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CNS infections

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

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CNS infections

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  1. CNS infections Dr. Amy Yu May 11, 2011

  2. Outline • Case-based with specific teaching points • Reference • AAN Continuum for CNS infections from 2006 • Bradley Chapter 57

  3. 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?

  4. Case 1 • CSF studies • 720 WBC (92% lymphocytes) • Gluc/Prot normal • Gram stain negative • Diagnosis? • Treatment?

  5. 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

  6. 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

  7. Why 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: deficiency or mutation to viral thymidine kinase • HHV-6 lacks thymidine kinase

  8. 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)

  9. 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

  10. Continuum CNS infections 2006

  11. Hematopoietic cell transplant • Chemotherapy +/- radiation  cells or cord blood infusion • 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

  12. 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

  13. 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

  14. Case 2 • 57F, SLE, Rx chronic prednisone + cyclophosphamide • 3 d h/a & confusion • Acute seizure today • CXR RLL nodule • Ring-enhancing lesions • RLL opacification

  15. Case 2 Which of the following is the least likely pathogenic organism? • Nocardia • Listeria • Aspergillus • Tuberculosis • Mucor

  16. Case 2 Which of the following is the least likely pathogenic organism? • Nocardia • Listeria basal meningitis • Aspergillus • Tuberculosis • Mucor Don’t forget neoplasm!

  17. 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!!!

  18. 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

  19. Case 2 Which other organism is angioinvasive? • CMV • West Nile virus • Cryptococcus • Toxoplasmosis • Mucor

  20. Case 2 Which other organism is angioinvasive? • CMV • West Nile virus • Cryptococcus • Toxoplasmosis • Mucor (Zygomycetes class: Rhizopus, Mucor, Absidia, Cunningbamella)

  21. Take 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 = ? Rocky mountain spotted fever!

  22. Case 2 • Who has prescribed Prednisone for > 1 month? • Who has prescribed PCP prophylaxis? • Who needs Septra?

  23. 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

  24. 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.

  25. Prophylaxis for CNS infections • Acyclovir • HSV 1 and 2 • Antifungal (e.g. Fluconazole) • Candida • TMP-SMX (Septra) • Listeria, nocardia

  26. Case 3 • 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

  27. Case 3 • Altered mental status • No clear cranial neuropathy • Left leg flaccid weakness • DTR 0 • Kinetic tremor

  28. 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)

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. Take home message – Encephalopathy • Infectious encephalitis • Fever, seizures, focal neuro signs, abnormal CSF • Autoimmune encephalopathy • ADEM • Steroid-responsive • Paraneoplastic • Seizure disorder • Metabolic/Toxic disturbances

  36. 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

  37. Encephalitis therapy • Antiviral agents • Acyclovir, Gancyclovir, etc. • Seizure control • Antipyretics • Monitor for SIADH • Monitor for increased ICP • Corticosteroids controversial

  38. Subacute/Chronic meningitis • A mimick of encephalitis

  39. 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

  40. 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)

  41. 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)

  42. 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)

  43. 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

  44. 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

  45. What is the #1 cause of chronic meningitis world-wide? • Treponema pallidum • Borrelia burgdorferi • Mycobacterium tuberculosis • Human immunodeficiency virus • Cryptococcus neoformans

  46. What is the #1 cause of chronic meningitis world-wide? • Treponema pallidum • Borrelia burgdorferi • Mycobacterium tuberculosis • Human immunodeficiency virus • Cryptococcus neoformans

  47. 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

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