CENTRAL NERVOUS SYSTEM INFECTIONS - Confex · Malaysia, Vietnam, Indonesia, Papua New Guinea,...

10/19/2011

IDSA: Vincent T. Andriole ID Board Review 1

CENTRAL NERVOUS SYSTEM INFECTIONS

Allan R. Tunkel, MD, PhD, MACPChair, Department of Medicine

Monmouth Medical CenterProfessor of Medicine

Drexel University College of Medicine

DISCLOSURES

NONE

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CASE #1

• 69-year-old man from Arizona on chronic corticosteroid therapy for severe COPD was admitted to the hospital with acute onset of high fever, chills, and lethargy

• T 1040F, P 120, RR 32, BP 90/60 mmHg• On examination, he was oriented only to person;

there was no nuchal rigidity• WBC 25,000/mm3 with 20% bands• CSF WBC 1,500/mm3 (75% neutrophils), glucose

20 mg/dL, and protein 200 mg/dL

EPIDEMIOLOGIC FEATURES OF PNEUMOCOCCAL MENINGITIS

• Most common etiologic agent in US

• Mortality of 19-26%

• Associated with other suppurative foci of infection

Pneumonia (25%)

Otitis media or mastoiditis (30%)

Sinusitis (10-15%)

Endocarditis (<5%)

Head trauma with CSF leak (10%)

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EPIDEMIOLOGIC FEATURES OF MENINGOCOCCAL MENINGITIS• Affects mostly children and young adults;

mortality 3-13%

• Epidemics usually caused by serogroups A and C

• Group Y strains associated with pneumonia

• Serogroup C disease increasing in the US

• Nasopharyngeal acquisition of infection

• Predisposition in those with congenital deficiencies in terminal complement components (C5-C9) and properdin deficiencies

EPIDEMIOLOGIC FEATURES OF GROUP B STREPTOCOCCAL

MENINGITIS• Important etiologic agent in neonates; mortality 7-27%

• Early-onset septicemia associated with prematurity, premature rupture of membranes, low birth weight

• Late onset meningitis (> 7 days after birth)

• Disease in adults associated with the following:

Diabetes mellitus Parturient women

Cardiac disease Malignancy

Collagen-vascular disorders Alcoholism

Hepatic and renal failure Corticosteroid use

HIV infection No underlying disease (43%)

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EPIDEMIOLOGIC FEATURES OF LISTERIA MENINGITIS

• Mortality 15-29%• Rare cause of bacterial meningitis in US (2%)• Serotypes 1/2b and 4b cause up to 80% of cases• Outbreaks associated with consumption of contaminated

coleslaw, raw vegetables, milk, cheese, processed meats• Common in neonates (~20% of cases)• Disease in adults associated with:

Elderly AlcoholismMalignancy Immune suppressionDiabetes mellitus Hepatic and renal diseaseIron overload Collagen-vascular disordersHIV infection (?)

EPIDEMIOLOGIC FEATURES OF MENINGITIS CAUSED BY AEROBIC

GRAM-NEGATIVE BACILLI• Klebsiella species, Escherichia coli, Serratia marcescens,

Pseudomonas aeruginosa, Salmonella species

• Isolated from CSF of patients following head trauma or neurosurgical procedures

• Cause meningitis in neonates, the elderly, immunocompromised patients, and in patients with gram-negative septicemia

• Associated with disseminated strongyloidiasis in the hyperinfection syndrome

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EPIDEMIOLOGIC FEATURES OF HAEMOPHILUS INFLUENZAE

MENINGITIS• Causes 7% of cases in US; mortality 3-6%

• Capsular type b strains were in >90% of serious infections

• Concurrent pharyngitis or otitis media in >50% of cases

• Previously in children <6 years of age (peak 6-12 months)

• Disease in persons >6 years of age associated with:

Sinusitis or otitis media Pneumonia

Sickle cell disease Splenectomy

Diabetes mellitus Immune deficiency

Head trauma with CSF leak Alcoholism

INCIDENCE OF BACTERIAL MENINGITIS (UNITED STATES)

Incidence (cases per 100,000)

Organism 1986 1995 2006-2007

H. influenzae 2.9 0.2 0.08

S. pneumoniae 1.1 1.1 0.81

N. meningitidis 0.9 0.6 0.19

Group B streptococcus 0.4 0.3 0.25

L. monocytogenes 0.2 0.2 0.05

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CEREBROSPINAL FLUID FINDINGS IN BACTERIAL MENINGITIS

CSF Parameter Typical FindingsOpening pressure 200-500 mm H2OWhite blood cell count 1000-5000/mm3

Percentage of neutrophils >80%Protein 100-500 mg/dLGlucose <40 mg/dLCSF:serum glucose <0.4Gram stain Positive in 60-90%Culture Positive in 70-85%

CEREBROSPINAL FLUID FINDINGS IN BACTERIAL

VERSUS VIRAL MENINGITISCSF Parameter Bacterial Viral

Opening pressure 200-500 mm H2O <250 mm H2O

WBC count 1000-5000/mm3 50-1000/mm3

WBC differential Neutrophils Lymphocytes

Glucose <40 mg/dL >45 mg/dL

CSF:serum gluc <0.4 >0.6

Protein 100-500 mg/dL <200 mg/dL

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CEREBROSPINAL FLUID FINDINGS IN TUBERCULOUS MENINGITIS

CSF Parameter Typical Findings

Opening pressure 180-300 mm H2O

WBC count 50-300/mm3

Percentage mononuclear* 60-100%

Glucose <45 mg/dL

Protein 50-300 mg/dL

Smear Positive in <25% (1 study 86%)

Culture Positive in 18-86% (usually <50%)

PCR Sensitivity 33-94%; specificity 80-100%

*Note the “therapeutic paradox”

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LABORATORY AND CEREBROSPINAL FLUID FINDINGS IN CRYPTOCOCCAL MENINGITIS

Parameter Non-AIDS (%) AIDS (%)

Blood cultures - 30-63

Serum cryptococcal antigen 66 99

Opening pressure >200 mm H2O 72 62-66

CSF glucose <40 mg/dL 73 33

CSF protein >45 mg/dL 89 58

CSF leukocytes >20/mm3 70 13-31

CSF India ink 60 72-88

CSF culture 96 95

CSF cryptococcal antigen 86 91-100

FEATURES OF COCCIDIOIDAL MENINGITIS

• May present acutely, although usually subacute to chronic

• Patients generally complain of headache, low-grade fever, weight loss, and mental status changes; signs of meningeal irritation are usually absent

• Serum complement-fixing antibody titers >1:32 to 1:64 suggest disseminated disease

• CSF examination may occasionally reveal a prominent eosinophilia; CSF protein is almost always elevated

• Only 25-50% of patients have positive CSF cultures

• CSF complement-fixing antibodies present in at least 70% of cases; titers parallel course of meningeal disease

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FEATURES OF ANGIOSTRONGYLUS CANTONENSIS MENINGITIS

• Reported from many countries of the world (Thailand, Malaysia, Vietnam, Indonesia, Papua New Guinea, Taiwan, Pacific Islands); recent outbreak in Jamaica

• Rat infection rate in urban Bangkok ~40%

• May spread as rats move freely from port to port on ships

• Symptoms begin 6-30 days after ingestion of raw mollusks or other sources of the parasite

• Clinical findings are headache (90%), stiff neck (56%), paresthesias (54%), and vomiting (56%)

• CSF reveals a moderate pleocytosis with 16-72% eosinophils; larvae are occasionally found in CSF

CASE #2

• 56-year-old female with a 2-day history of fever, chills, headache, and confusion. Saw her physician 5 days earlier with complaints of earache; received ciprofloxacin

• T 1030F, P 140, RR 32, BP 90/60 mmHg• Obtunded, stiff neck, purpuric rash on lower

extremities• CSF showed opening pressure of 280 mm H2O,

WBC 2,500/mm3 (99% neutrophils), glucose 15 mg/dL, protein 400 mg/dL

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Suspicion for bacterial meningitis

Immunocompromise, history of CNS disease, new onset seizure, papilledema, altered consciousness, or focal neurologic deficit; or

delay in performance of diagnostic lumbar puncture

Negative CT scan of the head

Dexamethasone + empiric antimicrobial therapy

Blood cultures STATBlood cultures and lumbar puncture STAT

CSF findings c/w bacterial meningitis

Positive CSF Gram’s stain

Dexamethasone + empiric antimicrobial therapy

Dexamethasone + targeted antimicrobial therapy

YesNo

Yes

No

Yes

Yes

Dexamethasone + empiricantimicrobial therapy

Yes

Perform lumbar puncture

EMPIRIC ANTIMICROBIAL THERAPY OF PURULENT MENINGITIS

Age Antimicrobial Therapy

<1 month Ampicillin + cefotaxime

1-23 months Vancomycin + a third generation cephalosporina

2-50 years Vancomycin + a third generation cephalosporina

Older than 50 years Vancomycin + ampicillin + a third generation cephalosporina

acefotaxime or ceftriaxone

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EMPIRIC ANTIMICROBIAL THERAPY OF PURULENT MENINGITIS

Predisposing Condition Antimicrobial TherapyImmunocompromise Vancomycin + ampicillin +

either ceftazidime or cefepimeBasilar skull fracture Vancomycin + a third generation

cephalosporina

Head trauma or after Vancomycin + either ceftazidimeneurosurgery or cefepime or meropenem

Cerebrospinal fluid shunt Vancomycin + either ceftazidimeor cefepime or meropenem


TARGETED ANTIMICROBIAL THERAPY IN BACTERIAL MENINGITIS

Microorganism Antimicrobial Therapy

S. pneumoniae Vancomycin + a third generation

cephalosporina,b

N. meningitidis Penicillin G, ampicillin, or a

third generation cephalosporina

H. influenzae type b Third generation cephalosporina

L. monocytogenes Ampicillin or penicillin Gc

S. agalactiae Ampicillin or penicillin Gc

E. coli Third generation cephalosporina

acefotaxime or ceftriaxonebaddition of rifampin may be considered, especially if dexamethasone givencaddition of an aminoglycoside may be considered

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Appelbaum PC. Clin Infect Dis 34:1613, 2002

PNEUMOCOCCAL SUSCEPTIBILITY TO PENICILLIN

MIC (g/mL)

Previous New (CLSI)

Susceptible < 0.06 < 0.06

Intermediate 0.1-1.0

Resistant > 2.0 > 1.2

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ANTIMICROBIAL THERAPY IN BACTERIAL MENINGITIS

Organism Antimicrobial Therapy of ChoiceStreptococcus pneumoniae

PCN MIC <0.g/mL Penicillin G or ampicillinPCN MIC 0.1-1.0 g/mL Third generation cephalosporina,b

PCN MIC >2.0 g/mL Vancomycin + a third generationcephalosporina,c

Cefotaxime or ceftriaxone Vancomycin + a third generationMIC >1.0 g/mL cephalosporina,c

acefotaxime or ceftriaxonebcefotaxime/ceftriaxone susceptible isolatescconsider addition of rifampin if ceftriaxone MIC >2 g/mL


Organism Antimicrobial Therapy of Choice

Neisseria meningitidis

PCN MIC <0.1 g/mL Penicillin G or ampicillin

PCN MIC 0.1-1.0 g/mL Third generation cephalosporina

Haemophilus influenzae

-lactamase-negative Ampicillin

-lactamase-positive Third generation cephalosporina


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Organism Antimicrobial Therapy of ChoiceEnterobacteriaceaeb Third generation cephalosporina

Pseudomonas aeruginosa Ceftazidime or cefepimec

Streptococcus agalactiae Ampicillin or penicillin Gc

Listeria monocytogenes Ampicillin or penicillin Gc

Staphylococcus aureusMSSA Nafcillin or oxacillinMRSA Vancomycin

acefotaxime or ceftriaxonebchoice of specific agent must be guided by in vitro susceptibility resultscaddition of an aminoglycoside should be considered

CASE #3• 60-year-old male with acute myelogenous leukemia

presented with fever, headache, ataxia, and altered mental status. Recently traveled to an outdoor family picnic in rural Virginia. He is allergic to penicillin (anaphylaxis)

• T 102oF, P 120, RR 24, BP 100/60

• On examination, he was obtunded and had nuchal rigidity. Funduscopic exam revealed no papilledema. Babinski responses were positive bilaterally

• WBC was 25,000/mm3 (30% bands)

• LP revealed a WBC 1500/mm3 (50 neutrophils, 50% lymphocytes), glucose 30 mg/dL, and protein 200 mg/dL

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ANTIMICROBIAL THERAPY IN MENINGITIS

Organism Antimicrobial Therapy of Choice

Mycobacterium tuberculosis Isoniazid + rifampin +

pyrazinamide +ethambutol

Cryptococcus neoformans Amphotericin Ba

Candida species Amphotericin Ba

Coccidioides immitis Fluconazole

aaddition of 5-flucytosine should be considered

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ADJUNCTIVE DEXAMETHASONE IN BACTERIAL MENINGITIS

• Attenuates subarachnoid space inflammatory response resulting from antimicrobial-induced lysis

• Clinical trials (predominantly in infants and children) have demonstrated reduction in neurologic and/or audiologic sequelae

• Recommended for infants and children with Haemophilusinfluenzae type b meningitis and considered for pneumococcal meningitis in childhood, if commenced with or before parenteral antimicrobial therapy

• Recommended in adults with pneumococcal meningitis

• Administer at 0.15 mg/kg every 6 hours for 2-4 days concomitant with or just before first antimicrobial dose

ADJUNCTIVE DEXATHASONE IN BACTERIAL MENINGITIS

• 301 adults with bacterial meningitis >17 years of age

• Randomized, double blind, placebo-controlled

• Dexamethasone (0.15 mg mg/kg q 6 hr for 4 days) given 15-20 minutes before first antimicrobial dose

• All patients: reduction in unfavorable outcome (15 vs 25% P=0.03) and mortality (7 vs 15%; P=0.04)

• Pneumococcal meningitis: reduction in unfavorable outcome (26 vs 52%; P=0.006) and mortality (14 vs 34%; P=0.02)

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ADJUNCTIVE DEXAMETHASONE IN BACTERIAL MENINGITIS

• Randomized, double-blind, placebo-controlled trial in adolescents and adults in Vietnam revealed reduction in risk of death or disability only in those with confirmed bacterial meningitis (Mai et al. NEJM 2007;357:2431)

• Randomized, double-blind, placebo-controlled trial of adults in Malawi revealed no significant differences in mortality (Scarborough et al. NEJM 2007;357:2441)

ADJUNCTIVE DEXAMETHASONE META-ANALYSIS

• No difference in mortality, but a trend to decreased mortality in adults

• Reduced mortality in S. pneumoniae meningitis• Lower rates of severe hearing loss, any hearing

loss, and short-term neurologic sequelae• Benefits for hearing loss, neurologic sequelae,

and mortality only in high-income countries

Brouwer MC, et al. Cochrane Rev 2010.

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ADJUNCTIVE THERAPY IN MENINGITIS

• Tuberculous Meningitis– Corticosteroids (extreme neurologic compromise,

elevated ICP, impending herniation, impending or established spinal block; some would use for CT/MR evidence of hydrocephalus or basilar meningitis)

– Corticosteroids improve survival in those >14 years

• Cryptococcal Meningitis– Reduction in intracranial pressure (frequent high-

volume lumbar punctures, VP shunts)

• Angiostrongylus Meningitis– Corticosteroids (controversial)

CASE #4

• An 80-year-old male is brought to the hospital by his family because of personality changes and olfactory hallucinations

• On exam, T 1010F, P 90, RR 16, BP 120/90 mmHg

• He is confused and oriented only to person. There is no meningimus or evidence of focal neurologic deficits

• CT of head without contrast is negative; CSF reveals a WBC of 90/mm3 (95% lymphocytes), glucose of 80 mg/dL (serum 100 mg/dl), and protein of 70 mg/dL

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ENCEPHALITIS

• Most etiologic agents in US are viruses– Herpes simplex

– West Nile virus

– Enteroviruses

• Etiology not identified in 32-75% of cases

• Target workup for specific etiologic agents based on epidemiologic factors

ENCEPHALITISETIOLOGY

• California Encephalitis Project (CEP) reviewed 1,570 cases over 7-year period (CID 2006;43:1565)

• Confirmed or probable etiology in 16%– 69% viral

– 20% bacterial

– 7% prion

– 3% parasitic

– 1% fungal

• Possible etiology in 13%

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HERPES SIMPLEX ENCEPHALITIS

• Causes 5-10% of cases worldwide

• HSV-1 in adults

• HSV-2 in neonates

• Clinical– Fever; hemicranial headache, cranial nerve deficits

– Behavioral abnormalities; memory impairment

– Seizures

CASE #5

• 50-year-old man evaluated for obtundation and fever

• Brain MRI with gadolinium reveals swelling and enhancement of the left temporal lobe; CSF analysis reveals a WBC of 10/mm3, normal glucose and elevated protein

• Intravenous acyclovir is initiated

• CSF PCR for HSV 1 and HSV 2 is negative

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HERPES SIMPLEX ENCEPHALITIS DIAGNOSIS

• Neuroimaging– MRI is procedure of choice– Edema and hemorrhage in temporal lobes– Bilateral temporal lobes

• CSF Analysis– Lymphocytes, increased protein, normal glucose– Polymerase chain reaction

• EEG– Periodic lateralizing epileptiform discharges

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ELECTROENCEPHALOGRAPHY

• Indicator of cerebral dysfunction

• Nonspecific, but may show characteristic patterns secondary to certain etiologic agents– Temporal focus with PLEDs in 80% of those

with HSV

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CSF PCR FOR DIAGNOSIS OF HSV ENCEPHALITIS

Biopsy + Biopsy -

PCR +

PCR -

53 3

1 44

Sensitivity 98%; Specificity 94%; PPV 95%; NPV 98%

DURATION OF POSITIVE CSF HSV PCR AFTER THERAPY

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BRAIN BIOPSY

• Rarely used today, but consider in those who continue to deteriorate neurologically despite treatment with acyclovir

• Neuroimaging as a guide to biopsy site

• DO NOT PLACE TISSUE IN FORMALIN

• Culture, PCR, immunofluorescence, EM, histopathology with appropriate staining

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CASE #6

• 75-year-old woman from Colorado presents with acute onset of altered mental status and fever

• Neurologic examination reveals bilateral tremors of the extremities and cogwheel rigidity

• Brain MRI reveals T1 hypodense lesions in the thalamus and basal ganglia that are hyperintense on T2 images

• CSF analysis reveals a WBC count of 300/mm3, normal glucose, and elevated protein

WEST NILE VIRUS

• First US cases reported in 1999 in New York City

• Birds are main reservoirs• Mosquito vector

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West Nile Virus Transmission Cycle

Bird reservoir hosts

Mosquito vector

Incidental infections

WEST NILE VIRUS OTHER MODES OF TRANSMISSION

• Transplanted organs

• Blood transfusions

• Breast milk

• Transplacental

• Occupational

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WEST NILE VIRUSCLINICAL SYNDROMES

• No clinical illness or symptoms (~80%)

• West Nile Fever (~20%)

• Severe WNV Disease (1 in 150)– Meningitis

– Encephalitis/Meningoencephalitis

– Poliomyelitis-like flaccid paralysis

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WEST NILE VIRUSDIAGNOSIS

• Serum IgM antibody (8-14 days of illness onset)

• CSF reveals lymphocytic pleocytosis and elevated protein; glucose is normal

• CSF IgM (preferred for CNS infection)

• CSF PCR (<60% sensitivity)

• Neuroimaging

Copyright restrictions may apply.

Sejvar, J. J. et al. JAMA 2003;290:511-515.

T2-Weighted Axial Magnetic Resonance Image From a Patient With West Nile Virus Encephalitis

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EMPIRIC THERAPY FOR ENCEPHALITIS

Acyclovir

+

?

EMPIRIC THERAPY FOR ENCEPHALITIS

Likely Etiology Additional TherapyBacterial meningitis Vancomycin + ampicillin +

a third-generation cephalosporin (cefotaxime or ceftriaxone)

R. rickettsii DoxycyclineE. chaffeensisA. phagocytophilum

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THERAPY FOR ENCEPHALITIS

Etiology Therapy

HSV Acyclovir

VZV Acyclovir

CMV Ganciclovir + foscarnet

HHV-6 Ganciclovir or foscarnet

B virus Valacyclovir

HIV HAART

JC virus HAART

THERAPY FOR ENCEPHALITIS

Etiology Therapy

SLE Interferon-2b

Nipah virus Ribavirin

Influenza Oseltamivir

SUPPORTIVE THERAPY FOR ALL

OTHER VIRUSES

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WEST NILE VIRUSTHERAPY

• Supportive care

• Ribavirin

• Interferon alpha

• Intravenous immunoglobulin

• MGAWN1

MGAWN1

• Humanized monoclonal antibody that recognizes the envelope protein of WNV

• Animal studies– Improves survival and clears virus from CNS– Serum:CSF concentration ratio ~400

• Phase I trial (half-life 640 hours)• Randomized, double-blind, placebo-

controlled trial (30 mg/kg)

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CENTRAL NERVOUS SYSTEM INFECTIONS - Confex · Malaysia, Vietnam, Indonesia, Papua New Guinea,...

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