ACUTE

CNS

INFECTIONS

James E. Peacock, Jr. MD

“The precise and intelligent recognition and appreciation of minor differences is the real essential factor in all successful medical diagnosis…Eyes and ears which can see and hear, memory to record at once and to recall at pleasure the impressions of the senses, and an imagination capable of weaving a theory or piecing together a broken chain or unraveling a tangled clue, such are the implements of his trade to a successful diagnostician.”

Joseph Bell

CNS INFECTIONSOverview

Life-threatening problems with high associated mortality and morbidity

Presentation may be acute, subacute, or chronic Clinical findings determined by anatomic site(s) of

involvement, infecting pathogen, and host response Vulnerability of CNS to effects of inflammation &

edema mandates prompt diagnosis with appropriate therapy if consequences to be minimized

ACUTE CNS INFECTIONS

1. Bacterial meningitis***

2. Meningoencephalitis

3. Brain abscess

4. Subdural empyema

5. Epidural abscess

6. Septic venous sinus

thrombophlebitis

THE PATIENT WITH ACUTE CNS INFECTIONOverall Goals in Management

1. To promptly recognize the patient with an acute CNS infection syndrome

2. To rapidly initiate appropriate empiric therapy

3. To rapidly and specifically identify the etiologic agent, adjusting therapies as indicated

4. To optimize management of complicating features

Does the patient have a “CNS infection syndrome”?

Prodromal/concurrent URI sxs Fever, HA, altered MS Compatible PE findings

- Meningismus - Active RT infxn

- Exanthems - Focal neuro signs

Symptoms and the Likelihood of Meningitis

Symptoms– HA & fever– HA, N/V– HA, fever, N/V– HA, fever, N/V,

photophobia– HA, fever, N/V,

photophobia, stiff neck

Odds of Meningitis .42

.49

.56

.54

.57

Diagnostic Accuracy of Signs of Meningeal Irritation in Pts with Suspected

Meningitis

Sign Sens Spec PPV NPV +LR -LR

Nuchal 30% 68% 26% 73% 0.94 1.02

rigidity

Kernig’s 5% 95% 27% 72% 0.97 1.0

Brudzin- 5% 95% 27% 72% 0.97 1.0

ski’s

From:Thomas KE et al, CID 2002, 35:46-52

If the patient has a “CNS infection syndrome”, is it antimicrobial requiring?

Untreated/partially Rx’ed bacterial meningitis Parameningeal suppurative foci M. tuberculosis/Fungi Syphilis/Borrelia/Rickettsia HSV/CMV/VZV Others (amebae, parasites, etc)

APPROACH TO THE PATIENT WITH POSSIBLE CNS INFECTION

If the patient has a CNS infection syndrome, is it antimicrobial

or non-antimicrobial requiring?

Crucial and recurring question addressed sequentially over time

Points in Decision- Available Data BaseMaking Process For Decision-Making

Within the 1st 30 mins Clinical assessment of patient contact

After 1-2 hours CSF analysisAt 24-48 hours CSF cultures

Thereafter as clinically indicated

APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS

Decision-Making Within the First 30 Minutes

Clinical Assessment

Mode of presentation Acute (< 24 hrs)

Subacute (< 7 days) Chronic (> 4 wks) Historical/physical exam clues

Clinical status of the patient

Integrity of host defenses

CSF STUDIES

Color/Clarity Cell counts/WBC diff Chemistries (protein, glucose) Stains/Smears (Gram) Cultures (routine) +/- Antigen screens

APPROACH TO THE PATIENT WITHSUSPECTED MENINGITIS

Decision-Making at 1-2 Hours

CSF Analysis

CSF smears/stainsCSF antigen screens

CSF “profile”

CSF SMEARS & STAINS

GmS + in 60-90% of pts with untreated bacterial meningitis

With prior ATB Rx, positivity of GmS decreases to 40-60%

REMEMBER: + GmS = Heavy organism burden & worse prognosis

CSF ANTIGEN SCREENS

Bacterial antigen screens detect S. pneumoniae, N. meningitidis, Hib, and GBS; + in 50-100% of pts (esp. useful in pts with prior ATB Rx)

Crypto antigen screen detects C. neoformans; + in 90-95% of pts with crypto meningitis

Should NOT be a ordered routinely

CEREBROSPINAL FLUID PROFILES*

Neutrophilic/Low glucose (purulent)

Lymphocytic/Normal glucose

Lymphocytic/Low glucose

*Profile designation based on WBC differential and glucose concentration. After NE Hyslop, Jr and MN Swartz, Postgrad Med 58:120, 1975.

BACTERIAL VS VIRAL MENINGITIS

Predictors of bacterial etiology: CSF glucose < 34 CSF: Serum glucose ratio < 0.23 CSF protein > 220 CSF WBC count > 2000 CSF neutrophil count > 1180

[Presence of any ONE of the above findings

predicts bacterial etiology with > 99% certainty]

APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS

Decision-Making at 24-48 hours

CSF Culture Results

Culture positive Adjust therapy based upon specific organism and sensitivities

Culture negative Evaluate for “aseptic” meningitis syndrome

TO LP OR NOT TO LP

Single most impt diagnostic test Mandatory, esp if bacterial

meningitis suspected If LP contraindicated, obtain BCs (+

in 50-60%), then begin empirical Rx

THE PATIENT WITH SUSPECTEDCNS INFECTION

Contraindications to LP

Absolute: Skin infection over site

Papilledema, focal neuro signs, ↓MS

Relative: Increased ICP without papilledema

Suspicion of mass lesion

Spinal cord tumor

Spinal epidural abscess

Bleeding diathesis or ↓ plts

CNS INFECTIONSCCT

Over-employed diagnostic modality Leads to unnecessary delays in Rx & added cost

Rarely indicated in pt with suspected acute meningitis

Mandatory in pt with possible focal infection Increased sensitivity with contrast

enhancement

CCT Before LP in Patients with Suspected Meningitis

301 pts with suspected meningitis; 235 (78%) had CCT prior to LP

CCT abnormal in 56/235 (24%); 11 pts (5%) had evidence of mass effect

Features associated with abnl CCT were age >60, immunocompromise, H/O CNS dz, H/O seizure w/in 7d, & selected neuro abnls

Hasbun, NEJM 2001;345:1727

CCT Before LP(Cont.)

Neuro abnls included altered MS, inability to answer 2 consecutive questions or follow 2 consecutive commands, gaze palsy, abnl visual fields, facial palsy, arm or leg drift, & abnl language

96/235 pts (41%) who underwent CCT had none of features present at baseline

CCT normal in 93 of these 96 pts (NPV 97%) Hasbun, NEJM 2001;345:1727

CNS INFECTIONSMRI

Not generally useful in acute diagnosis (Pt cooperation; logistics)

Very helpful in investigating potential complications developing later in clinical course such as venous sinus thrombosis or subdural empyema

THE PATIENT WITH SUSPECTED CNS INFECTIONRole of Repetitive LP’s

1. Rarely indicated in proven bacterial meningitis unless clinical response not optimal or as expected, fever recurs, or infection is due to ATB resistant pathogen

2. Essential in pts with “aseptic meningitis” syndromes to monitor course &/or response to empiric therapies

3. Essential in pts with subacute/chronic meningitis of proven etiology to assess response to Rx

4. Not routinely indicated at end-of-therapy for bacterial meningitis

BACTERIAL MENINGITIS

Incidence of 3 cases/100,000 population/yr (~25,000 total cases)

Fever, HA, meningismus, & altered mentation present in > 85% of pts

Other clinical findings– Cranial nerve palsies/focal signs 10-20%– Seizures 25-30%– Papilledema < 1%

BACTERIAL MENINGITISCaveats re: Antimicrobial Rx

Therapy is gen’ly IV, high dose, & bolus Dosing intervals should be appropriate for

drug being administered Utilize “cidal” therapy whenever possible Strive for CSF bactericidal index > 10 Initiate therapy promptly (ie, within 30 mins)

THE THERAPY OF MENINGITISDesirable Antimicrobic Properties

1. Activity vs suspected pathogen(s)

[preferably cidal]

2. Adequate CSF diffusion

3. Acceptable risk of toxicity

THE THERAPY OF MENINGITISCNS Penetration

Good Diffusion

Penicillins

3rd & 4th Gen Cephs

Chloramphenicol

Rifampin

TSX

Poor Diffusion

Early Gen Cephs

Clindamycin

AMGs

Tetracyclines

Macrolides

Bacterial MeningitisImportant Changes in Epidemiology

Marked decline in the occurrence of Hib ↑’ing incidence of S. pneumo (50+% of

cases in US) Shift from peds disease to adult disease ↑’ing incidence of ATB-resistant

organisms, esp. S. pneumo– PCN resistance ~ 35% (15-20% high level)– Ceph resistance 15-20% (5-10% high level)

COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS

Predisposing FactorAge 0-4 wk

4-12 wk

3 mo to 18 yr 18-50 yr >50 yr

Common Bacterial Pathogens

Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella pneumoniae, Enterococcus spp., Salmonella

spp.S. agalactiae, E. coli, L. monocytogenes, Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidisH. influenzae, N. meningitidis, S. pneumoniaeS. pneumoniae, N. meningitidisS. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli

COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS

Predisposing Factor

Immunocompromised state

Basilar skull fracture

Head trauma; postneurosurgery

Cerebrospinal fluid shunt

Common Bacterial Pathogens

S. pneumoniae, N. meningitidis, L.

monocytogenes, aerobic gram-negative bacilli (including P. aeruginosa)

S. pneumoniae, H. influenzae, group A β-

hemolytic streptococci

Staphylococcus aureus, Staphylococcus

epidermidis, aerobic gram-negative bacilli

(including P. aeruginosa)

S. epidermidis, S. aureus, aerobic gram- negative bacilli (including P. aeruginosa),

P. acnes

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT

Clinical Setting Likely Pathogens Therapy

Community-acquired S. pneumoniae Ceftriaxone

N. meningitidis 2 gm q12h

[Listeria] +

[H. influenzae] Vancomycin 1-2 gm 12h

+/-

Ampicillin 2 gm q4h

Closed head trauma S. pneumoniae Pen G 3-4 mu q4h

Streptococci + Vancomycin 1-2 gm q12h

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT

Clinical Setting Likely Pathogens Therapy

High risk patients S. aureus Vancomycin 2-3 gm/d Compromised hosts Gram negative + Neurosurgical bacilli Ceftazidime 2 gm q8h or Open head injury Listeria Cefepime 2 gm q8h Nosocomial [Ceftriaxone 2 gm q12h] Elderly [Cefotaxime 2 gm q4h] +/-

Ampicillin 2 gm q4h

SPECIFIC THERAPY FOR KNOWN PATHOGENS

Pathogen Recommended Therapy

S. pneumoniae* Pen G 18-24 mu/d

N. meningitidis or

Streptococci Ampicillin 12 gm/d

[Chloro 75-100 mg/kg/d]

[Ceftriaxone 2-4 gm/d]

H. influenzae Cefotaxime 12 gm/d

[Ceftriaxone 2-4 gm/d]

Group B strep Pen G 18-24 mu/d

or

Ampicillin 12 gm/d

[plus aminoglycoside]

SPECIFIC THERAPY FOR KNOWN PATHOGENS(continued)

S. aureus Nafcillin 12 gm/d

[Vancomycin 2-3 gm/d]

Listeria Ampicillin 12 gm/d

or

Pen G 18-24 mu/d

[plus aminoglycoside]

Gram negative Cefotaxime 12 gm/d

bacilli [Ceftriaxone 2-4 gm/d]

Pseudomonas Ceftazidime 6-8 gm/d or

Cefepime 6 gm/d

[plus aminoglycoside]

*Penicillin-susceptible (i.e. PCN MIC < 0.06). If penicillin resistant, see Table 7.

SUGGESTED TREATMENT REGIMENS FOR ANTIBIOTIC-RESISTANT BACTERIAL MENINGITIS

Suggested Regimen

Bacteria Antibiotic Dosage

N. meningitidis Ceftriaxone 2g q12h

Penicillin MIC 0.1-1.0 µg/ml or

Cefotaxime 2g q4-6h

H. influenzae Ceftriaxone 2 g every 12h

-Lactamase producing or

Cefotaxime 2 g every 4-6h

S. pneumoniae Vancomycin 1-2 g every 12h

Highly resistant to +

penicillin (MIC > 1 g/ml) Ceftriaxone 2 gm every 12h

+/-

Rifampin 600 mg every 12-24h

Relatively resistant to Ceftriaxone 2-3 g every 12h

penicillin (MIC 0.1-1.0 g/ml) or or

Cefotaxime 2 g every 4h

or

Vancomycin 1-2g every 12h

Risk Factors for Drug-Resistant S. pneumoniae (DRSP)

Extremes of age Recent ATB Rx Significant comorbid disease HIV infection or other immunodeficiency Day care or day care parent/sib Recent hospitalization Congregate settings (Institutions, military)

CORTICOSTEROIDS AND MENINGITIS

Role of steroids still somewhat uncertain Recent European study in adults suggested

that Rx with dexa associated with ↓ in risk of unfavorable outcome (25%→15%, RR 0.59) & in mortality (15%→7%, RR for death 0.48)

Benefit primarily ltd to pts w/S. pneumo Dose of dex was 10mg IV q6h X 4d; per

protocol, dex given concurrent with or 15-20 mins before 1st dose of ATBs

CORTICOSTEROIDS AND MENINGITIS(Cont)

Only pts with cloudy CSF, + CSF GmS, or CSF WBC count >1000 were enrolled

Accompanying editorial raised concerns about use of steroids in pts with DRSP who are being Rx’ed with vanc b/o ↓ in CNS conc of vanc with concurrent steroid use

Practically speaking, almost all pts with presumed bacterial meningitis are candidates for at least 1 dose of dexa NEJM 2002;347:1549

PREDICTORS OF ADVERSE CLINICAL OUTCOMES IN PTS WITH COMMUNITY-ACQUIRED BACTERIAL

MENINGITIS

Retrospecitve study; 269 pts (84% culture +) Adverse clinical outcome in 36% of pts (Death 27%, neuro deficit

9%) ↓BP, altered MS, and seizures on presentation all independently

associated with adverse clinical outcome Adverse outcomes in 5% of low risk pts (0 features), 37% of

intermediate risk pts (1 feature), and 63% of high risk pts (2-3 features)

Delay in administration of appropriate ATB Rx also associated with adverse clinical outcome

Aronin et al, AIM1998;129:862

BACTERIAL MENINGITISDuration of ATB Rx

Pathogen Duration of Rx (d)

H. influenzae 7

N. meningitidis 7

S. pneumoniae 10-14

L. monocytogenes 14-21

Group B strep 14-21

GNRs 21 NEJM 1997;336:708

VIRAL MENINGITIS/ENCEPHALITIS

Enteroviruses

Polioviruses

Coxsackieviruses

Echoviruses

Togaviruses Eastern equine

Western equine

Venezuelan equine

St. Louis

Powasson

California

West Nile

Herpesviruses

Herpes simplex

Varicella-zoster

Epstein Barr

Cytomegalovirus

Myxo/paramyxoviruses Influenza/parainfluenzae

Mumps

Measles

Miscellaneous Adenoviruses

LCM

Rabies

HIV

NONVIRAL CAUSES OF ENCEPHALOMYELITIS

Rocky Mountain spotted fever Acanthamoeba

Typhus Toxoplasma

Mycoplasma Plasmodium falciparum

Brucellosis Trypanosomiasis

Subacute bacterial endocarditis Whipple’s disease

Syphilis (meningovascular) Behcet’s disease

Relapsing fever Vasculitis

Lyme disease

Leptospirosis

Tuberculosis

Cryptococcus

Histoplasma

Naegleria

BRAIN ABSCESS Infrequent but not uncommon; pathogenesis diverse with

contiguous spread & blood-borne seeding most common Clinical features include HA (90%), fever (57%), MS changes

(67%), hemiparesis (61%), & papilledema (56%) Dx often suggested by neuroimaging (CCT or MRI) LP is contraindicated due to risk of herniation Infxns often polymicrobial (strep, enteric GNRs, &/or

anaerobes); S. aureus may cause abscesses in association with IE

Other less common etiologies include Nocardia, fungi, M. tuberculosis, T. gondii, & neurocysticercosis

Drainage often a necessary component of management

BRAIN ABSCESSEmpiric Therapy

Penicillin G 18-24 mu IV qd

Metronidazole 500 mg IV q6h

Add nafcillin 12 gm/d if staph suspected

(use vanc if MRSA a concern) Add cefotaxime, ceftriaxone, or ceftazidime if GNRs

suspected Substitute vanc 2-4 gm IV/d for pen G if DRSP

suspected