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CNS INFECTIONS Dr. Amy Yu May 11, 2011 OUTLINE Case-based with specific teaching points Reference AAN Continuum for CNS infections from 2006 Bradley Chapter 57 CASE 1 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? CASE 1 CSF studies 720 WBC (92% lymphocytes) Gluc/Prot normal Gram stain negative Diagnosis? Treatment? CASE 1 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 WHY NOT ACYCLOVIR? Acyclovir is converted into acycloguanosine 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: deficiency or mutation to viral thymidine kinase HHV-6 lacks thymidine kinase TRANSPLANT 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) TIMING OF CNS INFECTION S/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 HEMATOPOIETIC CELL TRANSPLANT Chemotherapy blood infusion +/- radiation cells or cord 11% had neurological infection 26% death due to CNS infection 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 more long-term immune suppression 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 TAKE 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 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) b) c) d) e) Nocardia Listeria Aspergillus Tuberculosis Mucor CASE 2 Which of the following is the least likely pathogenic organism? a) b) c) d) e) Nocardia Listeria basal meningitis Aspergillus Tuberculosis Don’t Mucor forget neoplasm! NOCARDIA 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!!! 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 surface Serum 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) CMV b) West Nile virus c) Cryptococcus d) Toxoplasmosis e) Mucor CASE 2 Which other organism is angioinvasive? a) CMV b) West Nile virus c) Cryptococcus d) Toxoplasmosis e) Mucor (Zygomycetes class: Rhizopus, Mucor, Absidia, Cunningbamella) TAKE HOME MESSAGE Narrow Clinical setting (age, degree + type of immunosuppression) Neurological condition (meningitis, abscess, encephalitis, ischemia, myelitis) Be your differential diagnosis alert for associated findings Respiratory, GI symptoms Rash, 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 Acyclovir HSV 1 and 2 Antifungal Candida TMP-SMX (e.g. Fluconazole) (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 Togavirus Flaviviruses (e.g. WNV, St Louis encephalitis) Alphaviruses (e.g. Eastern equine encephalomyelitis) Reovirus Bunyavirus (e.g. California encephalitis virus) WEST NILE VIRUS #1 cause epidemic meningoencephalitis NA 1st isolated in West Nile province of Uganda in 1937 1999 1st case in NA (New York state) 2002 1st case in Canada (Quebec/Ontario) Most widely distributed of all arboviruses Waves 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 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 WEST NILE 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 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 encephalitis Long-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 rodents Central & South America: dogs and cattles 8000 cases of rabies/yr in wild & domestic animals in US & Puerto Rico RABIES 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 TAKE HOME MESSAGE – ENCEPHALOPATHY Infectious encephalitis Fever, seizures, focal neuro signs, abnormal CSF Autoimmune encephalopathy ADEM Steroid-responsive Paraneoplastic Seizure disorder Metabolic/Toxic disturbances ENCEPHALITIS 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 ENCEPHALITIS THERAPY Antiviral agents Acyclovir, 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 Normal Abnormal EEG Diffuse slowing or epileptiform activity ID OF ORGANISM FROM CSF ESTABLISHES THE DX, BUT… Organism Bound to meninges, in granulomas, in exudates Fastidious colony in low number 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 SUBACUTE/CHRONIC 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 Bacteria, most fungus, non-infectious causes >10% predominance 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, parasites Neurosarcoidosis, neoplastic meningitis Focal signs (hemiparesis, aphasia, VF defect) Tuberculoma, abscess, infarction, hemorrhage Ophthalmological examination Papilledema Retinitis (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) b) c) d) e) Treponema pallidum Borrelia burgdorferi Mycobacterium tuberculosis Human immunodeficiency virus Cryptococcus neoformans WHAT IS THE #1 CAUSE OF CHRONIC MENINGITIS WORLD-WIDE? a) b) c) d) e) Treponema pallidum Borrelia burgdorferi Mycobacterium tuberculosis Human immunodeficiency virus Cryptococcus neoformans TUBERCULOUS 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 THE END: TAKE 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