Neuroinfectious Disease
What Do You Need to Know?
- Bacterial meningitis: do NOT delay antibiotics for imaging — give ceftriaxone + vancomycin + dexamethasone empirically; dexamethasone BEFORE or WITH first antibiotic dose reduces mortality in S. pneumoniae
- HSV encephalitis: temporal lobe + fever + seizures = start IV acyclovir immediately — do NOT wait for PCR; most common sporadic fatal encephalitis
- Brain abscess: DWI restriction distinguishes abscess from tumor — restricted diffusion in abscess, NOT in tumor
- HIV neurology: Toxoplasmosis (ring-enhancing, multiple, basal ganglia) vs. CNS lymphoma (single, periventricular, EBV+) — empiric toxo treatment first; biopsy if no response
- PML: multifocal white matter lesions + NO mass effect + immunosuppressed = JC virus; natalizumab risk stratification by JCV antibody index
- Neurosyphilis: Argyll Robertson pupil (accommodates but does NOT react to light) is pathognomonic; CSF VDRL is specific but NOT sensitive
- CJD: rapidly progressive dementia + myoclonus + cortical ribboning on DWI = sCJD; RT-QuIC is now the most sensitive and specific CSF test
Bacterial Meningitis
CSF Profiles Comparison
| Parameter | Bacterial | Viral | TB/Fungal | Carcinomatous |
|---|
| WBC | 1,000–10,000+ (PMNs) | 10–500 (lymphocytes) | 100–500 (lymphocytes) | 10–200 (lymphocytes) |
| Protein | ↑↑ (100–500+) | Normal–mildly ↑ | ↑↑↑ (100–500+) | ↑↑ (50–200+) |
| Glucose | ↓↓ (<40 or <2/3 serum) | Normal | ↓↓↓ (often <20) | ↓↓ |
| Opening pressure | ↑↑ (200–500+) | Normal–mildly ↑ | ↑↑ | ↑ |
| Special tests | Gram stain, culture, latex agglutination | PCR (enterovirus, HSV) | AFB smear/culture, India ink, CrAg | Cytology (×3 LPs), flow cytometry |
- PMN-predominant CSF + low glucose = bacterial until proven otherwise
- Early viral meningitis can have PMN predominance — repeat LP in 6–12 hours shows lymphocytic shift
- TB and fungal can initially show mixed or PMN-predominant cells
Empiric Antibiotic Therapy by Age
| Age Group | Common Organisms | Empiric Regimen |
|---|
| Neonates (<1 month) | GBS, E. coli, Listeria | Ampicillin + gentamicin + cefotaxime |
| Infants/Children (1 mo–18 yr) | S. pneumoniae, N. meningitidis, H. influenzae | Ceftriaxone + vancomycin + dexamethasone |
| Adults (18–50 yr) | S. pneumoniae, N. meningitidis | Ceftriaxone + vancomycin + dexamethasone |
| Elderly (>50 yr) / Immunocompromised | S. pneumoniae, Listeria, gram-negatives | Ceftriaxone + vancomycin + ampicillin + dexamethasone |
Dexamethasone in Bacterial Meningitis
- Timing: give BEFORE or WITH the first antibiotic dose — NOT after
- Dose: 0.15 mg/kg IV q6h × 4 days
- Proven benefit: primarily for S. pneumoniae — reduces hearing loss and mortality
- Mechanism: decreases subarachnoid inflammation → less vasogenic edema and cochlear damage
- Discontinue if organism is NOT S. pneumoniae (some experts continue for H. influenzae in children)
Chemoprophylaxis
| Organism | Prophylaxis Indicated | Regimen |
|---|
| N. meningitidis | Close contacts (household, daycare, direct exposure to secretions) | Rifampin × 2 days OR ciprofloxacin × 1 dose OR ceftriaxone IM × 1 dose |
| H. influenzae type b | Household contacts with unvaccinated children <4 yr | Rifampin × 4 days |
| S. pneumoniae | None (no prophylaxis for contacts) | — |
Complications of Bacterial Meningitis
- SIADH → hyponatremia (monitor sodium closely)
- Hydrocephalus — communicating (inflammatory adhesions) or obstructive
- Subdural empyema/effusion
- Cerebral venous sinus thrombosis
- Sensorineural hearing loss — most common long-term sequela; test audiometry in all survivors
- Seizures — occur in ~30% of bacterial meningitis
- Cerebral infarction — vasculitis/vasospasm of perforating arteries
- LP contraindications (focal neuro deficit, papilledema, altered consciousness, immunocompromised, seizures) — get CT first BUT do NOT delay antibiotics; give empiric treatment BEFORE imaging
- Add ampicillin for Listeria in neonates, elderly (>50), pregnant, and immunocompromised — cephalosporins do NOT cover Listeria
- Waterhouse-Friderichsen syndrome: bilateral adrenal hemorrhage from N. meningitidis sepsis → DIC + shock + purpura fulminans
Brain Abscess & Empyema
Ring-Enhancing Lesion — Differential Diagnosis
| Feature | Brain Abscess | Tumor (GBM/Metastasis) | Toxoplasmosis |
|---|
| DWI | Restricted diffusion (bright DWI, dark ADC) | NO restricted diffusion | Variable (mild restriction possible) |
| Enhancement | Thin, smooth ring | Thick, irregular ring | Ring or nodular |
| Wall | Uniform thickness; thinner medially | Irregular, variable thickness | Variable |
| Location | Gray-white junction; near source | Variable | Basal ganglia, gray-white junction |
| MR Spectroscopy | Amino acids, lactate, acetate, succinate | Elevated choline, ↓ NAA | Lipid/lactate peaks |
| Key clue | Fever, source (sinusitis, endocarditis) | No fever typically | HIV + CD4 <100 |
- DWI is the key differentiator: brain abscess = restricted diffusion; tumor = NO restriction — this is a high-yield board question
- Abscess wall is thinner on the medial (ventricular) side — this is why abscesses rupture into ventricles (catastrophic complication)
Microbiology by Source
| Source | Common Organisms | Notes |
|---|
| Contiguous (sinusitis, otitis, dental) | Streptococci, anaerobes (Bacteroides, Fusobacterium) | Frontal lobe (sinusitis), temporal lobe/cerebellum (otitis) |
| Hematogenous (endocarditis, lung abscess) | S. aureus, Streptococci | Often multiple; at gray-white junction (MCA territory) |
| Post-surgical/trauma | S. aureus, gram-negatives, Propionibacterium | At surgical site; early or delayed |
| Immunocompromised | Toxoplasma, Nocardia, Aspergillus, Listeria | Consider atypical organisms; Nocardia = filamentous gram+ rod |
| Cryptogenic (no source found) | Mixed or streptococcal | ~20% have no identifiable source |
Treatment
- Aspiration/excision: stereotactic aspiration for deep/eloquent locations; excision for superficial, accessible, or multiloculated
- IV antibiotics: 6–8 weeks; empiric = ceftriaxone + metronidazole ± vancomycin (if post-surgical or hematogenous)
- Medical only (no surgery): <2.5 cm, early cerebritis, multiple small abscesses, surgically inaccessible, or concurrent meningitis
- Serial imaging: follow with contrast MRI every 1–2 weeks to confirm resolution
Subdural Empyema
- Neurosurgical emergency — rapid deterioration over hours
- Most common source: sinusitis (frontal) in young males; also otitis, post-craniotomy
- Presentation: headache, fever, seizures, rapid focal deficits, meningismus
- MRI: subdural collection with rim enhancement; DWI restriction
- Treatment: urgent surgical drainage (craniotomy) + IV antibiotics 4–6 weeks
Spinal Epidural Abscess
- Classic progression: back pain → radiculopathy → weakness → paralysis
- #1 organism: S. aureus (60–70%)
- Risk factors: IVDU, diabetes, spinal procedures, bacteremia
- Diagnosis: MRI with gadolinium (entire spine — skip lesions in 10–15%)
- Treatment: surgical decompression + IV antibiotics 6–8 weeks; medical-only if no neurological deficits and close monitoring possible
- Prognosis: outcome depends on severity and duration of deficits pre-surgery — paralysis >24–48 hours is often irreversible
Spinal epidural abscess can be missed initially — maintain high suspicion in any patient with fever + back pain + risk factors. Delay in diagnosis is the most common cause of poor outcomes.
HSV Encephalitis
HSV-1 Encephalitis — Key Features
| Feature | Details |
|---|
| Epidemiology | Most common cause of sporadic fatal encephalitis; bimodal peak (children + elderly); no seasonal predilection |
| Mechanism | Reactivation from trigeminal ganglion (most adults) > primary infection; travels along CN V to temporal lobe |
| Presentation | Fever, altered mental status, seizures (focal > generalized), personality/behavioral changes, aphasia, olfactory hallucinations |
| MRI | Medial temporal lobe, insular cortex, orbitofrontal — T2/FLAIR hyperintensity; bilateral but asymmetric; hemorrhagic component; spares basal ganglia (vs. autoimmune encephalitis) |
| CT | May be normal early; later shows temporal lobe hypodensity ± hemorrhage |
| EEG | Periodic lateralized epileptiform discharges (PLEDs) over temporal region |
CSF & Diagnosis
| CSF Parameter | Findings |
|---|
| WBC | 10–500 cells; lymphocytic predominance |
| Protein | Mildly–moderately elevated |
| Glucose | Usually normal |
| RBCs | Often present (hemorrhagic encephalitis) — xanthochromic supernatant |
| HSV PCR | Sensitivity 98%, specificity 94%; can be NEGATIVE in first 72 hours — repeat if high clinical suspicion |
| Note | Normal CSF does NOT exclude HSV encephalitis (up to 5% initially normal) |
Treatment
- IV acyclovir 10 mg/kg q8h × 14–21 days — start empirically at first suspicion, do NOT wait for PCR results
- Untreated mortality: 70%; with acyclovir: ~20%
- Adverse effects: nephrotoxicity (crystalluria — ensure adequate hydration), thrombocytopenia
- Repeat PCR at end of treatment — if still positive, extend course
HSV-2 Neurological Syndromes
- Neonatal HSV encephalitis: acquired perinatally; diffuse brain involvement (not temporal-predominant); high mortality
- Mollaret meningitis: recurrent aseptic meningitis (HSV-2 > HSV-1); self-limited episodes; large endothelial cells (Mollaret cells) in CSF
- Sacral radiculitis: urinary retention, saddle anesthesia (Elsberg syndrome)
- Temporal lobe lesion + fever + seizures = start acyclovir immediately — do not wait for PCR; delay increases mortality
- HSV PCR can be negative in first 72 hours — repeat LP if initial PCR is negative but suspicion is high
- HSV encephalitis spares the basal ganglia — basal ganglia involvement suggests autoimmune encephalitis (anti-NMDA-R) or other viral causes
- Mollaret meningitis = recurrent lymphocytic meningitis — caused by HSV-2; benign self-limited episodes
Other Viral Encephalitides
Arboviruses
| Virus | Vector | Key Features | Board Buzzword |
|---|
| West Nile (WNV) | Culex mosquito | Acute flaccid paralysis (anterior horn cell); encephalitis in elderly; tremor, parkinsonism; IgM serum/CSF | Polio-like flaccid paralysis + encephalitis in summer |
| Eastern Equine (EEE) | Aedes/Culiseta mosquito | Worst prognosis of arboviruses (33–70% mortality); children & elderly; basal ganglia/thalamus involvement | Highest mortality arboviral encephalitis |
| St. Louis Encephalitis | Culex mosquito | Similar to WNV; elderly; SIADH common; Midwest/South US | SIADH + encephalitis |
| Japanese Encephalitis | Culex mosquito | Thalamic lesions on MRI; most common vaccine-preventable encephalitis worldwide; Asia | Bilateral thalamic lesions + Asia travel |
| Zika | Aedes mosquito | Congenital microcephaly; Guillain-Barré syndrome in adults; sexual transmission | Microcephaly + GBS |
| La Crosse | Aedes triseriatus | Children; Midwest US; seizures common; generally good prognosis | Pediatric encephalitis + seizures |
Non-Arboviral Encephalitides
| Virus | Key Neurological Manifestations | Board-Testable Facts |
|---|
| CMV | Ventriculoencephalitis (periventricular enhancement); polyradiculopathy; retinitis | HIV + CD4 <50; CMV polyradiculopathy has PMN-predominant CSF (unusual for viral); treat with ganciclovir + foscarnet |
| VZV | Vasculopathy (large + small vessel → strokes); multifocal leukoencephalopathy; cerebellitis; Ramsay Hunt | Ramsay Hunt = CN VII palsy + vesicles in ear + hearing loss; VZV vasculopathy can occur WITHOUT rash; CSF VZV IgG:albumin ratio > VZV PCR |
| EBV | Alice in Wonderland syndrome; cerebellitis; encephalitis; GBS; CNS lymphoma (immunocompromised) | Alice in Wonderland = metamorphopsia (objects appear distorted in size) |
| Rabies | Encephalitic (furious): hydrophobia, aerophobia, autonomic instability; Paralytic (dumb): ascending paralysis mimics GBS | Negri bodies (eosinophilic inclusions in Purkinje cells); fatal once symptomatic; post-exposure prophylaxis (PEP) is curative if given before symptoms |
| Enterovirus D68 | Acute flaccid myelitis (AFM); polio-like; anterior horn cell involvement | Children; late summer/fall; asymmetric limb weakness; MRI shows longitudinal gray matter lesion in cord |
| Measles (SSPE) | Subacute sclerosing panencephalitis — years after infection; cognitive decline, myoclonus, periodic complexes on EEG | Elevated measles antibody titers in CSF; periodic stereotyped EEG complexes (Radermecker complexes) |
- West Nile virus: asymmetric acute flaccid paralysis + encephalitis in summer/fall = WNV; anterior horn cells (like polio)
- CMV polyradiculopathy: the one viral infection causing PMN-predominant CSF — easily confused with bacterial
- VZV vasculopathy: can cause strokes WITHOUT rash — check CSF VZV IgG/albumin ratio (more sensitive than PCR)
- Rabies is 100% fatal once symptomatic — PEP with immunoglobulin + vaccine series is the only chance
HIV Neurology
HIV-Associated Neurocognitive Disorders (HAND)
| Category | Cognitive Impairment | Functional Impairment | Key Features |
|---|
| ANI (Asymptomatic Neurocognitive Impairment) | ≥1 SD below mean in ≥2 cognitive domains | None | Detected on formal testing only; most common HAND category on ART |
| MND (Mild Neurocognitive Disorder) | ≥1 SD below mean in ≥2 cognitive domains | Mild (self-reported or observed) | Difficulty with complex tasks, slowed processing |
| HAD (HIV-Associated Dementia) | ≥2 SD below mean in ≥2 cognitive domains | Marked impairment in ADLs | Subcortical dementia pattern: psychomotor slowing, apathy, poor concentration; MRI shows cerebral atrophy + white matter changes |
HIV-Associated Conditions by CD4 Count
| CD4 Count | Conditions |
|---|
| Any CD4 | HIV seroconversion meningitis, GBS/CIDP, DSPN, vacuolar myelopathy, myopathy, inflammatory myopathy |
| <500 | Herpes zoster (VZV), Kaposi sarcoma, oral hairy leukoplakia, TB |
| <200 | Toxoplasmosis, PML (JC virus), Cryptococcal meningitis, CNS lymphoma |
| <100 | CNS lymphoma (EBV-driven), CMV encephalitis/radiculopathy |
| <50 | CMV retinitis, MAC (Mycobacterium avium complex) |
Toxoplasmosis vs. CNS Lymphoma
| Feature | Toxoplasmosis | Primary CNS Lymphoma |
|---|
| CD4 count | <100 (usually <200) | <50–100 |
| Number of lesions | Multiple (usually) | Solitary (60–70%) or few |
| Location | Basal ganglia, corticomedullary junction | Periventricular, corpus callosum, deep gray matter |
| Enhancement | Ring-enhancing with edema | Homogeneous or ring-enhancing |
| Toxoplasma IgG | Usually positive (reactivation) | Usually negative (not related) |
| CSF EBV PCR | Negative | Positive (EBV-driven lymphoma) |
| Thallium SPECT / PET | No uptake (cold) | Increased uptake (hot) |
| Initial approach | Empiric treatment with pyrimethamine + sulfadiazine + leucovorin × 2–3 weeks | Brain biopsy if no response to empiric toxo therapy |
| Response to empiric Tx | Clinical + radiographic improvement in 2 weeks | No improvement → biopsy |
Other HIV-Associated Neurological Conditions
| Condition | Key Features |
|---|
| Vacuolar myelopathy | Posterior columns + corticospinal tracts; mimics B12 deficiency (subacute combined degeneration); progressive spastic paraparesis + sensory ataxia; thoracic cord; ART is primary treatment |
| DSPN (Distal Symmetric Polyneuropathy) | Most common neurological complication of HIV; stocking-glove distribution; painful burning; can be from HIV or ART (didanosine, stavudine); treat with ART optimization ± gabapentin/duloxetine |
| HIV-associated GBS/CIDP | Can occur at any CD4 count; CSF may show pleocytosis (unlike typical GBS where protein is up but cells are not); treat with IVIg/PLEX as standard + ART |
| Progressive polyradiculopathy (CMV) | CD4 <50; rapidly progressive cauda equina syndrome; PMN-predominant CSF; CMV PCR positive; ganciclovir + foscarnet |
Immune Reconstitution Inflammatory Syndrome (IRIS)
- Definition: paradoxical worsening after starting ART due to immune recovery and exaggerated inflammatory response to existing infection
- Timing: usually 2–8 weeks after ART initiation; more common with very low baseline CD4
- Common triggers: PML, TB, Cryptococcus, Toxoplasmosis, CMV
- Treatment: continue ART + treat underlying infection + corticosteroids for severe IRIS
- PML-IRIS: can cause fatal brain swelling — the most feared neurologic IRIS complication
- Empiric toxo treatment first, biopsy second: if HIV + CD4 <200 + ring-enhancing lesions + Toxo IgG positive → treat empirically; biopsy only if no improvement in 2 weeks
- Vacuolar myelopathy mimics B12 deficiency — check B12 level to exclude; both affect posterior columns and lateral corticospinal tracts
- CSF pleocytosis in HIV-associated GBS — unlike classic GBS where cells are low (albuminocytologic dissociation)
Progressive Multifocal Leukoencephalopathy (PML)
Key Features
| Feature | Details |
|---|
| Causative agent | JC virus (JCV) — polyomavirus; infects oligodendrocytes → demyelination |
| Risk groups | HIV (CD4 <200), natalizumab, rituximab, other immunosuppressants (mycophenolate, fingolimod), hematologic malignancies |
| Presentation | Subacute progressive focal deficits: hemiparesis, visual field cuts, cognitive decline, ataxia; NO fever, NO headache |
| MRI | Multifocal asymmetric white matter lesions; subcortical U-fibers involved; NO mass effect; NO enhancement (or minimal faint enhancement); T2/FLAIR hyperintense, T1 hypointense |
| CSF | JCV PCR — sensitivity ~80% (higher with ultrasensitive assays); specificity >95% |
| Pathology | Demyelination + bizarre giant astrocytes + oligodendroglial intranuclear inclusions (ground-glass appearance) |
| Brain biopsy | Gold standard if CSF JCV PCR is negative and clinical suspicion remains high |
| Treatment | Restore immune function: ART for HIV; stop offending drug (natalizumab, rituximab); no specific antiviral for JCV |
| Prognosis | HIV-PML: ~50% 1-year survival with ART; natalizumab-PML: ~25% mortality; survivors often have significant disability |
Natalizumab-Associated PML — Risk Stratification
| Risk Factor | Details |
|---|
| JCV antibody status | JCV Ab negative = very low risk (~0.1/1,000); JCV Ab positive = increased risk |
| JCV antibody index | Index ≤0.9 = lower risk; index >1.5 = highest risk |
| Treatment duration | >24 months = significantly increased risk (especially >48 months) |
| Prior immunosuppressant use | Prior use of azathioprine, methotrexate, cyclophosphamide → further ↑ risk |
| Highest-risk combination | JCV Ab+ (index >1.5) + >24 months natalizumab + prior immunosuppression → risk up to ~13/1,000 |
| Monitoring | JCV antibody testing every 6 months; brain MRI every 3–6 months in high-risk patients |
PML vs. MS Lesions
| Feature | PML | MS |
|---|
| Location | Subcortical U-fibers; parieto-occipital predominance | Periventricular; Dawson fingers |
| Enhancement | No or minimal | Active lesions enhance (open ring) |
| Mass effect | None | Tumefactive MS may have mass effect |
| Shape | Confluent, irregular borders; scalloped at cortex | Ovoid, well-defined |
| Progression | Relentlessly progressive | Relapsing-remitting or progressive |
- PML triad: white matter lesions + NO mass effect + immunosuppressed = PML until proven otherwise
- PML involves subcortical U-fibers (unlike MS which is periventricular) — key MRI differentiator
- Natalizumab risk: JCV Ab index >1.5 + duration >24 months + prior immunosuppression = highest risk; extended-interval dosing may reduce risk
- No specific antiviral exists for JCV — treatment is immune reconstitution only
Tuberculous Meningitis
Clinical Features
| Feature | Details |
|---|
| Classic presentation | Basilar meningitis — subacute course (days–weeks) with headache, fever, meningismus, CN palsies |
| Cranial nerve palsies | CN VI most common (long intracisternal course); also CN II, III, IV, VII |
| Hydrocephalus | Communicating (basilar exudates blocking CSF absorption); requires EVD or VP shunt |
| Vasculitis/Stroke | Basal perforating arteries involved → lacunar infarcts (basal ganglia, internal capsule, thalamus) |
| Tuberculomas | Ring-enhancing parenchymal lesions; can paradoxically enlarge on treatment |
| Spinal involvement | Arachnoiditis, radiculomyelopathy, Pott disease (vertebral TB) |
CSF & Diagnosis
| Test | Findings/Performance |
|---|
| WBC | 100–500 cells; lymphocytic predominance (may be PMN-predominant early) |
| Protein | Very high (100–500+ mg/dL); can exceed 1 g/dL |
| Glucose | Very low (<45 mg/dL; often <20) |
| AFB smear | Sensitivity only 10–30%; large-volume repeated samples increase yield |
| AFB culture | Gold standard but takes 2–8 weeks; sensitivity 50–80% |
| TB PCR (GeneXpert) | Rapid results; sensitivity ~60–80% in CSF; WHO recommended; if positive, confirms diagnosis |
| ADA (adenosine deaminase) | Elevated in TB meningitis; sensitivity ~80%; nonspecific |
MRI Findings
- Basal cistern enhancement (thick, nodular leptomeningeal enhancement) — most characteristic
- Hydrocephalus — communicating type
- Tuberculomas — ring-enhancing lesions; can be multiple; "target sign" (central calcification)
- Infarcts — basal ganglia, thalamus, internal capsule (perforator territory)
Treatment
| Phase | Regimen | Duration |
|---|
| Intensive phase | RIPE: Rifampin + Isoniazid + Pyrazinamide + Ethambutol | 2 months |
| Continuation phase | RI: Rifampin + Isoniazid | 7–10 months |
| Total duration | 9–12 months (longer than pulmonary TB) | — |
| Adjunctive dexamethasone | Proven mortality benefit — taper over 6–8 weeks | Started with anti-TB therapy |
| Pyridoxine (B6) | Always co-administer with isoniazid to prevent peripheral neuropathy | Throughout INH course |
- Basilar meningitis + CN palsies + hydrocephalus + strokes = think TB or sarcoid — these are the two classic causes of basilar meningitis
- Dexamethasone is proven to reduce mortality in TB meningitis — unlike most other forms of meningitis (except S. pneumoniae)
- Paradoxical worsening: tuberculomas can enlarge during treatment despite clinical improvement — this is NOT treatment failure; continue therapy
- CSF pattern: lymphocytic + very high protein + very low glucose = TB meningitis until proven otherwise
Neurosyphilis
Stages of Neurosyphilis
| Stage | Timing | Manifestations | Key Features |
|---|
| Asymptomatic | Any stage | CSF abnormalities only (pleocytosis, ↑ protein, + VDRL) | Diagnosed by LP in patients with syphilis and neurologic risk |
| Syphilitic meningitis | Early (months–years) | Headache, meningismus, CN palsies (VII, VIII, II) | CSF lymphocytic pleocytosis; hearing loss common |
| Meningovascular | 5–12 years | Strokes (especially MCA territory); Heubner arteritis (large vessel), Nissl-Alzheimer arteritis (small vessel) | Young patient with stroke + risk factors = screen for syphilis |
| General paresis (GPI) | 10–25 years | Frontal dementia: personality change, grandiosity, psychosis, cognitive decline; Argyll Robertson pupils | Mnemonic: PARESIS — Personality, Affect, Reflexes (↑), Eye (AR pupils), Sensorium (↓), Intellect (↓), Speech |
| Tabes dorsalis | 15–25 years | Lightning pains, posterior column loss (proprioception, vibration), sensory ataxia, Charcot joints, Argyll Robertson pupils, Romberg+ | Posterior column degeneration; absent DTRs (afferent arc disrupted) |
Diagnosis — Serologic Testing
| Test | Type | Use | Key Points |
|---|
| RPR / VDRL (serum) | Non-treponemal | Screening + activity monitoring | Quantitative; titers ↓ with treatment; false positives (lupus, pregnancy, antiphospholipid syndrome) |
| FTA-ABS (serum) | Treponemal | Confirmatory | Remains positive for life (even after treatment); cannot monitor treatment response |
| CSF VDRL | Non-treponemal | CSF diagnosis | Highly specific but NOT sensitive (~30–70% sensitivity); if positive, confirms neurosyphilis |
| CSF FTA-ABS | Treponemal | CSF diagnosis | Sensitive but NOT specific; if NEGATIVE, essentially rules out neurosyphilis |
Argyll Robertson Pupil
- Accommodates but does NOT react to light (“prostitute’s pupil” — accommodates but does not react)
- Bilateral, small, irregular pupils
- Lesion location: periaqueductal gray / pretectal area (disrupts light reflex but spares near reflex)
- Pathognomonic for neurosyphilis (though diabetes can produce a similar finding)
Treatment
| Regimen | Details |
|---|
| IV penicillin G | 18–24 million units/day (3–4 MU q4h) × 10–14 days |
| Alternative | IM procaine penicillin + oral probenecid × 10–14 days |
| Penicillin allergy | Desensitize and use penicillin (preferred); ceftriaxone 2g IV daily × 10–14 days as alternative |
| Follow-up | CSF every 6 months until normalization; CSF VDRL should decline; cell count normalizes first |
| Retreatment criteria | CSF pleocytosis not declining at 6 months, or CSF VDRL not declining at 2 years |
- Argyll Robertson pupil = neurosyphilis until proven otherwise — the most tested physical finding
- CSF VDRL: specific but NOT sensitive (if positive = neurosyphilis; if negative = does not exclude it)
- CSF FTA-ABS: sensitive but NOT specific (if negative = virtually rules out neurosyphilis)
- Tabes dorsalis: lightning pains + sensory ataxia + Romberg+ + absent knee jerks + Charcot joints + AR pupils
- Young stroke + CSF pleocytosis = consider meningovascular syphilis — always screen for syphilis in unexplained young stroke
Fungal & Parasitic CNS Infections
Fungal CNS Infections
| Organism | Risk Group | Key Features | Diagnosis | Treatment |
|---|
| Cryptococcus neoformans | HIV (CD4 <100); transplant | Subacute meningitis; ↑↑ opening pressure (>25 cmH2O); headache, fever, altered mental status; papilledema | India ink (budding yeast with capsule); cryptococcal antigen (CrAg) serum/CSF (sensitivity >95%) | Induction: amphotericin B + flucytosine × 2 weeks → consolidation: fluconazole × 8 weeks → maintenance: fluconazole until immune reconstitution; serial LPs for pressure management |
| Coccidioides immitis | Southwest US, Mexico (desert) | Basilar meningitis; hydrocephalus; CSF eosinophilia (sometimes); chronic course | CSF complement-fixing antibodies; serum serology | Fluconazole (high dose) — lifelong treatment; intrathecal amphotericin for refractory cases |
| Aspergillus | Neutropenic; transplant; chronic steroids | Angioinvasive → hemorrhagic infarcts; brain abscess; sinusitis with CNS extension | Tissue biopsy (septate hyphae with acute-angle branching); galactomannan (serum/CSF) | Voriconazole (first-line); surgical debridement for abscess |
| Mucormycosis (Zygomycetes) | DKA; neutropenic; iron overload (deferoxamine) | Rhinocerebral: sinusitis → orbita → brain; black eschar on palate/nasal turbinate; cavernous sinus thrombosis; CN palsies | Tissue biopsy (broad, non-septate hyphae, right-angle branching); cultures often negative | Amphotericin B (liposomal) + surgical debridement + correct underlying condition (DKA); mortality 50–70% |
| Histoplasma | Ohio/Mississippi River Valley; HIV | Chronic meningitis; brain granulomas; CNS histoplasmosis rare | Histoplasma antigen (urine/CSF); CSF antibody; culture | Liposomal amphotericin B → itraconazole maintenance |
- Cryptococcal meningitis: elevated ICP is the #1 cause of death — serial LPs with removal of 20–30 mL CSF to maintain OP <20 cmH2O; VP shunt if refractory
- Mucormycosis: black eschar + DKA + sinusitis = rhinocerebral mucormycosis; tissue biopsy is required (cultures often negative)
Parasitic CNS Infections
| Organism | Key Features | Diagnosis | Treatment |
|---|
| Neurocysticercosis (Taenia solium) | Most common cause of acquired epilepsy worldwide; stages: vesicular (viable cyst + scolex) → colloidal (degenerating, edema) → granular-nodular → calcified; seizures are #1 presentation | MRI/CT: cyst with scolex (dot within cyst); "Swiss cheese brain" (multiple cysts); serum/CSF antibodies (EITB — sensitivity ~95% for ≥2 cysts) | Viable cysts: albendazole + steroids (dexamethasone); calcified lesions: NO antiparasitic (treat seizures only); single enhancing lesion: steroids alone often sufficient; praziquantel for multiple cysts |
| Cerebral malaria (P. falciparum) | Children in sub-Saharan Africa; coma, seizures; ring-form trophozoites; parasitized RBC sequestration in cerebral microvasculature; retinal hemorrhages | Peripheral blood smear (ring forms); rapid diagnostic test (RDT) | IV artesunate (superior to quinine); exchange transfusion if parasitemia >10% |
| Toxoplasmosis | See HIV section; also congenital toxoplasmosis: chorioretinitis + intracranial calcifications + hydrocephalus | Serology; imaging; PCR | Pyrimethamine + sulfadiazine + leucovorin |
| Naegleria fowleri (PAM) | Primary amebic meningoencephalitis; swimming in warm freshwater; rapid fulminant course (death in 3–7 days); hemorrhagic meningoencephalitis | Motile trophozoites on wet mount of CSF | Amphotericin B + miltefosine (nearly always fatal despite treatment) |
| Acanthamoeba (GAE) | Granulomatous amebic encephalitis; immunocompromised; chronic course (weeks–months); multiple ring-enhancing lesions | Brain biopsy showing trophozoites/cysts | Miltefosine-based combinations; often fatal |
- Neurocysticercosis: do NOT give antiparasitics for calcified (dead) cysts — treat seizures only; albendazole + steroids only for viable cysts
- Scolex on imaging (dot-within-cyst) is pathognomonic for neurocysticercosis
- Cryptococcal meningitis: death is from elevated ICP, not the infection itself — aggressive CSF pressure management is critical
- Mucormycosis: rhinocerebral + DKA + black eschar = classic triad; Aspergillus has septate, acute-angle branching vs. Mucor has non-septate, right-angle branching
- Naegleria: swimming in warm freshwater → fulminant meningitis within days = PAM
Prion Diseases
Creutzfeldt-Jakob Disease (CJD) — Classification
| Type | Frequency | Age | Mechanism | Key Distinguishing Features |
|---|
| Sporadic (sCJD) | 85% | 60–70 yr | Spontaneous PrPC → PrPSc misfolding | Rapidly progressive dementia + myoclonus; cortical ribboning on DWI; PSWCs on EEG |
| Familial (fCJD) | 10–15% | Variable (younger) | PRNP gene mutations (autosomal dominant) | Family history; includes GSS (Gerstmann-Sträussler-Scheinker) and FFI (Fatal Familial Insomnia) |
| Variant (vCJD) | <1% | Young (median 28 yr) | BSE (mad cow) exposure | Psychiatric onset; pulvinar sign on MRI; tonsil biopsy positive for PrPSc; longer course (14 months) |
| Iatrogenic (iCJD) | Rare | Variable | Contaminated dura mater grafts, corneal transplants, growth hormone, neurosurgical instruments | Presentation depends on route of exposure; cerebellar symptoms predominate in peripheral inoculation |
Sporadic CJD — Diagnostic Features
| Test | Findings | Board-Testable Points |
|---|
| MRI (DWI/FLAIR) | Cortical ribboning (cortical DWI hyperintensity); caudate/putamen hyperintensity | DWI is the most sensitive MRI sequence; can precede clinical symptoms |
| CSF RT-QuIC | Detects misfolded PrPSc by seeded amplification | Most sensitive (92–95%) AND specific (99–100%); has replaced 14-3-3 as preferred test |
| CSF 14-3-3 | Elevated (marker of rapid neuronal destruction) | Sensitive but NOT specific (positive in stroke, encephalitis, seizures); now largely superseded by RT-QuIC |
| CSF t-tau | Markedly elevated (>1,150 pg/mL) | More specific than 14-3-3; combined with RT-QuIC for highest accuracy |
| EEG | Periodic sharp wave complexes (PSWCs) — 1–2 Hz generalized | Seen in ~67% of sCJD; often absent in early disease and in vCJD; can be obscured by myoclonus |
| Pathology (gold standard) | Spongiform change, neuronal loss, astrogliosis, PrPSc immunostaining | Brain biopsy rarely needed given RT-QuIC availability; autopsy confirmatory |
CJD Variants & Related Prion Diseases
| Variant/Disease | Key Features |
|---|
| Heidenhain variant | Visual cortex predominant → cortical blindness, visual agnosia, Balint syndrome as initial presentation; occipital cortical ribboning |
| MV2 subtype | Longer course (~17 months); prominent ataxia; less myoclonus; less prominent EEG changes |
| Gerstmann-Sträussler-Scheinker (GSS) | PRNP mutation; cerebellar ataxia predominant; slower course (2–10 years); multicentric PrP plaques |
| Fatal Familial Insomnia (FFI) | PRNP D178N mutation (codon 129 Met); progressive insomnia → dysautonomia → dementia; thalamic gliosis; death in 7–36 months |
| Variably Protease-Sensitive Prionopathy (VPSPr) | Sporadic; slower course than sCJD; psychiatric symptoms and speech difficulties; less protease resistance of PrP |
Rapidly Progressive Dementia — CJD Mimics
- Autoimmune encephalitis (anti-NMDA-R, anti-LGI1, anti-CASPR2) — treatable, must exclude
- CNS lymphoma / Intravascular lymphoma
- Hashimoto encephalopathy (SREAT) — anti-TPO antibodies; steroid-responsive
- CNS vasculitis
- Neurosyphilis
- Whipple disease — oculomasticatory myorhythmia is pathognomonic
- Toxic/metabolic: lithium, bismuth, heavy metals
- Rapidly progressive dementia + myoclonus + cortical ribboning on DWI = CJD — the classic board question triad
- RT-QuIC has replaced 14-3-3 as the preferred CSF test — sensitivity 92–95%, specificity 99–100%
- Variant CJD: young patient + psychiatric onset + pulvinar sign on MRI = vCJD; confirm with tonsil biopsy
- Fatal Familial Insomnia: PRNP mutation + progressive insomnia + thalamic atrophy + dysautonomia
- Always exclude treatable mimics before accepting CJD diagnosis — autoimmune encephalitis and CNS lymphoma are the most important to rule out
- 14-3-3 is NOT specific — elevated after stroke, seizures, and encephalitis; RT-QuIC is far superior
