Meningitis

Infections of the Central Nervous System: Meningitis and Brain Abscesses

Robyn S. Klein, M.D., Ph.D.Washington University School of Medicine

Case Presentation

60 year old woman presents to ER in NC during the summer with new onset seizures. She had been well until four days prior whenshe developed a URI. One day ago she developed a fever and HA.Last evening the HA worsened and she appeared confused at times.This morning she entered her kitchen, poured a box of cereal on the table, then drove her car through the closed garage door.There is no history of travel and she has no other significant medicalhistory.

PE reveals an acutely ill, irritable patient. She is oriented to placeand year but cannot calculate. Temp is 101.6 F (38.7 C), pulse is100/min, RR 24/min and BP 110/60 mm Hg. There is no rash. Pupilsare equal and reactive, neck is moderately stiff to passive motion. There are no localizing neurologic findings.

Laboratory Studies

Hematocrit 36%WBC 11 (85% PMNs, 12% lymphs, 3% monos)BUN 12Plasma glucose 105Elecrolytes normal

Head CT+contrast: nonenhancing, low-density temporal lobe lesionCSF: normal OP, cell count 200 (65% lymphs, 35% PMNs), 2 RBCs glucose and protein are normal.Gram stain: negative for bacteria

Which antimicrobials would you start?a. Ampicillin and ceftriaxoneb. Ampicillin, vancomycin and ceftriaxonec. Ampicillin, ceftriaxone and acyclovird. Ampicillin and metronidazole

Ampicillin, ceftriaxone and acyclovir

Approach to the Diagnosis of CNS Infections

Assess risk for infectionExposures

SeasonConcomitant illnesses

Physical ExaminationAssess safety of LP

Identify other findings

Diagnostic EvaluationPathogen specific vs. nonspecific

CSF and neuroimaging

liklihood of herniationviral meningitisencephalitissubarachnoid hemorrhagemost bact. meningitis

liklihood of herniationsevere bact. Meningitissubdural empyemabrain abscesssevere HSVrickettsial encephalitisReye syndrome

Pathogenesis

1. Nasopharyngeal acquisition2. Bloodstream invasion3. Bacterial entry into CSF4. Multiplication within CSF5. Subarachnoid space inflammation6. Increased BBB permeability and vasogenic,

cytotoxic and interstitial edema7. Increased intracranial pressure

• CNS devoid of classical APCs•dendritic cells localized to meninges, vessels and choroid plexus

• CNS without lymphatics

• CNS lacks constitutive MHC•MHC II expression restricted to recruited APCs

• Blood-brain/CSF barrier

Immune surveillance/activation in the CNS

Flugel, Nature, 2009; 462, 94-98

Routine CSF Studies

CSF pressureGross examination for turbidity/color

Cell countMeasurement of [protein] and [glucose]

Gram stainBacterial culture

Mycobacterial culture (AFB smear)Fungal culture (cryptococcal Ag)

Viral culture and/or PCRVDRL

Oligoclonal bands

Meningitic Syndrome• Classic triad (>90% of cases)

– Fever (>100.5) – Headache– Nuchal rigidity (“stiff neck”)

• Kernig’s sign (no extension)• Brudzinski’s sign (responsive flexion)

• Altered MS (75%)– Seizures in 40% (adults)– Cerebral herniation in 1-8%

• Common complaints– Nausea/vomiting esp. in kids– photophobia

• Rash in 11%

• CT findings: distention of SAS, meningeal enhancement

• Leading causes: bacteria and viruses

• Differential diagnosis includes RMSF, SLE, Behcet’s syndrome and chemical causes (NSAIDs)

An audit of acute bacterial meningitis in a large teaching hospital 2005-10.Stockdale AJ, Weekes MP, Aliyu SH.QJM. 2011 Aug 11.

Press. WBC/mm3 Glucose Protein CSF bugs?

Normal <180 0-5 50-75 15-40 None

Bacterial meningitis

100-5,000

PMNs

<40 100-1,000

Gram stain + Culture +

Brain abscess

10-200

lymphs

Normal 70-400 None

Subdural empyema

10-2,000

lymphs*

Normal 50-500 None

TB meningitis

<500

lymphs

<50 100-200

Mtb

Crypto

Meningitis

10-200

lymphs

<40 50-200 Crypto Ag

Viral meningitis

10-1,000

lymphs*

Normal 50-100 Virus

CSF Findings

Imaging of Intracranial Infections

CT • Rapid (~10 min)• High density=white (bone

and blood)• Low density=gray (brain,

CSF, air)• Iodinated contrast

evaluates BBB

MRI• Takes time • Images in 3 planes• Can assess

– Morphology/pathology– Blood flow– BBB (Gadolinium)

• Contrast resolution• Technological advantages

– FLAIR– MTI– DWI

MRI Imaging in Meningitis

Axial FLAIR: cerebritis Post-contrast T1WI: area of enhancement

Pyogenic Meningitis

• Leptomeningitis

Inflammation of arachnoid tissue/space

Dura

Arachnoid

Space

Pia

Parenchyma

Copyright protected material used with permission of the authors and the University of Iowa’s Virtual Hospital, www.vh.org

Clinical Clues to Etiology• Age• Predispositions

– URIs– smoking– pregnancy

• Immune status• Epidemiologic considerations

– Meningococcal outbreaks– H. flu. Infections in family– Season

• Rashes– Petechial-purpuric vs. Maculo-petechial

• Atypical presentations– Think: brain/parameningeal abscess– Think: BE– Think: tumor-related CSF leak

General Management of Suspected Meningitis

• Early recognition often difficult• Initial clinical survey

– Secure airway, vascular access– Provide oxygen– Evaluated for altered MS– Administer mannitol

• Empiric antibiotics!• THEN LP• Treatment delay increases morbidity/mortality• Vaccination: Hib type 2, MCV-4 (serogroups A, C, Y

and W-135)

Determination of Etiologic Agent• CSF gram stain

– Past: used to guide initial Rx; now thought to be misleading– In pneumococcal meningitis, gram stain positive in 70-90%

• CSF/blood cultures positive in 77% of episodes in adults– Positive in 60-80% of untreated patients (yield is 20% lower with

prior antibiotic therapy)– Sensitive, but this varies with offending organism:

• 90%: pneumococci or staphylococci• 86%: H. influenzae (now eradicated by Hib vaccine)• 75%: N. meningitidis A,C,Y,W135

• 50%: gram negs. Listeria or anaerobes, fungi (nonAIDS)• 37%: mTB (requires large volumes)

Incidence of Bacterial Meningitis in USA

Percentage Incidence

(per 100K)

Fatality Rate (%)

S. pneumo.* 71 1.1 21

N. mening. 12 0.6 3

Gp B Strep. 7 0.3 7

L. monocyt. 4 0.2 15

H. Influ. 6 0.2 6

Others: Staph/Strep,

Gram negs

*44% intermediate or high level resistance to penicillin

Pneumococcal conjugate vaccine (PCV7): •Added in 2000•Effective in preventing IPD•Provides herd immunity•2003: drop in 30K cases•Overall 33% decrease in cases, esp <5yo

• Other causes of erythematous or petechial rash:– Enterovirus– ECHO virus type 9– H. influenzae– S. pneumoniae– RMSF– S. aureus endocarditis

Petechial/Ecchymotic Rash: Meningococcemia

Invasive meningococcal disease occurs in three common clinical forms: meningitis (50% of cases), blood infection (30%) and pneumonia (10%); other forms account for the remainder (10%) of the cases.

Onset can be abrupt and course of disease rapid.

Case fatality rate is 10%-14%; 11%-19% of survivors suffer serious sequelae (a condition caused by previous disease) including deafness, neurologic deficit, or limb loss.

Meningococcal Disease

Causative Bacteria

Meningococci are carried only by humans in the nasopharynx—their only reservoir

Overall 5%-10% of the population carries the bacteriaAdolescents and young adults have the highest carriage ratesFew carriers develop disease

Transmission occurs when close, face-to-face contact permits the exchange of salivary secretions from people who are ill or are carriers

Worldwide, the vast majority of disease is caused by 5 serogroups (A, B, C, Y, W-135) of the bacterium

In the United States, almost all cases are caused by serogroups B, C and Y; there is currently no licensed vaccine that protects against serogroup B in the U.S.

Meningococcal Conjugate Vaccine (MCV4)Licensed in the United States for persons 2–55 years of ageCovers Serogroups A, C, Y and W-135Included in the Vaccines for Children (VFC) ProgramCost to private sector per dose: $100.00-$110.00Indications:

college freshmen living in a dormitorymilitary recruitsSplenectomyComplement deficiencyOccupational exposureTravel to endemic countries (Sub-Saharan Africa)

Meningococcal Polysaccharide Vaccine (MPSV4)Licensed in 1981Recommendations for use: MPSV4 is recommended for individuals who are at elevated risk aged over 55

Complications of Meningitis• Brain swelling with increased IC pressure/herniation• Cortical vein phlebitis/cerebral arteritis and infarction• Subdural effusions/empyema• Hydrocephalus• Ventricular empyema• Sagittal sinus thrombosis• Focal cortical necrosis

• 10% still die• 40% survivors: mental retardation, paralysis, blindness

Meningitis in Tropical Areas• Hib, S. pneumo. with >30% resistance• Unusual pathogens

– Nontyphoidal Salmonella spp.– S. Aureus– S. Suis– mTB (especially elderly, IC)– Angiostrongylus cantonensis (rat lung

worm)Paralysed and in agony: How one man's dream trip became a holiday from hell after he was struck by crippling 'rat lungworm' parasite By HANNAH ROBERTSUPDATED: 08:19 EST, 21 January 2012

Initial Therapy for Community Acquired Purulent Meningitis

Age Pathogens Drugs

3mo-50y S. pneumo. Vanco + CeftriaxN. mening. 500mg q6hr 2g q12hr

>50y L. monocyt. Above + Ampicillin2g q4hr

Skull fx S. pneumo. Vanco + Cefepime or MeroCSF leakvarious Strep. 2g q8hr

Corticosteroids: 0.15 mg/kg, q6hr, starting with first dose of antibx

Antibiotic Penetration into the CSF

Class Antibiotic CommentsStandard dose

adequate

Chloramphenicol,

Sulphonamides, trimethoprim, fluoroquinolones, metronidazole, rifampicin, isoniazid, pyrazinamide

Good oral availability

Require high dose Penicillins, cephalosporins

Penetration enhanced by inflamed meninges

Standard dose only when meninges inflamed

Vancomycin, clindamycin, ethambutol

Toxicity prevents high dose

Do not penetrate CNS Aminoglycosides Requires intrathecal administration

Chemoprophylaxis for contacts of index case

• Neisseria meningitidis– Household contacts including pupils in same dormitory or sharing a kitchen– Any mouth-to-mouth contact– Unprotected ET intubation during 7 days prior– Immunize contacts as well– Agents: rifampin, cipro

• Hemophilus influenzae type b– Household contacts if one is <4 and unimmunized– Household contacts of IC child regardless of immunization status– All school contacts regardless of age when 2 or more cases occur in <120

days– Index case <2 yrs or member of household with a susceptible contact

treated with regimen other than ceftriaxone, cefotaxime– Agents: rifampin

An audit of acute bacterial meningitis in a large teaching hospital 2005-10.Stockdale AJ, Weekes MP, Aliyu SH.QJM. 2011 Aug 11.

Diseases resembling chronic meningitis– Infectious

• Aseptic meningitis• Viral encephalitis• partially treated BM• endocarditis

– Noninfectious• Metabolic encephalopathies• Brain tumors• Subdural hematoma• MS• SLE• Post-infectious encephalitis• Giant cell arteritis• TTP

Causes of Chronic Meningitis

Infectious• Tuberculosis• Fungal infections• Syphillis• Neuroborreliosis

Noninfectious• Carcinoma• Sarcoid• Granulomatous

angiitis• SLE • Behcet’s disease• Vogt-Kohanagi

Harada syndrome

Diagnostic Evaluation of Chronic Meningitis

• CBC, chemistry panel• Blood/urine/sputum Cx• CXR• Head CT +contrast• ANA, RF, EST• Serologies: histo, cocci, syphillis, lyme• PPD• CSF: glucose, protein, cell count, Cx for bacteria, fungi, AFB

Cryptococcal Ag/Ab, CSF VDRL, cytology

Granulomatous Meningitis: Subacute or Chronic Syndromes

• Course runs weeks to years

• Symptoms and signs may fluctuate

• Fever, HA, stiff neck, photophobia, MS --time course gradual, lethargy common

Granulomatous Meningitis: TB

• Primarily in patients from underdeveloped countries; <10% of all meningitis in USA

• Occurs secondary to hematogenous spread

• Tuberculomas form in or near arachnoid layer--> rupture and induce intense inflammatory response

• Diagnosis requires large volumes CSF

TB Meningitis

A. CT: tuberculomas

B. Fourth Ventricle

C. caseating granuloma

www.vh.org

www.vh.org

A. MRI: Basilar meningitis

Treatment of TB Meningitis

• Required anti-TB chemotherapy– INH, RIF, PZA, ETH

• Duration of therapy– 4 drugs x 3 mos– 3 drugs x 6 mos

• Corticosteroids: improves survival not disability– IV Dexamethasone 4 wks– Oral Dexamethasone 4 wks

• Clinical & diagnositic follow-up

Granulomatous Meningitis: Fungi

• Cryptococcus– CSF Ag: positive in 83-98% of patients

• Candida– IVDU, trauma, surgery

• Coccidioides immitis– Complement fixing Abs in up to 95%

• Histoplasma (rare)– CSF vs. urine Ag

Copyright protected material used with permission of the authors and the University of Iowa ’s Virtual Hospital, www.vh.org

Treatment of Fungal Meningitis

• Cryptococcal– Ampho B + Flucytosine (pk 70-80; tr 30-40 mg/L)– Fluconazole– Suppression: Fluconazole or Itraconazole

• Candidal– Ampho B + Flucytosine or + Fluconazole

• Coccidioidomycosis– Fluconazole indefinitely– Ampho B

• Histo/blasto– Ampho B

Fungal Cerebritis/Abscess

• Opportunistic invaders • Granulomatous

inflammation with hemorrhagic necrosis

• Most common pathogens:– Candida– Aspergillus– Zygomycetes

• Differential Diagnoses• Treatment

– Ampho B– Azoles– Flucytosine– Extensive drainage

Copyright protected material used with permission of the authors and the University of Iowa ’s Virtual Hospital, www.vh.org

Lymphocytic (Aseptic) Meningitis

• Usually of viral etiology• Produces minimal changes grossly• Negative CSF cultures and stains

Common Less common RareEnteroviruses HSV-1 Adenovirus LCMV CMVArboviruses Mumps EBV EBVHSV-2 LCMV Influenza A, BHIV-1 ?VZV Measles

ParainfluenzaRubella

Copyright protected material used with permission of the authors and the University of Iowa ’s Virtual Hospital, www.vh.org

Approach to the Patient with Aseptic Meningitis

History: history of travel, organ transplant

exposures to HIV, TB, STDs, rodents, insects, drugs systemic signs; season

PE: skin: exanthem, enanthem, vesiclesParotitis: mumps, LCMV, coxsackievirus Orchitis: mumps, LCMVLAD: EBV, HIV, CMV

Lab eval: CSF studies (PCR, cultures)PPD, VDRL, HIV Abacute and convalescent serologies

Amplification of Viral Nucleic AcidsPCR, NAS-BA, BC-DNA

Single most important method for diagnosis of:HerpesvirusesEnterovirus 71

Treatment of Viral Meningitis

• Enteroviruses: Pleconaril (VP 63843) 400 mg tid• Herpesviruses: Acyclovir 10mg/kg IV with hydration• LaCrosse Virus or HF viruses: Oral Ribavirin

– Loading dose 30 mg/kg – then 15 mg/kg q6 x 6 dys; 7.5 mg/kg q6 x 6 dys

• WNV: High titer IVIG has had variable results• Corticosteroids• Airway protection/Mannitol

Brain Abscesses

• Relatively uncommon: 1/100,000 persons/yr• 75% are associated with peripheral infections

– Pre-antibiotic era: mastoiditis, otitis media or paranasal sinusitis– Current era: pulmonary infections and endocarditis

• Opportunistic infections• Parasites• Course of primary infection: months to years• Presents with HA (>75%), focal neurologic deficit (>60%),

seizure (25-30%)• HA, N/V often begin intermittently, progress to crisis• Mortality: 33-50%

Stages of Abscess Development

1

2

3

Cerebritis: inflamed areawith discoloration and softening.

Formation of capsulewith soft center.

Formation of fibro-glioticcapsular wall withpus-filled center.

(Tung and Rogg, 2003, AJNR, 24:1110)

Bacterial Abscesses

• Most Common Organisms (80%):– Anaerobic streptococci– Pneumococcus sp– Staphylococcus sp.

• Less Common Organisms (15%):– Coliforms– Actinomyces

• Occasional Findings (5%):– Multiple organisms– No organisms

• Differential Diagnoses– CNS infections– CNS neoplasms– Cerebrovascular disease

• Treatment– PCN– Metronidazole– 3rd gen Ceph– Nafcillin or Vanco– Drainage– Anticonvulsants