CNS Infections Pathology

• Pathogen Entry and CNS Penetration: Microorganisms cross the blood-brain barrier through multiple mechanisms: (1) transcellular route via endothelial cells; (2) paracellular route through tight junction disruption mediated by bacterial lipopolysaccharides and inflammatory cytokines; (3) Trojan horse mechanism using infected leukocytes; (4) direct extension from adjacent parameningeal foci (sinusitis, otitis, bone infections); and (5) hematogenous dissemination during bacteremia. Factors facilitating CNS invasion include bacterial polysaccharide capsules (reducing complement-mediated clearance), adhesins (mediating endothelial binding), and IgA proteases (degrading mucosal immunity).

• Inflammatory Cascade and Meningeal Inflammation: Upon bacterial CNS invasion, pattern recognition receptors (TLRs, NOD-like receptors) on resident microglia and astrocytes recognize pathogen-associated molecular patterns (PAMPs), triggering robust production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) and chemokines (MCP-1, GRO-α). These mediators increase vascular permeability via tight junction protein disruption (occludin, claudins, ZO-1), promoting massive leukocytic infiltration (predominantly neutrophils initially, then lymphocytes) into the subarachnoid space. Activation of the complement cascade (classical and alternative pathways) amplifies inflammation through C3a and C5a generation, perpetuating chemotaxis and inflammatory cell activation. Paradoxically, the CNS's limited capacity for immune regulation allows unchecked inflammation causing cerebral edema (both vasogenic from BBB breakdown and cytotoxic from cellular swelling), increased intracranial pressure, and ischemic injury from microvascular thrombosis.

• Pathogen-Specific Mechanisms and Tissue Damage: Different pathogens employ distinct pathogenic strategies: bacterial meningitis causes direct parenchymal invasion and abscess formation (with liquefactive necrosis), while viral encephalitis primarily targets neurons and glial cells through direct cytolytic infection with subsequent neuronal apoptosis and microglial activation. Fungal infections elicit granulomatous inflammation with epithelioid histiocytes and Langhans giant cells, characteristic of chronic meningitis. Parasitic infections trigger eosinophilic inflammation and may cause cyst formation or granulomatous lesions. Prion diseases cause spongiform degeneration through accumulation of pathological prion protein (PrP-scrapie), which propagates by recruiting normal PrP (PrP-cellular) to undergo conformational change, creating infectious proteinaceous particles. Viral persistence mechanisms include latency (HSV in sensory ganglia) and chronic productive infection (HIV with ongoing CNS replication in macrophages and microglia).

BACTERIAL MENINGITIS (Most Common Overall)

• Age-dependent epidemiology:
• Neonates (0-3 months): Group B Streptococcus (GBS), Escherichia coli (K1 capsule), Listeria monocytogenes
• Infants and children (3 months-18 years): Streptococcus pneumoniae, Neisseria meningitidis, (pre-Hib vaccine: Haemophilus influenzae type b)
• Adults (18-50 years): S. pneumoniae (most common, ~50% of cases), N. meningitidis
• Elderly (>50 years): S. pneumoniae, L. monocytogenes, gram-negative bacilli

• Risk factors for bacterial meningitis: Asplenia (functional or surgical), complement deficiencies (C5-C9 → meningococcal/gonococcal risk), immunoglobulin deficiency, CSF leak (from skull fracture, neurosurgery, cochlear implant), recent neurosurgical procedures, diabetes mellitus, alcoholism, CSF shunt placement, head trauma

VIRAL MENINGITIS/ENCEPHALITIS

• Enterovirus group (most common viral meningitis): Coxsackievirus A/B, echovirus, EV-71 → typically aseptic meningitis with lymphocytic CSF pleocytosis
• Herpes simplex virus (HSV): HSV-1 (most common cause of sporadic encephalitis worldwide, ~10% of all encephalitis), HSV-2 (neonatal disseminated infection, primary genital infection ascending to CNS)
• Varicella-zoster virus (VZV): Primary infection (chickenpox) → postinfectious encephalitis; reactivation → vasculopathy with stroke risk
• Mumps: Pre-vaccination pathogen, causes both meningitis and encephalitis
• Measles: Can cause acute encephalitis and subacute sclerosing panencephalitis (SSPE) months-years after initial infection
• Arboviruses: West Nile virus (most common arboviral encephalitis in North America), St. Louis encephalitis, Japanese encephalitis, dengue
• HIV: Opportunistic CNS infections (toxoplasmosis, cryptococcal meningitis, PML from JC virus); also direct HIV encephalitis
• Cytomegalovirus (CMV): CD4 <50 → ventriculoencephalitis and polyradiculomyelitis; characteristic "hemorrhagic necrosis"
• EBV: Lymphocytic meningitis, encephalitis, rarely post-transplant lymphoproliferative disorder involvement

FUNGAL MENINGITIS (Chronic Meningitis Pattern)

• Cryptococcus neoformans: Most common cause of meningitis in HIV/AIDS (CD4 <100); polysaccharide capsule creates minimal inflammation ("acellular" CSF); risk factors include pigeon exposure
• Coccidioides immitis: Endemic to Southwestern US (desert dust); both pneumonia and CNS dissemination risk
• Histoplasma capsulatum: Ohio/Mississippi river valleys; CNS involvement in disseminated disease
• Blastomyces dermatitidis: North American endemic, CNS dissemination rare
• Aspergillus species: Immunocompromised patients; vascular invasion → hemorrhagic infarction
• Candida species: Catheter-associated, disseminated disease in ICU patients

PARASITIC INFECTIONS

• Toxoplasma gondii: CD4 <100 → ring-enhancing lesions from abscess formation; most common CNS opportunistic infection in HIV (pre-ART era)
• Plasmodium falciparum: Cerebral malaria from sequestration in microvessels → seizures, coma, death
• Naegleria fowleri: Freshwater exposure → fulminant hemorrhagic encephalitis (nearly 100% fatal)
• Acanthamoeba: Contact lens contamination or immunocompromise → granulomatous amoebic encephalitis (GAE)
• Taenia solium: Cysticercosis → cystic lesions with inflammatory rim (parenchymal, ventricular, subarachnoid forms)
• Strongyloides stercoralis: Hyperinfection syndrome → meningitis with larvae in CSF

PRION DISEASES

• Creutzfeldt-Jakob disease (CJD): Sporadic (85%, age >60), familial (PRNP mutations), iatrogenic (transfusion, contaminated instruments), variant (vCJD from BSE exposure) → transmissible spongiform encephalopathy
• Kuru: Historical human-to-human transmission via cannibalism in Papua New Guinea

MYCOBACTERIAL INFECTIONS

• Mycobacterium tuberculosis: Chronic tuberculous meningitis with granulomatous basal meningitis and caseous necrosis; risk factors include primary TB, reactivation, immunosuppression
• Atypical mycobacteria (MAC, M. marinum): In AIDS and severely immunocompromised

SPIROCHETAL INFECTIONS

• Treponema pallidum: Secondary syphilis → aseptic meningitis, tertiary → parenchymatous neurosyphilis
• Borrelia burgdorferi: Lyme meningitis/encephalitis; Lyme arthritis with CNS involvement
• Leptospira: Occupational exposure → aseptic meningitis phase of biphasic illness

BACTERIAL MENINGITIS - CLASSIC TRIAD

• Fever (>38.5°C) with acute onset (24-48 hours typically)
• Nuchal rigidity (inability to touch chin to chest due to meningeal irritation of cervical nerve roots)
• Altered mental status (confusion, lethargy, delirium from cerebral edema and inflammatory mediator effects on neuronal function)

• Additional signs of meningeal irritation:
• Kernig sign (pain with passive knee extension when hip is flexed 90°, from nerve root tension)
• Brudzinski sign (involuntary knee/hip flexion with passive neck flexion, testing meningeal irritation)
• Headache (often severe, photophobia, phonophobia from increased intracranial pressure)

• Petechial/purpuric rash: Specifically with N. meningitidis (lipopolysaccharide endotoxin triggers Shwartzman reaction - thrombosis and vasculitis with DIC); non-blanching rash classically appears on trunk and extremities, correlating with hemorrhagic necrosis of small vessels and leukostasis

• Focal neurological deficits (indicating parenchymal involvement/complications):
• Cranial nerve palsies (CN VI most common from increased ICP, CN VII/VIII from direct inflammation)
• Hemiparesis/hemiplegia from ischemic stroke secondary to vasculitis
• Seizures (acute from irritation, late from scar formation)
• Altered gait from ventriculitis involvement

• Sepsis physiology: Tachycardia, tachypnea, hypotension, hypothermia or hyperthermia reflecting cytokine-mediated systemic inflammation

VIRAL MENINGITIS

• Prodrome: Upper respiratory or gastrointestinal symptoms (particularly with enterovirus)
• Aseptic meningitis pattern: Fever, headache, nuchal rigidity WITHOUT altered mental status (preserves consciousness unlike bacterial disease)
• Enterovirus: Peak summer/fall seasonality; benign course, typically resolves in 7-10 days
• HSV encephalitis: Temporal lobe predilection from primary infection site in trigeminal ganglion; presents with focal seizures, behavioral changes, hallucinations (olfactory or gustatory), speech disturbance, corresponding to mesial temporal involvement with hemorrhagic necrosis
• VZV meningitis: Associated with rash in dermatomal distribution; VZV vasculopathy causes large and small vessel stroke (visible on imaging as hyperintensities on T2/FLAIR)

ENCEPHALITIS (vs. Meningitis)

• Encephalitis = inflammation of brain parenchyma itself (neuronal and glial infection/inflammation) → altered mental status, behavioral changes, personality changes, seizures, focal deficits predominate over meningeal signs
• Meningitis = primarily meningeal inflammation (pia and arachnoid) → meningeal signs prominent, mental status relatively preserved early
• Seizures more common in encephalitis (from neuronal irritation and edema) than meningitis

FUNGAL MENINGITIS - CHRONIC PRESENTATION

• Cryptococcal meningitis (most common fungal CNS infection): Insidious onset over weeks with fever, headache, cognitive changes; may lack classic meningeal signs due to minimal inflammatory response (polysaccharide capsule is poorly immunogenic); risk of increased intracranial pressure from impaired CSF reabsorption; in HIV patients typically CD4 <100
• Tuberculous meningitis: Basilar meningitis affecting cranial nerves at skull base; subacute fever, headache, cranial nerve palsies (CN II, III, VI, VII), strokes from vasculitis

MYELITIS

• Viral myelitis (enterovirus, VZV, WNV): Ascending paralysis, flaccid weakness, urinary retention, sensory level (indicating spinal cord cross-sectional involvement)
• Transverse myelitis: Affects one spinal cord level; causes bilateral weakness, sensory loss, and bowel/bladder dysfunction acutely

• Presents as space-occupying lesion → focal neurological deficits, seizures, raised ICP
• "Ring-enhancing lesion" on contrast MRI (from central liquefactive necrosis surrounded by inflammatory granulation tissue and collagen capsule)

LUMBAR PUNCTURE (CSF ANALYSIS) - GOLD STANDARD

• Cloudy/turbid (bacterial) vs. clear (viral, TB early) vs. xanthochromic (blood-stained or very high protein)
• Pellicle formation on standing (TB meningitis - tuberculous nodules in CSF form characteristic web-like clot)

• Bacterial meningitis: Hypercellular with neutrophilic predominance (PMNs >80%), WBC typically 100-10,000/µL (but early may be lymphocytic)
• Viral meningitis: Lymphocytic predominance (mononuclear >50%), WBC typically 10-1,000/µL, early phase may show neutrophils before lymphocytic shift
• Fungal meningitis: Lymphocytic predominance (chronic pattern), often with monocytes, WBC 20-500/µL typically, no organisms on Gram stain
• Tuberculous meningitis: Lymphocytic predominance with early neutrophil predominance possible, WBC 100-500/µL typical, low glucose (CSF glucose <45 mg/dL, CSF:serum ratio <0.4)

• Glucose: LOW in bacterial (CSF:serum <0.4, absolute CSF glucose <40 mg/dL) and TB meningitis; NORMAL in most viral (except enterovirus, which can be low)
• Protein: ELEVATED in all infections; very high (>500 mg/dL) suggests TB or fungal; >1,000 mg/dL suggests block (spinal cord compression) or severe inflammation
• CSF:serum glucose ratio and CSF:serum chloride ratio useful for differential diagnosis

• Gram stain: POSITIVE in ~60% of untreated bacterial meningitis; negative in TB, fungi (except cryptococcal latex antigen), and most viruses
• Bacterial culture: Gold standard; most

Immediate stabilisation

• Airway, seizure control, and ICP measures: treat status epilepticus with benzodiazepines then an antiseizure drug (e.g., levetiracetam or fosphenytoin); elevate the head, and use hyperosmolar therapy (mannitol or hypertonic saline) for impending herniation.
• Do not delay antibiotics for imaging: per the IDSA practice guideline for bacterial meningitis, obtain blood cultures and give empiric antibiotics immediately when CT before LP is indicated (immunocompromise, focal deficit, papilledema, new seizure, depressed consciousness, prior CNS disease).

First-line empiric therapy (community-acquired bacterial meningitis, IDSA)

• Third-generation cephalosporin + glycopeptide: ceftriaxone plus vancomycin, covering S. pneumoniae (including cephalosporin-resistant strains) and N. meningitidis. Vancomycin is dosed to a 24-hour AUC targeting AUC/MIC 400–600 per the 2020 IDSA/ASHP consensus, not a trough goal.
• Add ampicillin whenever Listeria is plausible — neonates, age >50, pregnancy, immunosuppression — because cephalosporins have no Listeria activity. Neonates receive ampicillin plus cefotaxime or an aminoglycoside.
• Adjunctive dexamethasone (0.15 mg/kg IV q6h) given before or with the first antibiotic dose blunts the TNF-α/IL-1β surge and reduces hearing loss and mortality in pneumococcal meningitis; stop it if pneumococcus is excluded.
• Empiric acyclovir IV for any encephalitic picture until HSV PCR returns (IDSA encephalitis guideline) — the cost of missing HSV-1 is devastating.

Pathogen-directed and definitive therapy

• Cryptococcal meningitis: liposomal amphotericin B plus flucytosine induction, then fluconazole consolidation and maintenance (IDSA cryptococcosis and HHS/NIH OI guidelines); serial therapeutic LPs — not steroids or shunts first — control elevated opening pressure.
• Tuberculous meningitis: RIPE therapy with adjunctive corticosteroids and prolonged duration (ATS/CDC/IDSA).
• Toxoplasma encephalitis: pyrimethamine + sulfadiazine + leucovorin.
• Neurocysticercosis: albendazole (± praziquantel) with corticosteroids and antiseizure drugs (IDSA/ASTMH); calcified-only lesions need no antiparasitic.
• Brain abscess: neurosurgical aspiration/excision plus prolonged IV antibiotics — antibiotics alone rarely suffice for large or mass-effect lesions.
• Neurosyphilis: IV aqueous penicillin G (CDC STI guidelines).

Contraindicated/avoid

• LP with mass effect or uncorrected coagulopathy; corticosteroids in HIV cryptococcal meningitis (harmful); withholding antibiotics pending CSF results; there is no antimicrobial therapy for prion disease or specific antiviral for PML (restore immunity/ART).

Neurologic complications of the infection

• Cerebral edema with herniation (emergency): cytotoxic plus vasogenic edema from BBB breakdown; signalled by declining GCS, unilateral fixed dilated pupil, Cushing reflex (hypertension, bradycardia, irregular respirations), or post-LP deterioration.
• Hydrocephalus (emergency): purulent or basal granulomatous exudate (classically TB) fibroses arachnoid granulations (communicating) or blocks the aqueduct/foramina (obstructive); progressive somnolence with ventriculomegaly on imaging demands external ventricular drainage.
• Septic vasculitis and arterial/venous infarction: inflammatory thrombosis of subarachnoid vessels or cortical veins/dural sinuses; new hemiparesis, aphasia, or seizures during treatment. VZV vasculopathy is the classic stroke mimic in a zoster patient.
• Subdural empyema or effusion: fever and focal deficits persisting despite adequate antibiotics; empyema requires surgical drainage. Effusions are common and often benign in infants.
• Sensorineural hearing loss: cochlear inflammation via the cochlear aqueduct, most often pneumococcal — audiologic testing before discharge is standard pediatric practice.
• Seizures and epilepsy: acute cortical irritation, later gliotic scar; HSV encephalitis is the archetype.
• Hyponatremia: SIADH versus cerebral salt wasting — distinguish by volume status, since the treatments (fluid restriction vs. salt/volume repletion) are opposite.
• Waterhouse–Friderichsen syndrome (emergency): meningococcal endotoxin-driven DIC with bilateral adrenal hemorrhage → purpura fulminans, refractory shock, hypoglycemia; give stress-dose hydrocortisone.
• Abscess rupture into the ventricle (emergency): sudden headache and deterioration with ventriculitis; very high mortality.
• IRIS: after ART initiation in cryptococcal or TB meningitis, paradoxical worsening as immune function returns.

Treatment-related complications

• Amphotericin B: nephrotoxicity, potassium and magnesium wasting, infusion reactions; liposomal formulation mitigates but does not eliminate this.
• Flucytosine: dose-dependent myelosuppression — follow CBCs and levels.
• Vancomycin: AKI, amplified by concurrent piperacillin–tazobactam.
• Acyclovir: crystalline nephropathy — prevent with generous hydration and slow infusion.
• Pyrimethamine: megaloblastic marrow suppression, prevented by leucovorin (never folic acid alone).
• Corticosteroids: hyperglycemia, GI bleeding, and reduced CSF penetration of vancomycin.

• Antibiotics before the scanner: in suspected bacterial meningitis with an indication for pre-LP CT, the single best next step is blood cultures → dexamethasone + empiric antibiotics → CT → LP. The classic distractor is "perform LP first" or "await CT before treating."
• **Ampicillin is the Listeria add-on**: neonates, age >50, pregnancy, and cell-mediated immunodeficiency. Ceftriaxone plus vancomycin alone is the trap answer in an elderly or immunosuppressed stem.
• HSV-1 encephalitis: temporal lobe hemorrhagic necrosis, olfactory/gustatory hallucinations and personality change, RBCs and xanthochromia in CSF, temporal hyperintensity on MRI, Cowdry A intranuclear inclusions. Start IV acyclovir empirically — do not wait for PCR.
• Cryptococcus: India ink halo and mucicarmine-positive capsule, but CSF cryptococcal antigen is the more sensitive test; the tested management point is serial therapeutic lumbar punctures for raised opening pressure, and that steroids are harmful here.
• Ring-enhancing lesion in AIDS: multiple lesions at the gray–white junction/basal ganglia = Toxoplasma (treat empirically and reimage); a solitary periventricular lesion with EBV DNA in CSF = primary CNS lymphoma. PML is the non-enhancing, non-mass-effect confluent white-matter lesion from JC virus infecting oligodendrocytes.
• CJD: rapidly progressive dementia with startle myoclonus, periodic sharp wave complexes on EEG, cortical ribboning on DWI, RT-QuIC/14-3-3 in CSF, spongiform change without inflammation. Standard autoclaving does not decontaminate instruments.
• Terminal complement (C5–C9) deficiency → recurrent Neisseria infection; asplenia → encapsulated organisms. Both are the association examiners return to for meningococcal stems.
• Neonatal meningitis triad: GBS, E. coli K1, Listeria; a neonate may show only irritability, poor feeding, or a bulging fontanelle without nuchal rigidity — its absence never rules out meningitis.