ACUTE

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• ACUTE
• CNS
• INFECTIONS

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• 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

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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

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ACUTE CNS INFECTIONS

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

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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

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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

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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

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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
• Kernigs 5 95 27 72
  0.97 1.0
• Brudzin- 5 95 27 72
  0.97 1.0
• skis
• FromThomas KE et al, CID
  2002, 3546-52

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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)

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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 Base
• Making Process For Decision-Making
• Within the 1st 30 mins Clinical assessment
• of patient contact
• After 1-2 hours CSF analysis
• At 24-48 hours CSF cultures
• Thereafter as clinically indicated

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APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS

• Decision-Making Within the First 30 Minutes
• Clinical Assessment
• Mode of presentation
• Acute (lt 24 hrs)
• Subacute (lt 7 days)
• Chronic (gt 4 wks)
• Historical/physical exam clues
• Clinical status of the patient
• Integrity of host defenses

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CSF STUDIES

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

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APPROACH TO THE PATIENT WITHSUSPECTED MENINGITIS

• Decision-Making at 1-2 Hours
• CSF Analysis
• CSF smears/stains
• CSF antigen screens
• CSF profile

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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

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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 routinely ordered study

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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 58120, 1975.

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BACTERIAL VS VIRAL MENINGITIS

• Predictors of bacterial etiology
• CSF glucose lt 34
• CSF Serum glucose ratio lt 0.23
• CSF protein gt 220
• CSF WBC count gt 2000
• CSF neutrophil count gt 1180
• Presence of any one of the above finding
• predicts bacterial etiology with gt 99 certainty

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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

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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

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THE PATIENT WITH SUSPECTEDCNS INFECTIONContraind
ications 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

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CNS INFECTIONSCCT

• Over-employed diagnostic modality ? Leads to
  unnecessary delays in Rx added expense
• Rarely indicated in pt with suspected acute
  meningitis
• Mandatory in pt with possible focal infection
• Increased sensitivity with contrast enhancement

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CCT Before LP in Patients with Suspected
Meningitis

• 301 pts with suspected meningitis 235 (78) had
  CCT prior to LP
• CCT abnl in 56/235 (24) 11 pts (5) had
  evidence of mass effect
• Features associated with abnl CCT were age gt60,
  immunocompromise, H/O CNS dz, H/O seizure w/in
  the previous wk, selected neuro abnls
• Hasbun, NEJM
  20013451727

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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 CT had none of
  features present at baseline
• CT normal in 93 of these 96 pts (NPV 97)
• Hasbun, NEJM
  20013451727

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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

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THE PATIENT WITH SUSPECTED CNS INFECTIONRole 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
• 2. Essential in pts with aseptic meningitis
  syndromes to monitor course/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

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BACTERIAL MENINGITIS

• Incidence of 3 cases/100,000 population/yr
  (25,000 total cases)
• Fever, HA, meningismus, altered mentation
  present in gt 85 of pts
• Other clinical findings
• Cranial nerve palsies/focal signs 10-20
• Seizures 25-30
• Papilledema lt 1

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BACTERIAL MENINGITISCaveats 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 gt 10
• Initiate therapy promptly (ie, within 30 mins)

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THE THERAPY OF MENINGITISDesirable Antimicrobic
Properties

• 1. Activity vs suspected pathogen(s)
• preferably cidal
• 2. Adequate CSF diffusion
• 3. Acceptable risk of toxicity

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THE THERAPY OF MENINGITISCNS Penetration

• Good Diffusion
• Penicillins
• 3rd 4th Gen Cephs
• Chloramphenicol
• Rifampin
• TSX

• Poor Diffusion
• Early Gen Cephs
• Clindamycin
• AMGs
• Tetracyclines
• Macrolides

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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)
• Ceph resistance 15-20 (5-10 high)

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COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING
FACTOR IN PATIENTS WITH MENINGITIS

• Predisposing Factor
• Age
• 0-4 wk
• 4-12 wk
• 3 mo to 18 yr
• 18-50 yr
• gt50 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 meningitidis
• H. influenzae, N. meningitidis, S. pneumoniae
• S. pneumoniae, N. meningitidis
• S. pneumoniae, N. meningitidis, L.
• monocytogenes, aerobic gram-negative bacilli

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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 ß-
• 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

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EMPIRIC THERAPY OF MENINGITIS IN THE ADULT

• Clinical Setting Likely Pathogens Therapy
• Community-acquired S. pneumoniae Ceftriaxone
• N. meningitidis 2 gms q12h
• Listeria
• H. influenzae Vancomycin 1-2 gms 12h
• /-
• Ampicillin 2 gm q4h
• Closed head trauma S. pneumoniae Pen G 3-4
  mµ q4h
• Streptococci
  Vancomycin 1-2 gm q12h

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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
• Open head injury Listeria
  Ceftriaxone 2 gm q12h
• Nosocomial Cefotaxime 2 gm q4h
• Elderly /-
• Ampicillin 2 gm q4h

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SPECIFIC THERAPY FOR KNOWN PATHOGENS

• Pathogen Recommended Therapy
• S. pneumoniae Pen G 18-24 mµ/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 mµ/d
• or
• Ampicillin 12 gm/d
• plus aminoglycoside

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SPECIFIC THERAPY FOR KNOWN PATHOGENS(continued)

• S. aureus Nafcillin 12 gm/d
• Vancomycin 2 gm/d
• Listeria Ampicillin 12 gm/d
• or
• Pen G 18-24 mµ/d
• plus aminoglycoside
• Gram negative Cefotaxime 12 gm/d
• bacilli Ceftriaxone 2-4 gm/d
• Pseudomonas Ceftazidime 6-8 gm/d
• plus aminoglycoside
• Penicillin-susceptible (i.e. PCN MIC lt 0.06).
  If resistant to penicillin,
• refer to Table 7.

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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 gt 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

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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)

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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

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CORTICOSTEROIDS AND MENINGITIS(Cont)

• Only pts with cloudy CSF, CSF GmS, or CSF WBC
  count gt1000 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 20023471549

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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 9 of low risk pts (0
  features), 33 of intermediate risk pts (1
  feature), and 56 of high risk pts (2-3 features)
• Delay in administration of appropriate ATB Rx
  also associated with adverse clinical outcome
• 
  Aronin et al, AIM1998129862

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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 1997336708

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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

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NONVIRAL CAUSES OF ENCEPHALOMYELITIS

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

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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

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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