November 4th 2009

PROMPT recognition of Meningitis Rapid Diagnostic testing to identify

the etiologic pathogen and adjust therapy

Rapid Initiation of appropriate Empiric Antimicrobial therapy

Targeted Antimicrobial therapyDo’s and Don’ts for the Boards

1805-1900’s: ~100% fatal 1913: Flexner: intrathecal

meningococcal antiserum. Prevented some deaths

1930’s: Antibiotics. Improved survival Current data:

Adults: 25% mortality, 21-28% neurologic sequelae

Bacterial meningitis remains a medical emergency!

aLTERED mENTAL sTATUS

FEVER HEADACHE

URI interrupted by one of the “meningeal symptoms”: vomiting, headache, lethargy, confusion, stiff neck

1. AGE 2.SEASON 3.Geography 4.Predisposing factors

(immunocompromised state; basilar skull fracture with CSF leak; head trauma; post neurosurgical procedures ~wound and FB)

5.Onset and duration of illness (acute; subacute and chronic) ~community aquired or nosocomial

6.Travel,occupational and recreational exposures( insect and animal contact)

7. Vaccination history and current meds (ABX)

8.Parameningeal foci or septic emboli from IE

9. Imaging before Lumbar puncture 10. Gram stain and Interpretation of

the CSF formula

14-year-old male with no significant PMH is admitted to the hospital with acute onset of high fever, chills, sore throat, stiff neck, and lethargy

T 1040F, P 120, RR 32, BP 70/30 mmHg

On examination, he was oriented only to person,

and had evidence of nuchal rigidity WBC 25,000/mm3 with 20% bands CSF WBC 1,500/mm3 (98% neutrophils),

glucose 20 mg/dL, and protein 200 mg/dL

A Haemophilus influenzae type bB Neisseria meningitidisC Streptococcus pneumoniaeD Enterovirus 71E Cryptococcus neoformans

LOOK @ AGE/ARMY RECRUITS/COLLEGE

STUDENTS/Rash

Affects mostly children and young adults; mortality 3-13% (SPORADIC 98% cases B) 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

PEN G and AMPICILLIN are DRUGS OF CHOICE

Empiric therapy with Third Generation Cephalosporins recommended

Nasopharyngeal carrier state 10 to 15%

Infection control DROPLET precautions ~surgical mask

21-year-old male without significant PMH was found difficult to arouse by his roommate in his college dormitory. Patient taken via fire rescue to ER

On exam, he was lethargic, febrile to 1030F, tachycardic, tachypnec, and hypotensve. His neck was stiff and he had a petechial rash on the lower extremities

CSF revealed a neutrophilic pleocytosis, low glucose, and elevated protein. Gram’s stain showed gram-negative diplococci

The patient received IV penicillin G and made a full recovery. Blood and CSF grew Neisseria meningitidis

For which of the following persons is antimicrobial chemoprophylaxis recommended?

The Dean of the collegeThe ambulance driverThe emergency room physicianThe triage nurseThe patient

Household members Day care center contacts Persons directly exposed to patient’s

oral secretions - kissing, mouth-to-mouth resuscitation

- endotracheal intubation or endotracheal tube management

Index patient if not treated with a third generation cephalosporin

Chemoprophylactic regimens - rifampin - ceftriaxone - ciprofloxacin - azithromycin

Immunocompromised patients

H/O CNS disease New onset SEIZURE Focal neurological

signs Altered

consciousness Papilledema Delay in performing

LP

Do Blood Cx STAT Dexamethasone

and empiric antimicrobials

CT scan LP if CT negative

NormalNormal BacterialBacterial Viral Viral TBTBCellsCells 0-50-5 >1000>1000 <1000<1000 25-50025-500PolymorphsPolymorphs 00 PredominatePredominate EarlyEarly +/- increased+/- increased

LymphocytesLymphocytes 55 LateLate PredominatePredominate IncreasedIncreased

GlucoseGlucose 60-8060-80 DecreasedDecreased NormalNormal DecreasedDecreased

CSF CSF plasma:plasma:

Glucose Glucose ratioratio

66%66% <40%<40% NormalNormal < 30%< 30%

ProteinProtein 5-405-40 IncreasedIncreased +/- Increased+/- Increased IncreasedIncreased

CultureCulture NegativeNegative PositivePositive NegativeNegative +TB+TB

Gram stain Positive in 60-90%

Culture CSF Positive in 70-85%**

Blood Culture Positive in 50%

** Beware of partially treated meningitis with abx for 2-3 days this may give you negative Cx although CSF remains abnormal; Shift from PMN to polys and lymphs or lymphocytic predominance

Do NOT assume this is NOT a bacterial infection

Gram negative:Gram negative:Diplococci: Diplococci: MeningococcusMeningococcus

Bacilli: E. coliBacilli: E. coli

Coccobacilli: H Coccobacilli: H influenzaeinfluenzae(small, pleomorphic)(small, pleomorphic)

Gram Positive:Gram Positive:Diplococci: Diplococci: PneumococcusPneumococcus

Chains: Strep Group BChains: Strep Group B

Clusters: StaphClusters: Staph

Rods & cocobacilli: Rods & cocobacilli: ListeriaListeria

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

Which of the following regimens should be initiated?

A Dexamethasone + Penicillin G B Dexamethasone + Ceftriaxone C Dexamethasone + Vancomycin +

Ampicillin D Dexamethasone + Vancomycin +

Ceftriaxone E Vancomycin + Ceftriaxone

Most common etiologic agent in USMortality of 19-26%Associated with other

suppurative foci of infection ~ Pneumonia (25%)

Otitis media or mastoiditis (3 0%)Sinusitis (10-15%)Endocarditis (<5%)Head trauma with CSF leak (10%)

PCN MIC µg/ml Antimicrobial therapy

<0.1 PCN G or Ampicillin

0.1-1.0 Third generation Cephalosporin

>1.0 Vancomycin + third generation cephalosporin*

>2.0 Vancomycin + third generation cephalosporin **

•*Cefotaxime or ceftriaxone

!! REMEMBER SUSCEPTIBILITIES ARE NOT ROUTINELY DONE

**Consider addition of Rifampin if Ceftriaxone MIC > 2

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 G*

S. agalactiae Ampicillin or penicillin G*

E. coli Third generation cephalosporina

acefotaxime or ceftriaxone

baddition of rifampin may be considered, especially if dexamethasone given

*addition of an aminoglycoside may be considered

Attenuates subarachnoid space inflammatory response resulting from antimicrobial-induced lysis

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

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

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

Tuberculous Meningitis – Corticosteroids (extreme neurologic

compromise, elevated ICP, impending herniation, impending or established spinal block;

CT/MR evidence of hydrocephalus or basilar meningitis)

Cryptococcal Meningitis– Reduction in intracranial pressure (frequent high- volume lumbar punctures, VP shunts)

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

Which of the following antimicrobial regimens should be initiated?

A Vancomycin administered intravenously and intrathecally

B Vancomycin + rifampinC ChloramphenicolD Trimethoprim-sulfamethoxazoleE Erythromycin

Mortality 15-29% Rare cause of bacterial meningitis in US

(8%) 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 Alcoholism Malignancy Immune suppression Diabetes mellitus Hepatic and renal

disease Iron overload Collagen-vascular disorders

CASE #2 46-year-old male executive from

Phoenix,Arizona presents to the ER with recent history of going on a cruise to Jamaica. One week after returning, he developed headaches, stiff neck, and vomiting.

He had no significant PMH and was sexually active with multiple partners.

Physical exam revealed low-grade fever and meningismus, but was otherwise negative.

CSF examination revealed a WBC count of 300/mm3 with 60% eosinophils, glucose of 45 mg/dL and protein 150 mg/dL.

Gram stain was negative.

Which of the following is the most likely cause of this patient’s illness?

Treponema pallidumMycobacterium tuberculosisCoccidioides immitisAngiostrongylus cantonensisLymphoma

Most common cause of eosinophilic 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

Usually self limited course and recover completely

Analgesics

Corticosteroids

Frequent but careful LPs if increased intracranial pressure

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 prominenteosinophilia; 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

60 year old male with ESRD immigrated from Brazil to US and underwent a cadaveric renal transplant. Prior to transplant, he had recurrent epigastric pain.

WBC 6,500 with 15% eosinophils After transplant received Prednisone

and Azathioprine Presented 1 month later with T 39ºC,

headache, meningismus and altered mental status

Lumbar puncture showed

WBC 2500/mm³ (98% neutrophils) Glucose 20 mg/dl Protein 450mg/dl Placed on Empiric Vancomycin,

Ampicillin and Ceftriaxone

Blood cultures and CSF Cx grew E.coli

Which of the following diagnostic test would most likely establish the pathogenesis of E.coli meningitis in this patient?

A. CT scan of the head and sinuses B. Bronchoscopy with transbronchial

lung biopsy C. Serial stool examinations D. Meningeal Biopsy E. Metrizimide cisternography

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

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 aWBC of 90/mm3 (95% lymphocytes), glucose of 80mg/dL (serum 100 mg/dl), and protein of 70 mg/dL

Which of the following is the best test for establishing the diagnosis in this patient?

A ElectroencephalogramB MRI of head with gadoliniumC Brain biopsyD CSF polymerase chain reactionE CSF antibody studies

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 are negative

Which of the following is the appropriate management for this patient?

A. Discontinue acyclovirB. Perform a brain biopsyC. Begin ganciclovir + foscarnetD. Send CSF for HHV6 PCRE. Perform HSV PCR on a new CSF

specimen

Neuroimaging – MRI is procedure of choice (AFTER LP) – Edema and hemorrhage in temporal lobes

– Bilateral temporal lobes (pathognomonic)CSF Analysis – Lymphocytes, increased protein, normal

glucose – Polymerase chain reactionEEG – Periodic lateralizing epileptiform discharges

Published reports have found that false negatives can occur due to testing

Too early or too late, improper sample transport, or low volumes of CSF tested. HSVE is frequently fatal untreated.

Therefore, if MRI shows compatible temporal lobe findings and no alternative diagnosis is established, continued treatment with acyclovir should be strongly considered.

A second spinal tap with repeat CSF PCR or a brain biopsy may be indicated.

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

Neurological examination reveals bilateral tremors of theextremities 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 of 300/mm³ glucose of 70 and protein of 105.

Which of the following tests is most likely to confirm the diagnosis in this patient?

A. Serum Ig M antibody B. Serum Ig G antibody C. CSF IgM antibody D. CSF PCR E. Brain Biopsy

First US cases reported in 1999 in New York City

Birds are main reservoirsTransmission

-mosquito vector -transfusion -transplantation -Breast feeding

Age >50 years~ increased incidence

1/150 develop neuroinvasive disease

Tremors and Myoclonus Parkinsonism Poliomyelitis like flaccid paralysis Serum IgM and IgG capture ELISA

(cross reactivity with other flaviviruses)

CSF IgM antibodies (diagnostic of neuroinvasive disease)

CSF PCR (positive in <60%)

Clinical features of WNV

THERAPY FOR ENCEPHALITISEtiology Therapy HSV Acyclovir VZV Acyclovir CMVGanciclovir + foscarnet HHV-6 Ganciclovir or

foscarnet HIV HAART JC virus HAART

Echo virusCoxsakie and

EnterovirusesHerpes SimplexWest Nile virusUn identified

etiology 32- 75%

Herpes Encephalitis is

“NOT SEASONAL” sporadic

**Clues !!!epidemiological

factors

56 year old man s/p Kidney transplant in 2006 s/p Left mastectomy for a painful mass on Sept 1st 2009 discharged POD # 3

re-admitted a week later with urinary retention and rectal bleeding.

Unclear cause of urinary retention relieved after foley catheter insertion

Rectal bleeding attributed to constipation and a bowel regimen ordered by general surgery

Day 4 of admission patient began to have some hallucinations and beginning confusion.

Agitation increased gradually over the next few days.

CT Brain No acute abnormality MRI ( X AICD )

Day 7 after admission; after a bowel movement patient is turned back to supine position turns gray codes and is intubated ( ?Aspiration)

Day 14 ID is consulted for a persistent fever on Vancomycin and Cefepime with a RLL Pneumonia

Patient was on Haldol round the clock for severe agitation attributed to ICU delirium..initially sleep deprivation

WHAT ARE WE MISSING?

Fever, altered mental status in an Immuno-compromised host ???????

CONFOUNDERS pneumonia with Achromobacter Xylosoxidans I to

cefepime

Noninvasive testing was ordered and so was and LP

Serum Cryptococcal Antigen was 1:1024!!!!

CSF CrAG was 1:2084 Protein was 594 Glucose was 37 CSF wbc Neutrophils Lymphocytes

Patient was initiated on High dose Fluconazole and 5 Flucytosine without reversal of neurological status.

He underwent trach and peg and died 2 weeks after initiation of therapy.

CSF parameter NON –AIDS(%) AIDS(%)

Blood cultures - 30- 63%

Serum CrAG 66% 99%

Opening pressure>200 mm H2O

72% 62- 66%

CSF Glucose < 40mg/dl

73% 33%

CSF protein>45mg/dl 89% 58%

CSF Leukocytes > 20/mm³

70% 13 -31%

CSF Culture 96% 95%

CSF CrAG 86% 91-100%

Septic Emboli with Infective Endocarditis Brain Abscess Secondary Syphilis Parameningeal focus Rocky mountain Spotted fever ~ Doxycycline Aspetic Meningitis like picture

Leptospirosis~ water rodent exposure Hepatitis/ meningitis

LYME disease Lymphocytic choriomeningitis ~grip like illness Influenza

like 2000-3000 lymphocytes / winter peak Mumps~ peaks in winter with orchitis and parotitis Brucellosis

Midline tumors craniopharyngiomas MEDS NSAIDs ( afebrile)

Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:11267-84.

Spanos A, Harrell FE Jr, Durack DT. Differential diagnosis of acute meningitis: an analysis of the predictive value of initial observations. JAMA 1989;262:2700-7.