Meningitis and Encephalitis

Bacterial causes by age (hematogenous spread predominates)

• Neonates (<1 month): Group B Streptococcus (S. agalactiae), Escherichia coli (K1 capsule), Listeria monocytogenes — organisms acquired from maternal genital/GI flora during delivery
• Infants, children, and adults: S. pneumoniae is the leading cause overall; N. meningitidis peaks in adolescents and young adults in crowded settings; Haemophilus influenzae type b is now rare in the U.S. because of conjugate vaccination (ACIP schedule)
• Age >50, pregnancy, cell-mediated immune defects: add Listeria, which cephalosporins do not cover — the reason ampicillin is in the empiric regimen (IDSA bacterial meningitis guideline)

Non-bacterial and non-infectious mechanisms

• Viral (aseptic): enteroviruses (coxsackie, echovirus) are the most common cause overall, typically summer–fall; HSV-2 causes recurrent benign lymphocytic meningitis (Mollaret meningitis), whereas HSV-1 causes necrotizing temporal-lobe encephalitis; also arboviruses (West Nile), mumps, and acute HIV seroconversion
• Fungal/mycobacterial: Cryptococcus neoformans and M. tuberculosis cause subacute basilar meningitis, almost always with impaired T-cell immunity
• Non-infectious mimics: drug-induced aseptic meningitis (NSAIDs, TMP-SMX, IVIG), carcinomatous/leptomeningeal metastasis, sarcoidosis, and autoimmune encephalitis — classically anti-NMDA receptor encephalitis in a young woman with an ovarian teratoma

Non-modifiable risk factors

• Extremes of age and immaturity/senescence of immunity
• Terminal complement deficiency (C5–C9) or eculizumab therapy: impaired membrane attack complex → recurrent Neisseria infection
• Asplenia or sickle cell disease: loss of splenic opsonophagocytosis → encapsulated organisms (S. pneumoniae)
• Anatomic communication: basilar skull fracture with CSF leak, cochlear implant, dermal sinus tract, or CSF shunt → recurrent pneumococcal or staphylococcal/coagulase-negative infection

Modifiable risk factors

• Missed vaccination (pneumococcal, Hib, meningococcal ACWY/B per ACIP), crowded living (dormitories, military barracks), smoking, alcohol use disorder, untreated HIV, injection drug use, and untreated parameningeal foci (otitis media, sinusitis, mastoiditis)

• Initial inoculation and bloodstream invasion: Pathogens reach the CNS via hematogenous spread (most common), direct extension from parameningeal foci (sinusitis, otitis media, mastoiditis), or through defects in anatomical barriers (CSF leaks, neurosurgical procedures); causative organisms vary with entry mechanism
• Blood-brain barrier disruption and meningeal inflammation: Bacterial lipopolysaccharides and lipoteichoic acids trigger endothelial cells and resident microglia to produce inflammatory cytokines (TNF-α, IL-1β, IL-6); increased vascular permeability leads to neutrophil infiltration into subarachnoid space and CSF pleocytosis
• Increased intracranial pressure and cerebral edema: Inflammatory mediators cause vasogenic edema (blood-brain barrier dysfunction) and cytotoxic edema (cellular swelling); impaired cerebral blood flow, accumulation of lactate and other toxic metabolites within CSF, and direct neuronal injury from inflammatory cascades result in altered mental status and potential herniation
• Encephalitis-specific mechanism: Direct viral invasion of neurons and glia (particularly concerning with HSV, VZV, and arboviruses) causes neuronal apoptosis, microglial activation, and often involves specific gray matter regions; can present with seizures, behavioral changes, and focal neurologic deficits
• Outcome determination: Bacterial burden, host immune response adequacy, timing of antibiotic administration, and degree of inflammatory response collectively determine prognosis; some pathogens (e.g., Neisseria meningitidis) produce toxins causing sepsis and multi-organ dysfunction independent of meningeal inflammation

• Classic meningitis triad: Fever, nuchal rigidity (neck stiffness), and altered mental status; notably, this triad is present in only 44-46% of bacterial meningitis cases, and absence does NOT rule out disease
• Additional meningeal signs: Kernig's sign (pain with knee extension when hip is flexed) and Brudzinski's sign (spontaneous hip/knee flexion with neck flexion) are specific but insensitive; photophobia and phonophobia reflect meningeal irritation
• Age-specific presentations: Neonates (<3 months) present atypically with fever, irritability, poor feeding, hypothermia, or seizures WITHOUT meningeal signs; older infants and children present with fever, headache, irritability, and vomiting; elderly patients may present only with altered mental status or fever without meningeal signs
• Encephalitis-specific features: Behavioral changes, personality alterations, hallucinations, and seizures are prominent; focal neurologic deficits (hemiparesis, aphasia) suggest specific brain involvement; HSV encephalitis classically involves temporal lobes causing hallucinations and memory disturbance
• Fulminant meningococcemia presentation: Petechial or purpuric rash (non-blanching) developing rapidly over hours indicates Neisseria meningitidis with sepsis; can progress to meningococcal sepsis syndrome with DIC, shock, and multi-organ failure independent of meningitis development
• Immunocompromised patient variants: Atypical presentations with minimal meningeal signs; Cryptococcus and Tuberculosis cause subacute/chronic meningitis; Listeria monocytogenes may present with brainstem signs (rhombencephalitis)

• CSF analysis via lumbar puncture (LP): Gold standard diagnostic test; obtain cell count with differential, protein, glucose, Gram stain, and cultures before antibiotics if possible; bacterial meningitis shows neutrophil predominance (>80%), markedly elevated protein (>200 mg/dL), and low glucose (<40 mg/dL or CSF:serum ratio <0.4); viral meningitis shows lymphocytic predominance (though early viral may show neutrophils), mildly elevated protein (50-100 mg/dL), and normal glucose
• When NOT to perform immediate LP: Papilledema, focal neurologic deficit, immunocompromise (consider CT first), or signs of herniation; obtain blood cultures and start empiric antibiotics immediately, then perform CT before LP
• Blood cultures and PCR testing: Draw blood cultures before antibiotics in all suspected meningitis cases (positive in ~50-80% of bacterial meningitis); multiplex PCR panels for meningitis pathogens increasingly available and can guide therapy within hours, particularly for viral etiologies
• Neuroimaging interpretation: CT shows obliteration of subarachnoid spaces, hydrocephalus, or enhancement of meninges; MRI with gadolinium more sensitive for meningeal enhancement and encephalitis, showing gray matter involvement in HSV and arboviruses
• CSF Gram stain sensitivity by organism: N. meningitidis 60-80%, Streptococcus pneumoniae 60-90%, Group B Streptococcus 40%, gram-negative rods 40-60%, Listeria <50%; negative Gram stain does NOT exclude bacterial meningitis
• Etiologic clues: Rash suggests meningococcemia; CSF glucose <10 mg/dL suggests Mycobacterium tuberculosis, Cryptococcus, or Listeria; very high protein (>500 mg/dL) suggests TB or fungal disease; temporal lobe enhancement on MRI suggests HSV

• Empiric antibiotics—STAT (within 1 hour of presentation): Do NOT delay for LP or imaging; ceftriaxone 2g IV Q12H (meningitis dosing) or cefotaxime 2g IV Q4-6H covers N. meningitidis, S. pneumoniae, and susceptible gram-negative rods; add vancomycin 15-20 mg/kg IV Q8-12H (AUC-guided dosing, AUC/MIC 400-600 per the 2020 IDSA/ASHP consensus; trough-only targets are no longer recommended) for pneumococcal resistance coverage in all empiric regimens
• Age and risk-specific modifications: Neonates (0-3 months) require ampicillin 50 mg/kg IV Q6H (covers Listeria) PLUS cefotaxime; patients >50 years or immunocompromised add ampicillin for Listeria coverage; gram-negative rod coverage with ceftazidime or meropenem for post-neurosurgical patients or ventriculitis
• Dexamethasone adjunctive therapy: 10 mg IV Q6H for 4 days started with or before first antibiotic dose significantly reduces mortality and hearing loss in bacterial meningitis (particularly pneumococcal); associated with reduced CSF penetration of vancomycin, necessitating higher dosing; withhold in immunocompromised patients with Listeria (reduces ampicillin penetration)
• Acyclovir for encephalitis: 10 mg/kg IV Q8H initiated empirically in all encephalitis cases until HSV ruled out by CSF PCR (can take 24-48 hours); continue only if HSV or VZV positive; critical because HSV encephalitis has 70% mortality untreated but excellent response to early acyclovir
• Antifungal therapy: Amphotericin B liposomal 3-4 mg/kg IV daily for suspected Cryptococcus (CSF India ink smear or cryptococcal antigen); add flucytosine 25 mg/kg IV Q6H for synergy; fluconazole for consolidation therapy after clinical improvement
• Antituberculous therapy: **Isoniazid, rifampin, pyrazinamide,

Neurologic complications of the disease

• Cerebral edema with herniation — emergency: inflammatory vasogenic plus cytotoxic edema raises ICP; signaled by declining GCS, unilateral fixed dilated pupil, posturing, or Cushing triad (hypertension, bradycardia, irregular respirations). Requires airway control, head elevation, hyperosmolar therapy (mannitol or hypertonic saline), and neurosurgical consultation — not another LP
• Sensorineural hearing loss: cochlear inflammation and labyrinthitis, most common after pneumococcal disease and the sequela dexamethasone is given to prevent; all children need formal audiometry after recovery
• Seizures and focal deficits: cortical irritation and inflammatory vasculitis of subarachnoid vessels causing arterial infarction or septic venous sinus thrombosis; new hemiparesis or aphasia should prompt repeat imaging
• Hydrocephalus: purulent exudate obstructs arachnoid granulations (communicating) or the basal cisterns in TB meningitis; presents as worsening headache, vomiting, and lethargy after initial improvement — emergency if acute, needing external ventricular drainage
• Subdural empyema or brain abscess: fever and focal signs that fail to defervesce on appropriate antibiotics; ring-enhancing collection on MRI, drainage required
• SIADH with hyponatremia: nonosmotic ADH release; euvolemic hyponatremia with concentrated urine, which can itself precipitate seizures

Systemic complications

• Meningococcal purpura fulminans and DIC — emergency: endotoxin-driven consumptive coagulopathy with non-blanching purpura, thrombocytopenia, prolonged PT/PTT
• Waterhouse–Friderichsen syndrome — emergency: bilateral adrenal hemorrhage → refractory shock and hypoglycemia; give stress-dose corticosteroids alongside vasopressors

Treatment-related complications

• Dexamethasone: blunted CSF inflammation reduces vancomycin penetration (a reason for AUC-guided dosing per the 2020 IDSA/ASHP consensus); also hyperglycemia and GI bleeding
• Vancomycin: AKI, potentiated by concurrent piperacillin–tazobactam
• Ceftriaxone: biliary sludging; avoid in neonates receiving calcium and in hyperbilirubinemia (kernicterus risk) — use cefotaxime
• Acyclovir: crystalline nephropathy — prevent with generous IV hydration
• Amphotericin B/flucytosine: nephrotoxicity with hypokalemia and hypomagnesemia; flucytosine causes marrow suppression. In HIV-associated cryptococcal disease, immune reconstitution inflammatory syndrome may cause paradoxical worsening after ART initiation
• Antituberculous drugs: isoniazid hepatotoxicity and pyridoxine-responsive neuropathy; ethambutol optic neuritis

• Antibiotics before imaging, always: if the stem gives papilledema, focal deficit, or coma, the correct sequence is blood cultures → empiric antibiotics (+ dexamethasone) → CT → LP. The distractor is "obtain CT scan" as the single next step with no mention of antibiotics
• Dexamethasone must precede or accompany the first antibiotic dose: giving it after antibiotics have already lysed organisms provides no mortality or hearing benefit. Its best-proven benefit is in pneumococcal meningitis (IDSA bacterial meningitis guideline)
• Temporal lobe hemorrhagic necrosis = HSV-1 encephalitis: personality change, olfactory or gustatory hallucinations, aphasia, and RBCs in CSF with lymphocytic pleocytosis. Start empiric IV acyclovir immediately; CSF HSV PCR is the confirmatory test (IDSA encephalitis guideline). Never wait for the PCR result
• **Cephalosporins do not cover *Listeria***: add ampicillin for neonates, adults over 50, pregnant patients, and anyone with impaired cell-mediated immunity. Brainstem/rhombencephalitis signs point the same way
• **Recurrent Neisseria infection = terminal complement (C5–C9) deficiency**; recurrent pneumococcal meningitis = anatomic defect (basilar skull fracture with CSF rhinorrhea, cochlear implant) or asplenia. Examiners test this pairing more than any other in this topic
• **Chemoprophylaxis is for close contacts of N. meningitidis (and H. influenzae type b), not for pneumococcus**: rifampin, ciprofloxacin, or ceftriaxone per CDC recommendations; ceftriaxone is preferred in pregnancy
• Distractor to avoid: a negative CSF Gram stain or a CSF profile obtained after antibiotics does not exclude bacterial meningitis — partially treated meningitis retains neutrophil predominance and low glucose
• Young woman with psychiatric symptoms, seizures, orofacial dyskinesias, and autonomic instability: think anti-NMDA receptor encephalitis and search for an ovarian teratoma — the answer is pelvic imaging plus immunotherapy, not more antivirals