T FORGET

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ENERAL EXAMINATION  Lungs, joints, and skin  Unusual skin lesion or nodule  biopsy  Swollen, warm joints  XRay & aspirate  Pulmonary illness  Bronchoscopy & consider TTNA/open biopsy

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ENINGEAL 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

a) b) c) d) e) W HAT IS THE #1 CAUSE OF CHRONIC MENINGITIS WORLD WIDE ?

Treponema pallidum Borrelia burgdorferi Mycobacterium tuberculosis Human immunodeficiency virus Cryptococcus neoformans

a) b) c) d) e) W HAT IS THE #1 CAUSE OF CHRONIC MENINGITIS WORLD WIDE ?

Treponema pallidum Borrelia burgdorferi Mycobacterium tuberculosis Human immunodeficiency virus Cryptococcus neoformans

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UBERCULOUS MENINGITIS     >50% active TB meningitis do not have an active pulmonary infection  CXR: 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 recommended  Role of empiric corticosteroids is unclear

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AKE HOME MESSAGES      History is key    Place of origin & recent travel Sick contacts or similar symptoms in contacts Animal exposure (pets and diet habits)  Systemic illness (eyes, joints, lungs, liver,…) Immune status  Degree 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