Transcript CNS infections - McGill University

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
(39C 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