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 diagnosisEyes 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 INFECTIONS Overview

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. 2. 3. 4. 5. 6. Bacterial meningitis*** Meningoencephalitis Brain abscess Subdural empyema Epidural abscess Septic venous sinus thrombophlebitis

THE PATIENT WITH ACUTE CNS INFECTION Overall 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
Nuchal rigidity Kernigs Brudzinskis

Sens Spec PPV NPV +LR -LR

30% 5% 5% 68% 95% 95% 26% 27% 27% 73% 72% 72% 0.94 0.97 0.97 1.02 1.0 1.0

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

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

Untreated/partially Rxed 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 DecisionMaking Process Within the 1st 30 mins of patient contact Available Data Base For Decision-Making Clinical assessment

After 1-2 hours CSF analysis At 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 WITH SUSPECTED MENINGITIS

Decision-Making at 1-2 Hours

CSF Analysis
CSF smears/stains CSF 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 SUSPECTED CNS 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 INFECTIONS CCT

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 INFECTIONS MRI

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 INFECTION Role of Repetitive LPs

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 Essential in pts with aseptic meningitis syndromes to monitor course &/or response to empiric therapies Essential in pts with subacute/chronic meningitis of proven etiology to assess response to Rx Not routinely indicated at end-of-therapy for bacterial meningitis

2. 3. 4.

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 MENINGITIS Caveats re: Antimicrobial Rx

Therapy is genly 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 MENINGITIS Desirable Antimicrobic Properties 1. 2. 3. Activity vs suspected pathogen(s) [preferably cidal] Adequate CSF diffusion Acceptable risk of toxicity

THE THERAPY OF MENINGITIS

CNS Penetration
Good Diffusion Penicillins 3rd & 4th Gen Cephs Chloramphenicol Rifampin TSX Poor Diffusion Early Gen Cephs Clindamycin AMGs Tetracyclines Macrolides

Bacterial Meningitis
Important 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 Factor Age 0-4 wk 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 meningitidis H. influenzae, N. meningitidis, S. pneumoniae S. pneumoniae, N. meningitidis S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli

4-12 wk

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

COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS

Predisposing Factor Immunocompromised state Common Bacterial Pathogens S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli (including P. aeruginosa) S. pneumoniae, H. influenzae, group A hemolytic streptococci Staphylococcus aureus, Staphylococcus epidermidis, aerobic gram-negative bacilli (including P. aeruginosa) S. epidermidis, S. aureus, aerobic gramnegative bacilli (including P. aeruginosa), P. acnes

Basilar skull fracture Head trauma; postneurosurgery

Cerebrospinal fluid shunt

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT

Clinical Setting Community-acquired Likely Pathogens S. pneumoniae N. meningitidis [Listeria] [H. influenzae] Therapy Ceftriaxone 2 gm q12h + Vancomycin 1-2 gm 12h +/Ampicillin 2 gm q4h Pen G 3-4 mu q4h + Vancomycin 1-2 gm q12h

Closed head trauma

S. pneumoniae Streptococci

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT

Clinical Setting High risk patients Compromised hosts Neurosurgical Open head injury Nosocomial Elderly

Likely Pathogens S. aureus Gram negative bacilli Listeria

Therapy Vancomycin 2-3 gm/d + Ceftazidime 2 gm q8h or Cefepime 2 gm q8h [Ceftriaxone 2 gm q12h] [Cefotaxime 2 gm q4h] +/Ampicillin 2 gm q4h

SPECIFIC THERAPY FOR KNOWN PATHOGENS

Pathogen S. pneumoniae* N. meningitidis Streptococci Recommended Therapy Pen G 18-24 mu/d or Ampicillin 12 gm/d [Chloro 75-100 mg/kg/d] [Ceftriaxone 2-4 gm/d] Cefotaxime 12 gm/d [Ceftriaxone 2-4 gm/d] Pen G 18-24 mu/d or Ampicillin 12 gm/d [plus aminoglycoside]

H. influenzae

Group B strep

SPECIFIC THERAPY FOR KNOWN PATHOGENS (continued)

S. aureus Nafcillin 12 gm/d [Vancomycin 2-3 gm/d] Ampicillin 12 gm/d or Pen G 18-24 mu/d [plus aminoglycoside] Cefotaxime 12 gm/d [Ceftriaxone 2-4 gm/d] Ceftazidime 6-8 gm/d or Cefepime 6 gm/d [plus aminoglycoside]

Listeria

Gram negative bacilli Pseudomonas

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

SUGGESTED TREATMENT REGIMENS FOR ANTIBIOTICRESISTANT BACTERIAL MENINGITIS

Suggested Regimen Bacteria N. meningitidis Penicillin MIC 0.1-1.0 g/ml Antibiotic Ceftriaxone or Cefotaxime Ceftriaxone or Cefotaxime Dosage 2g q12h 2g q4-6h 2 g every 12h 2 g every 4-6h

H. influenzae -Lactamase producing

S. pneumoniae Highly resistant to penicillin (MIC > 1 g/ml)

Vancomycin + Ceftriaxone +/Rifampin

Ceftriaxone or Cefotaxime or Vancomycin

1-2 g every 12h

2 gm every 12h 600 mg every 12-24h 2-3 g every 12h or 2 g every 4h 1-2g every 12h

Relatively resistant to penicillin (MIC 0.1-1.0 g/ml)

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 Rxed 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 MENINGITIS
Duration 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
Herpesviruses Herpes simplex Varicella-zoster Epstein Barr Cytomegalovirus Myxo/paramyxoviruses Influenza/parainfluenzae Mumps Measles Miscellaneous Adenoviruses LCM Rabies HIV Enteroviruses Polioviruses Coxsackieviruses Echoviruses Togaviruses Eastern equine Western equine Venezuelan equine St. Louis Powasson California West Nile

NONVIRAL CAUSES OF ENCEPHALOMYELITIS

Rocky Mountain spotted fever Typhus Mycoplasma Brucellosis Subacute bacterial endocarditis Syphilis (meningovascular) Relapsing fever Lyme disease Leptospirosis Tuberculosis Cryptococcus Histoplasma Naegleria Acanthamoeba Toxoplasma Plasmodium falciparum Trypanosomiasis Whipples disease Behcets disease Vasculitis

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 ABSCESS Empiric Therapy

Penicillin G Metronidazole

18-24 mu IV qd 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