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CNS Fungal Infections

CNS Fungal Infections. Neuropathology Conference Robyn Massa, MD and Clayton Wiley, MD, PhD January 26, 2015. Case Report: History.

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CNS Fungal Infections

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  1. CNS Fungal Infections Neuropathology Conference Robyn Massa, MD and Clayton Wiley, MD, PhD January 26, 2015

  2. Case Report: History • HPI: 64 yo M initially presenting to OSH on 6/24/13 and transferred to PUH on 6/26/13 with new onset daily 10/10 headaches for 2 months. Headaches are diffuse and feel like pressure. • Associated symptoms: lightheadedness, nausea, right ear pain, mild neck stiffness, “staggering” gait, 8lb wound loss in 2 weeks • Denies: photophobia, phonophobia,vision changes, fevers, night sweats, travel, sick contacts • Later revealed has had change in affect, cognitive slowing, and generalized weakness

  3. History continued • PMH: Nephrolithiasis, “spot on lungs” • SH: Denies tobacco/etoh/drugs. Lives with wife. Unemployed. • FH: Father had rectal cancer • Medications: none • Allergies: NKDA • ROS: As per HPI

  4. Physical Exam • VS: T 36.2, BP 155/70, HR 73, RR 14, Pulse ox 98% • Gen: NAD. Sleepy but easily arousable. Cachectic appearing • Neck: Moderately decreased ROM in the “yes-yes” motion • Heent, Resp, CV, GI exams wnl • Neuro: • MS: Alert and oriented to person, place, date. Sleepy but easily arousable to voice. Speech fluent and appropriate. Cognition and memory grossly intact • CN: Intact • Motor: Full and symmetric strength throughout • Sensory: Intact to vibration and temperature throughout • Reflexes: 2+ throughout. Flexor plantar responses. • Coordination: No dysmetria, normal RAMs • Gait: Patient reported severe lightheadedness on standing. Gait was somewhat unsteady and slowed but not ataxic

  5. OSH Data • CMP, CBC wnl • CSF: xanthrochromic • WBC 16 (neut 1, lymph 61), RBC 255 • Protein 254, Glucose 3 • Gram stain: no organisms, moderate WBCs • CSF culture: pending at time of transfer • Brain MRI w/wout contrast: “unremarkable” • CTA head and neck: “patent vessels” • Lumbar puncture #2 attempted at a different OSH but unsuccessful

  6. Differential Diagnosis • Bacterial meningitis • Fungal meningitis • Viral meningitis/encephalitis • Leptomeniningeal metastasis • Paraneoplastic syndrome

  7. Initial Labs • Serum labs notable for mild leukocytosis 12.5 • WNL: ESR, CRP, RPR • Lumbar puncture #2 • Opening pressure: “oscillated between 26 and 32cm H20,” clear fluid • Micro pending

  8. What happened next • Empirically started Ampicillin, Ceftriaxone, Vancomycin, Acyclovir • Consulted Infectious Disease team • However later that afternoon… • CRYPTOCOCCAL ANTIGEN = POSITIVE with a titer of 1:2048 • Patient started on induction treatment x 4 weeks: • Liposomal amphotericin 250mg (4mg/kg) IV q24h • Flucytosine 1500mg (25mg/kg) PO q6h • Planned for consolidation treatment with Fluconazole

  9. Cryptococcal Meningitis (CM): Epidemiology • Encapsulated saprophytic yeast, transmitted by inhalation • Human pathogens • C. neoformans • C. neoformans var. grubii: most common, 82% of disease worldwide • C. neorformans var. neoformans • C. gattii: immunocompetent individuals in tropical and subtropical regions; sporadic cases in North America • Mostly affects those with impaired cell-mediated immunity • HIV: 95% in middle to low income countries, 80% in high income countries • Immunosupressant medications • Immunocompetent hosts: autoimmune disease, malignancy, immune disorder? • Higher mortality, likely due to late diagnosis

  10. CM: Presentation • Subacute headache • Confusion • Increased ICP-> CN palsies, seizures • Meningism <20% of patients • Cryptococcomas (granulomas) -> hydrocephalus, blindness • Ocular (papilledema, uveitis, chorioretinitis, optic nerve dysfunction) • Pulmonary, cutaneous, and bloodstream infections also occur

  11. CM: Diagnosis • Lumbar puncture • Elevated opening pressure • Associated with greater fungal burden and higher mortality • Lymphocytic pleocytosis • Low glucose, elevated protein • May be normal, especially with underlying HIV • India ink staining, light microscropy: variable sensitivity • Cryptococcal antigen: latex-agglutination test or lateral flow immunoassay (LFA) • LFA may be used with urine sample • Fungal culture on Sabouraud media, grows after 36 hours • Radiology: role is to detect complications • Cryptococcomas and pseudocysts in midbrain or basal ganglia • Dilated perivascular spaces • Hydrocephalus

  12. CM: Treatment IDSA and WHO Guidelines • Rate of fungal clearance from CSF in first 2 weeks (early fungicidal activity) predicts 10 week survival • CSF sterilization by 14 days predicts long term prognosis

  13. CM: Treatment • Amphotericin B • SEs: nephrotoxicity, hypokalemia, hypomagnesemia • Lipid formulations are less nephrotoxic • Greatest early fungicidal activity • Flucytosine • SEs: bone marrow suppression • Reduction of raised ICP • Serial LPs, CSF drainage catheter, VP shunt • Acetazolamide may cause harm • Management of immune reconstitution inflammatory syndrome (IRIS) • ART for HIV patients: start 4-10 weeks after initiating antifungal treatment, however need further research

  14. CryptococcalmeningitisNeuropathology

  15. CryptococcalmeningitisNeuropathology • Fungal meningitis • Crypto • H&E • PAS • Mucicarmine • GMS • Aspergillus • H&E • GMS • Tuberculosis • H&E • FITE • Streptococcal meningitis • H&E • Gram Stain • Viral meningitis • Enteroviral meningitis • H&E • CMV radiculitis • H&E

  16. Back to the case, data further on in hospital course • CT C/A/P: negative for malignancy • WNL: paraneoplastic panel, HIV • CSF: • Fungal culture: Light Cryptococcos neoformans var. grubii • Negative AFB

  17. Hospital Course • Patient had 6 more LPs…. • Additional CSF fungal cultures were negative

  18. Hospital Course • Improvement in personality and headache • Induction antifungal therapy extended for 1 week • Planned for Fluconazole 400mg PO daily x 8 week, followed by 200mg PO daily x 6-12 months • Discharged to home on 7/16/13 with ID follow-up in 1 week

  19. And bounce back • Patient returns on 7/27/13 with headache and dizziness, as well as difficulty with PICC. Missed several days of antifungals. • Discharged on 7/29/13 • Patient returns on 8/2/13 with abnormal gait and falls • Head CT obtained…

  20. Head CT 8/2/13

  21. Brain MRI 8/2/13

  22. MRI continued

  23. Opening pressure improving…

  24. …But not MRI on 8/5/13 (3 days later)

  25. MRI Continued Patient started on Decadron per Thwaite’s protocol for TB meningitis

  26. Brain MRI 8/12/13 (1 week later)

  27. MRI Continued • Improved! Less enhancement too (not shown) • Lesions felt to be IRIS rather than cryptococcomas • Patient discharged to SNF on 8/14/13

  28. Cryptococcomas

  29. Cryptococcomas

  30. Cryptococcomas

  31. Cryptococcomas

  32. Cryptococcomas

  33. IRIS (PML) • H&E • PAS • Mucicarmine • GMS • CD3 • IBA1

  34. IRIS • Host immune recovery triggers inflammation in response to antigens • Unmasking: when cryptococcal disease occurs after starting ART in HIV patients • Paradoxical: initial response to antifungals, followed by deterioration after starting ART or pausing antirejection medications • May occur in immunocompetenthosts as their immune system recovers from high fungal burden • Risk factors: severe disease, slow fungal elimination • Benefit of steroids is unclear • Mortality up to 36%

  35. Back in the hospital • Returned to PUH on 9/18/13 with weakness and cough • Completed induction therapy, now on Fluconazole • Completed steroid taper (however was to continue for several more weeks) • Seen by ENT: sensorineural hearing loss. Concern for labyrinthitis ossificans 2/2 meningitis • Patient discharged home and returned on 9/25/13 with difficulty ambulating and progressive hearing loss

  36. MRI IAC 9/25/13 ID felt presentation consistent with IRIS, Decadron restarted. Patient discharged to SNF

  37. Back in the hospital • Patient returns on 12/1/13 with a headache • Serum crypt ag remains positive (titer 1:512). Discharged from hospital. • On 8/28/14, serum titer is down to 1:16 • Per outpatient notes, discharged from ID clinic 9/2014. Doing well at home. • Patient decided not to receive cochlear implant

  38. Candida species • Hyphal and yeast forms • Found on skin and mucous membranes • Mostly C. albicans, causing meningitis or brain abscesses • Risk factors: dissemination or direct inoculation into CNS • Ex. Premature infant with neural tube defect or neurosurgical intervention • Check for 1,3-beta-D glucan in CSF (cell wall component of some fungi) • Treatment: amphotericin B + fluctytosine

  39. Aspergillus species • Septated hyphae with acute angle branching • Found in soil and decaying vegetation • Transmission via respiratory tract, CNS spread by direct route or hematogenous • Most commonly results in brain abscesses or granulomas • May also lead to vascular invasion causing infarcts, hemorrhage, mycotic aneurysms • Isolated meningitis is rare • Risk factors: immunosupression. Can occur in immunocompetent hosts • Galactomannan antigen and 1,3-beta-D glucan in CSF (not specific to aspergillosis) • Treatment: Voriconazole + Amphotericin B

  40. Zygomycetes • Ex. Mucor and Rhizopus species (broad, irregularly branched, rare septate hyphae) • Found in soil and decaying vegetation • Transmission via respiratory tract • Risk factors: • Environment rich in acid and carbohydrates (ex. Diabetic ketoacidosis) • Neutropenia • Excess iron and chelating agent deferoxamine • IVDU • Causes brain abscess and vascular invasion (infarcts, hemorrhage, mycotic aneurysms, cavernous sinus thrombosis) • Treatment: Amphotericin B

  41. Coccidioides immitis • Found in Southwest US • Transmitted by inhaling spores • Spherules -> Endospores • Causes meningitis, usually within a few months of pulmonary infection • Rarely causes brain abscesses • May affect immunocompetent hosts • Treatment: Fluconazoleor Itraconazoleand/or intrathecal Amphotericin B

  42. Histoplasma capsulatum • Found in Ohio and Mississippi River valleys • Yeast form, less likely hyphae • Found in soil mixed with bird or bat droppings, especially in caves • Causes meningitis, infrequently brain abscesses (miliary non-caseating granuloma) • May affect immunocompetent hosts • Treatment: Amphotericin B followed by Itraconazole

  43. References • Chakrabarti, Arunaloke. “Epidemiology of central nervous system mycoses.” Neurology India. 55;3:191-197. 2007. • McCarthy M et al. “Mold Infections of the Central Nervous System.”The New England Journal of Medicine. 371;2:150-160. July 2014. • Sloan DJ and Parris V. “Cryptococcal meningitis: epidemiology and therapeutic options.” Clinical Epidemiology. 13;6:169-182. May 2014.

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