DIAGNOSIS AND MANAGEMENT OF ACUTE BACTERIAL MENINGITIS

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DIAGNOSIS AND MANAGEMENT OF ACUTE BACTERIAL
MENINGITIS

• Amanda Peppercorn, MD
• Assistant Professor of Medicine
• Division of Infectious Diseases

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Case Example

• 25 year old WM presents in July with 4 days of
  fever (Tm 101F), malaise, headache, anorexia and
  mild watery diarrhea
• Presents for evaluation when he starts to notice
  faint rash on trunk, back and arms
• No known sick contacts
• PMHx episode of gonorrhea 2 years ago
• All PCNrash
• Meds ibuprofen prn, more recently with onset of
  HA
• Soc Hx MSM, one new partner, HIV negative one
  year ago, no IDU, tob, etoh, no overseas travel,
  lives in Massachusetts, works at Starbucks
• Fam Hx unremarkable

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• PE T 100.5F HR 100 BP 105/70 RR 15 Sat 98
• Gen Ill appearing young man, uncomfortable on
  stretcher, fatigued
• HEENT photophobia, no papilledema or
  conjunctival petechiae or injection, OP benign,
  no thrush, mouth sores or pharyngitis, no
  cervical LAD
• Neck meningismus with any movement
• Lungs CTA
• Cor tachy, reg, no m/r/g
• Abd slight tenderness diffusely, no HSM
• Ext no c/c/e
• Skin faint macular rash on trunk, back and
  extremities, spares face and palms/soles
• Genital no external lesions
• Neuro sleepy but arousable, AO x 3, CN intact,
  reflexes 2 and symmetric, motor and sensory
  intact, coordination intact, no asterixis, GCS 13

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Labs

• WBC 3.2, Hct 38, Plts 350K, normal diff
• Chemistries Bun 18 Cr 0.9 LFTs normal Glucose
  75
• PT/PTT/INR normal
• EKG 1st AVB
• CXR Clear
• LP OP 15, TNC 200 50P 40L 10Other
• RBC 50 Gluc 45 TP 55

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What does he have?

• Questions to address
• Meningitis or encephalitis?
• Bacterial or aseptic
• Likely pathogen?
• Clues?
• Appropriate isolation?
• Appropriate immediate management?
• Treatment?
• Prognosis?

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EPIDEMIOLOGY

• Incidence and pathogens vary by age
• Incidence and pathogens vary by host defense
  factors (e.g., immunocompromising conditions,
  neurosurgery)
• Incidence and pathogens change over time due to
  improvements in immunizations
• Conjugate pneumococcal vaccine
• Conjugate H. influenzae vaccine
• Conjugate quadrivalent meningococcal vaccine
  (covers type A, C, Y and W-135) omits coverage
  for type B

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ETIOLOGIES OF SINGLE EPISODE ACUTE BACTERIAL
MENINGITIS, MGH 1962-88

• Community Acquired (N253)
• S. pneumoniae 38
• N. menigitidis 14
• L. monocytogenes 11
• Streptococci 7
• H. influenzae 4
• GNR 4
• Mixed 2
• Other 2
• Culture negative 13

• Nosocomial (n151)
• GNR 38
• Streptococci 9
• Coag neg staph 9
• S. aureus 9
• S. pneumoniae 5
• H. influenzae 4
• L. monocytogenes 3
• Enterococcus 3
• N. menigitidis 1
• Mixed 7
• Other 3
• Culture negative 11

Durand M, Calderwood SB, Weber DJ, et al. NEJM
199332821
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EPIDEMIOLOGY OFBACTERIAL MENINGITIS, US, 1996

• Worldwide 1.2 million cases each year
• 10th most common cause of infectious death
• 135,000 deaths annually
• Neurologic sequelae common

Schuchat A, et al. NEJM 1997337970-6
10

• Swartz M, NEJM 2004

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MANAGING ACUTE MENINGITISHISTORY

• Duration/pace of symptoms
• Recent exposure to someone with meningitis
• Tick exposure
• Rash (viral exanthems, ulcerations, petechial or
  palpable purpura)
• A recent infection (especially respiratory or
  otic infection)
• A history of recent head trauma, otorrhea or
  rhinorrhea
• Recent travel, particularly to areas with endemic
  meningococcal disease such as sub-Saharan Africa
• A history of injection drug use
• HIV serostatus, sexual history
• Any other immunocompromising conditions
• Recent use of antibiotics
• Serious antibiotic allergies
• TB exposure
• Pregnancy

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Nosocomial

• Risk Factors
• Head trauma
• Neurosurgery
• CSF leak
• VP shunt, hardware
• Underlying illness (DM, luekemia, AIDS,
  cirrhosis)
• Pathogens
• Staph aureus (MSSA and MRSA)
• Enteric GNRs (E coli, Klebsiella)
• Polymicrobial gram negative meningitis think
  Strongyloides hyperinfection syndrome
• Mortality
• Up to 35

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CLINICAL FINDINGS IN COMMUNITY-ACQUIRED BACTERIAL
MENINGITIS
Symptom US, MGH 1962-88 (296) Netherlands 1998-92 (N696)
Fever, neck stiffness ? MS 67 44
1 sign present 99 (fever, neck stiffness, ? MS) 99 (fever, HA, neck stiffness, ? MS)
2 signs present NA 95 (as above)
Fever 95 77
Neck stiffness 88 83
Headache NA 87
Rash 11 26
22/30 N. menigitidis, rash also present with S.
pneumoniae, H. influenzae, negative culture
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CSF FINDINGS IN COMMUNITY-ACQUIRED ACUTE
BACTERIAL MENINGITIS, MGH

• Opening pressure (mm H20)
• 0-139 9
• 140-299 52
• 300-399 20
• gt400 19
• WBC per mm3
• 0-99 13
• 100-4999 59
• 5000-9999 15
• gt10,000 13

• Percent PMNs
• 0-19 2
• 20-79 19
• gt80 79
• Glucose mg/dL
• lt40 50
• Gram stain
• Positive 60
• Culture
• Positive 73

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Neurologic Complications

• Systemic
• Septic shock
• ARDS
• DIC
• Septic or reactive arthritis
• Death (25)
• Older age
• Obtundation at presentation
• Seizures within 24 hours
• Strep pneumonia

• Neurologic
• Impaired mental status
• Increased ICP, herniation
• Seizures (25)
• CN palsies, focal neurologic deficits
• Sensorineural hearing loss
• Neurocognitive/intellectual impairment

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TREATMENTGENERAL GUIDELINES

• Use bactericidal drugs
• Cover potential for resistance
• S pneumonia Vanc (20 PCN-R, 5 CTX-R)
• Neisseria mening Ceftriaxone
• Use highest safe dose
• Use antibiotics that penetrate CNS
• Provide all antibiotics by intravenous route
• If bacteristatic antibiotic is used (e.g.,
  doxycycline) initiate after bactericidal drug
• Ideally initiate antibiotics within 30 minutes
  for acute bacterial meningitis

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TREATMENTEMPIRIC THERAPY

• Age 18-50
• S. pneumoniae, N. meningitidis much less likely
  H. influenzae, L. monocytogenes, Grp B
  streptococcus
• Ceftriaxone 2 mg IV Q12 hr plus vancomycin 1 gm
  IV Q12 hr
• Consider adding doxycycline 100 mg IV Q12 hr
  (RMSF season)
• Acyclovir if HSV or VZV suspected
• Age gt50
• S. pneumoniae, N. meningitidis, L. monocytogenes
  less often Grp B streptococcus, H. influenzae,
  GNR
• Above plus ampicillin 2 gm IV Q4 hr
• Consider adding doxycycline 100 mg IV Q12 hr
  (RMSF season)
• Acyclovir if HSV or VZV suspected

30-45 mg/kg per day divided every 8-12 hours
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TREATMENTEMPIRIC THERAPY

• Impaired cellular immunity
• L. monocytogenes, Gram-negative bacilli
• Ceftazidime 2 g IV Q8 hr plus vancomycin 1 gm IV
  Q12 hr plus ampicillin 2 mg IV Q4 hr
• Consider adding doxycycline 100 mg IV Q12 hr
  (RMSF season)
• Nosocomial meningitis
• Coagulase negative staphylococcus, S. aureus,
  Gram-negative bacilli, streptococci
• Ceftazidime 2 g IV Q8 hr plus vancomycin 1 gm IV
  Q12 hr

Use ceftazidime instead of ceftriaxone for
improved coverage of P. aeruginosa
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TREATMENTPENICILLIN-ALLERGIC PATIENT

• Options
• Replace ceftriaxone or ceftazidime with meropenem
  (carbapenem approved for meningitis) small risk
  of cross reactivity
• Coverage MSSA, streptococci, penicillin-suscepti
  ble pneumococci, meningococcus, GNRs, P.
  aeruginosa
• Replace ceftriaxone or ceftazidime with aztreonam
  (monobactam) low risk of cross reactivity (no
  coverage for pneumococcus)
• Coverage Meningococcus, GNRs, P. aeruginosa
• Replace ceftriaxone with chloramphicol (or
  moxifloxacin)
• Coverage chloramphenicol Streptococci,
  pneumococci, RMSF, meningococcus, H. influenzae

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DURATION OF THERAPY

• Neisseria meningitidis 7 days
• Hemophilus influenzae 7 days
• Streptococcus pneumoniae 10-14 days
• Streptococcus agalactiae 14-21 days
• Aerobic GNR 21 days
• Listeria monocytogenes gt21 days

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ETIOLOGIES OF ACUTE MENINGITISIN HIV INFECTED
PATIENTS

• Usual bacterial agents S. pneumoniae, N.
  meningitidis, H. influenza
• Other bacteria TB, Syphilis, L. monocytogenes
• Viruses (acute HIV, CMV, HSV, VZV)
• Fungi Cryptococcus (most common), Histoplasma,
  Coccidioides

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CASE FATALITY RATE,BACTERIAL MENINGITIS
Pathogen MGH (N493) 1962-88 4 states (N248) 1995 Netherlands (N696) 1998-02
S. pneumoniae 25 (28) 21 21
N. meningitidis 10 (10) 3 7
H. Influenza 11 (11) 6 ---
L. monocytogenes 21 (32) 15 ---
GNR 23 (36) --- ---
S. aureus 28 (39) --- ---
Streptococci 17 (25) 7 (GBS) ---
Enterococcus 25 (50) ---- ---
NEJM 199332821-28 ( total mortality) NEJM
1997337970-6 NEJM 20043511849-59
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MANAGEMENT OF MENINGITISKEY CLINICAL DECISIONS

• Clinical presentation
• Meningitis Viral, bacterial, fungal,
  mycobacterial
• Encephalitis (abnl brain functionmotor/sensory,
  change in MS, personality, speech/movement)
  Arboviruses, HSV
• Onset
• Acute S. pneumoniae, N. meningitidis
• Chronic Fungal, mycobacterial
• Recurrent S. pneumoniae
• Host
• Normal
• Immunocompromised HIV, organ transplant, steroids

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Aseptic Meningitis

• Definition signs/sx/laboratory evidence of
  meningitis with negative standard bacterial cx
• Most common cause enteroviral (summer,
  coxsackie, echovirus, nonpolio enteroviruses, dx
  by PCR)
• Other etiologies spirochetes (lyme, RMSF,
  syphilis), mycobacteria (TB), mycoplasma, drugs
  (NSAIDS, sulfa), cancer, parameningeal focus,
  autoimmune (neurosarcoid, behcets, SLE)
• Viruses primary HSV, VZV, HHV6, CMV, acute HIV,
  mumps, LCM, West Nile virus, adenovirus
• Parasites Angiostrongylus cantonensis (rat
  lungworm, SE Asia), CSF eosinophilia
• Recurrent aseptic (Mollarets) meningitis HSV-2

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ED MANAGEMENTSUSPECTED MENINGITIS

• Initiate droplet precautions (N. meningitidis)
• Appropriate resuscitation (fluids, airway, etc.)
• Blood cultures x 2
• LP within 30 minutes
• If LP cannot be performed within 30 minutes
  initiate empiric antibiotics
• Consider dexamethasone for bacterial meningitis,
  especially if pneumococcal disease suspected or
  demonstrated
• CT with contrast or MRI with gadolinium if CNS
  mass lesion suspected

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INDICATIONS FOR BLOOD CULTURES

• Before the use of parenteral or systemic
  antimicrobial therapy in ANY hospitalized patient
  with fever (gt38 oC) combined with leukocytosis or
  leukopenia
• Systemic and localized infections including
  suspected acute sepsis, meningitis,
  osteomyelitis, arthritis, acute untreated
  bacterial pneumonia, and fever of unknown origin
  in which abscesses or other bacterial infection
  is possible.
• Test of cure 48-72 hours after initiation of
  therapy for bacteremia or fungemia

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DOs AND DONTs OF OBTANING BLOOD CULTURES

• Always obtain using strict aseptic technique to
  prevent contamination (i.e., a false positive
  result)
• Label bottles properly (name, hospital number)
• Fill bottles with proper volume
• Adults 10 mL per bottle
• Children 0.5-5 mL per bottle (based on weight)
• Obtain at least 2 blood cultures
• Yield related to number of cultures obtained
• Allows assessment of skin commensals
  contaminating cultures

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DOs AND DONTs OF OBTANING BLOOD CULTURES

• Obtain cultures from different sites (or same
  site separated by at least 30 min)
• Never split blood obtained at single time from
  single site into multiple blood culture sets
• Avoid femoral site (if possible)
• Avoid obtaining blood through non-intact skin (if
  possible)
• Obtain via an arterial line only if no other site
  available

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DOs AND DONTs OF OBTANING BLOOD CULTURES

• Do not obtain blood via a peripheral catheter
• Rate of contamination 9.1 (via catheter) vs 2.8
  (via peripheral stick) Weinstein M. CID
  19962340
• Do not change needles between venipuncture and
  inoculation of blood culture bottles

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CONTAMINATION AND TRUE INFECTION RATE OF BLOOD
CULTURES, UNC
2007
2008
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ISOLATION FORAIRBORNE/DROPLET DISEASES

• Airborne isolation
• Private room, direct out exhausted air, negative
  pressure
• N95 respirator for entering room
• Diseases TB, measles, varicella

• Droplet isolation
• Private room
• Mask for entering room
• Diseases invasive meningococcal infection,
  influenza, pertussis

Any healthcare worker can initiate isolation Only
a physician can discontinue isolation
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Post Exposure Prophylaxis

• Regimen options
• Ciprofloxacin 500 mg PO x 1
• Ceftriaxone 250 mg IM x 1 (children, pregnant
  women)
• Rifampin 600 mg PO 2x/day for 2 days (resistance
  described)
• Definition of exposure
• Droplet spread disease
• Close contact with respiratory secretions
  (mouth-to-mouth resuscitation, intubation,
  nasotracheal suctioning)

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IMPACT OF DELAYED ANTIBIOTIC THERAPY

• Retrospective study of 269 patients with
  community acquired meningitis (Aronin SI, et al.
  Ann Intern Med 1998129862-9)
• Indicators of poor outcome (death, neurologic
  deficit) Altered mental status, hypotension
  and/or seizures
• Delay in therapy associated with worse outcome if
  patient developed all 3 above signs
• Retrospective study of 123 patients with
  community acquired meningitis (Proulx N, et al.
  QJM 200598291-98)
• OR for mortality Door-to-antibiotics gt6 hr, 8.4
  afebrile at presentation, 39.4 severely impaired
  mental status, 12.6

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IMPACT OF DELAYED ANTIBIOTIC THERAPY

• Prospective study of 156 patients with
  pneumococcal meningitis found a delay of gt3 hours
  was independently associated with 3-month
  mortality (Crit Care Med 2006342758)

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REASONS FOR OBTAINING CSF

• Allows exclusion of meningitis
• Provides diagnosis of meningitis
• Allows specific etiologic diagnosis of acute
  bacterial meningitis (e.g., S. pneumoniae, N.
  meningitidis)
• May make alternative diagnosis (e.g.,
  cryptococcus, HSV)
• Allows susceptibility testing of isolate (esp.
  important for S. pneumoniae)
• May have prognostic significance

Rarely CSF may be normal in early bacterial
meningitis
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EMPIRIC DIAGNOSISBASED ON CSF PROFILE
Pattern PMN predominant Low glucose Lymphocytic Normal glucose Lymphocytic Low glucose
Spectrum Bacterial Parameningeal Viral Mycobacterial Fungal
Pathogens S. pneumonia, N. meningitidis Enteroviruses Brain abscess M. tuberuculosis Endemic fungi Mumps, LCM
Non-infectious Sulfa drugs Non-steroidals Auto-immune diseases
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EFFECTS OF PRIOR ANTIBIOTICS ON CSF FINDINGS

• A short period of antibiotic therapy prior to LP
  does not change cerebrospinal fluid (CSF) white
  blood cell count, protein, or glucose
• The yield of CSF gram stain and culture may be
  reduced by a short period of antibiotic therapy,
  but these tests often remain positive

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EFFECTS OF PRIOR ANTIBIOTICS ON CSF FINDINGS

• Retrospective study of 1,316 patients 54.6 had
  received antibiotics before presentation
  (Geiseler PJ, et al. RID 19802725)
• No significant differences in CSF WBC, glucose,
  or protein concentrations for S. pneumoniae, H.
  influenzae, N. menigitidis
• Significantly lower frequency of positive blood
  and CSF cultures for all 3 organisms, esp. N.
  meningitidis
• Retrospective study of 128 patients (Kanegaye JT.
  Pediatr 20011081169)
• 3/9 patients with N. meningitis were sterile
  within 1 hour (1 15 min) and all negative by 2
  hours
• Pneumococcal disease first negative at 4.3
  hours, 5/7 negative at 4-10 hours

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MANAGEMENT ISSUE

• CT or MRI before LP

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INDICATIONS FOR CT/MRI BEFORE LP

• Immunocompromised state (eg, HIV infection,
  immunosuppressive therapy, active cancer, BMT or
  organ transplantation)
• History of CNS disease (mass lesion, stroke, or
  focal infection)
• New onset seizure (within one week of
  presentation)
• Papilledema
• Abnormal level of consciousness
• Focal neurologic deficit

Tunkel AR, et al. CID 2004 391267-84 (IDSA)
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EVALUATING RISK OF LP WITHOUT CT

• Reports of harm (herniation post-LP) only case
  reports with temporal relationship (Ann Neurol
  19807524, Pediatr 2003112e174, J Neurol
  Psychopathol 193314116)
• Even with focal CNS lesions, herniation post-LP
  uncommon
• 200 patients with increased ICP from brain tumor
  no adverse effects of LP (Res Nerv Ment Dis Proc
  19278422)
• 103 patients with increased ICP death during
  hospitalization in 4, no herniation (J Neurol
  Psychoopath 193314116)
• Even with papilledema LP almost always safe (J Mt
  Sinai Hosp NY 195623808, Neurol 19599290)

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EVALUATING RISK OF LP WITHOUT CT

• Among patients dying with meningitis, herniation
  is a common cause of death (even with a normal LP
  herniation may occur) MGH 8/27 autopsied
  patient had herniation
• Prediction rules for abnormal CT have been
  proposed (Hasbun R, et al. NEJM 20013451727)
• 235 patients with CT before LP 5 had mass
  effect
• Age gt60 years, seizure within 7 days,
  immunocompromised, hx of CNS disease, altered
  mental status, gaze or facial palsy, inability to
  answer 2 questions or follow 2 commands, visual
  field abnormalities, arm or leg drift, or
  abnormal language

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MANAGEMENT ISSUE

• Use of dexamethasone

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RECOMMENDATIONS REGARDING DEXAMETHASONE

• RCT in 301 patients (de Gans J. NEJM
  20023471549)
• Dose 10 mg IV Q6 hr x 4 days (dosed before or at
  the time of first antibiotic administration to
  reduce cytokine response and damage)
• Outcome Decreased mortality (7 vs 15),
  decreased unfavorable outcomes (15 vs 25)
• Benefits seen only with S. pneumoniae with
  moderate glasgow coma scores at presentation, due
  to decreased systemic toxicity (e.g., shock,
  ARDS, pneumonia) not neurologic complications
• Pediatric studies showed clear prevention of
  hearing loss
• Benefits demonstrated in meta-analysis (Cochrane
  Rev 2007)
• Steroids reduce CSF levels of vancomycin but not
  ceftriaxone
• Unclear if reduces bacterial clearance time
• Maximize vanc dosing
• Not beneficial in areas with high HIV prevalence
  (Malawi study, no significant differences)
• D/C corticosteroids if pathogen other than Strep
  pneumoniae cultured
• Recommended dose .15 mg/kg q 6 hours x 4 days
• Corticosteroids also important in management of
  TB meningitis

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Tunkel AR, et al. CID 2004 391267-84
46
Case Answers

• HIV Elisa negative, HIV RNA PCR negative
• HSV, VZV pcr negative
• Gram stain, culture negative
• Lyme ab negative, RPR/VDRL negative
• Enteroviral PCR of stool and CSF positive
• Rash viral exanthem
• EKG myocarditis
• Management supportive

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GENERAL REFERENCES

• Durand ML, et al. Acute bacterial meningitis in
  adults. NEJM 199332821-28.
• Van de Beek, D, et al. Community-acquired
  bacterial meningitis in adults. NEJM
  200635444-53.
• Weisfelt M, et al. Bacterial menigitis a review
  of effective pharmacotherapy. Expert Opin
  200781493-1504.
• Fitch MT, et al. Emergency diagnosis and
  treatment of adult meningitis. Lancet ID
  20077191-200.
• Fitch MT, et al. Emergency department management
  of meningitis and encephalitis. ID Clin NA
  20082233-52.
• Tunkel AR, et al. Practice guidelines for the
  management of bacterial meningitis. Clin Infect
  Dis 2004391267-84

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Thanks