Download CNS Fungal Infections

CNS Fungal
Infections
Neuropathology Conference
Robyn Massa, MD and Clayton Wiley, MD, PhD
January 26, 2015
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
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
Physical Exam
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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
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
Differential Diagnosis
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Bacterial meningitis
Fungal meningitis
Viral meningitis/encephalitis
Leptomeniningeal metastasis
Paraneoplastic syndrome
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
WBC
Neut
Lymph Mono
RBC
Glucose Protein
Tube 3 206
10
50
27
333
<10
Tube 4 211
41
29
24
319
• Micro pending
280
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
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
CM: Presentation
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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
CM: Diagnosis
• Lumbar puncture
• Elevated opening pressure
• Associated with greater fungal burden and higher mortality
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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
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
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
Cryptococcal meningitis
Neuropathology
Cryptococcal meningitis
Neuropathology
• Fungal meningitis
• Crypto
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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
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
Hospital Course
• Patient had 6 more LPs….
LP
OP
WBC Neut Lymph Mono RBC Glucose Protein Crypt
ag titer
#3 (7/2)
25
9
7
63
26
5
<10
238
#4 (7/5)
26
120
2
52
25
38
<10
200
1:2048
#5 (7/9)
35
95
1
71
27
8
<10
186
1:1024
#6 (7/11) 32.8 153
1
65
26
10
10
256
1:1024
#7 (7/13) 24.2 149
2
36
46
10
<10
171
#8 (7/15) 21.8 145
2
70
28
1
11
174
• Additional CSF fungal cultures were negative
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
And bounce back
• Patient returns on 7/27/13 with headache and dizziness,
as well as difficulty with PICC. Missed several days of
antifungals.
LP
OP
#9 (7/27) 25
WBC Neut Lymph Mono RBC Glucose Protein Crypt
ag titer
114
7
74
17
1
22
295
1:1024
• Discharged on 7/29/13
• Patient returns on 8/2/13 with abnormal gait and falls
• Head CT obtained…
Head CT 8/2/13
Brain MRI 8/2/13
MRI continued
Opening pressure improving…
LP
OP
WBC Neut Lymph Mono RBC Glucose Protein Crypt
ag titer
#10 (8/3) 14.5 54
4
85
8
0
19
383
1:1024
…But not MRI on 8/5/13 (3
days later)
MRI Continued
Patient started on Decadron per Thwaite’s protocol for TB meningitis
Brain MRI 8/12/13 (1 week
later)
MRI Continued
• Improved! Less enhancement too (not shown)
• Lesions felt to be IRIS rather than cryptococcomas
• Patient discharged to SNF on 8/14/13
Cryptococcomas
Cryptococcomas
Cryptococcomas
Cryptococcomas
Cryptococcomas
IRIS (PML)
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H&E
PAS
Mucicarmine
GMS
CD3
IBA1
IRIS
• Host immune recovery triggers inflammation in response
to antigens
1. Unmasking: when cryptococcal disease occurs after
starting ART in HIV patients
2. Paradoxical: initial response to antifungals, followed
by deterioration after starting ART or pausing
antirejection medications
• May occur in immunocompetent hosts 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%
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)
LP
OP
WBC Neut Lymph Mono RBC Glucose Protein Crypt
ag titer
#11
(9/17)
16
33
54
19
27
6
45
243
1:256
• 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
MRI IAC 9/25/13
ID felt presentation consistent with IRIS, Decadron restarted.
Patient discharged to SNF
Back in the hospital
• Patient returns on 12/1/13 with a headache
LP
OP
WB
C
#12 (12/2) 22.5 8
prone
Neut Lymph Mono RBC Glucose Protein Crypt
ag titer
28
56
16
1
40
123
NEG!
• 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
Candida species
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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
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
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
Coccidioides immitis
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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: Fluconazole or Itraconazole and/or
intrathecal Amphotericin B
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
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;2:150160. July 2014.
• Sloan DJ and Parris V. “Cryptococcal meningitis:
epidemiology and therapeutic options.” Clinical
Epidemiology. 13;6:169-182. May 2014.