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Neuroinfectious Disease

What Do You Need to Know?

Bacterial meningitis: do NOT delay antibiotics for imaging — give vancomycin + ceftriaxone/cefotaxime + dexamethasone empirically; ADD ampicillin if age ≥50, pregnant, or immunocompromised (Listeria coverage); 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: central restricted diffusion is characteristic — pyogenic abscesses usually restrict; necrotic tumors usually do not. Not pathognomonic: some metastases / high-cellularity tumors can restrict.
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

🚩 Don’t Miss — Test-Day Priorities

Bacterial meningitis empiric therapy: vancomycin + ceftriaxone for all adults; ADD ampicillin if ≥50, immunocompromised, or pregnant (Listeria); dexamethasone BEFORE or WITH first antibiotic dose for suspected pneumococcal — do NOT delay antibiotics for CT/LP
HSV-1 encephalitis: fever + AMS + focal seizures + TEMPORAL/INSULAR/ORBITOFRONTAL T2/FLAIR/DWI hyperintensity (often bilateral asymmetric, gyral enhancement) → start IV acyclovir 10 mg/kg q8h empirically; CSF lymphocytic with RBCs; PCR confirms; ≥50% develop epilepsy; anti-NMDAR encephalitis can follow
TB meningitis: subacute BASAL meningitis + cranial neuropathies (III, VI) + hydrocephalus + basal vasculitis infarcts; CSF lymphocytic + very low glucose + very high protein; RIPE × 12 mo + ADJUNCTIVE DEXAMETHASONE (improves survival)
Cryptococcal meningitis (HIV CD4 <100): amphotericin B + flucytosine induction → fluconazole consolidation/maintenance; SERIAL LPs (NOT shunt initially) for elevated ICP — ICP management drives survival
Toxoplasmosis vs PCNSL in HIV: toxo = MULTIPLE ring-enhancing lesions at basal ganglia + GW junction, serum IgG+ → empiric pyrimethamine + sulfadiazine; PCNSL = SINGLE periventricular, EBV+, thallium SPECT/PET avid — biopsy if no response to toxo therapy in 2 weeks
Neurocysticercosis: seizures + Mexico/Central America exposure + cysts at GW junction. 1–2 viable cysts: albendazole monotherapy × 10–14 d + corticosteroids started BEFORE antiparasitic. >2 viable cysts: albendazole + praziquantel + steroids. Single enhancing lesion: albendazole + steroids (NOT steroids alone). Calcified lesions: symptomatic/seizure management only — no antiparasitic
PML: JC virus reactivation in HIV / natalizumab / rituximab / ocrelizumab / fingolimod; multifocal SUBCORTICAL T2 hyperintensities, NO mass effect, NO enhancement; CSF JCV PCR; treat by REVERSING immunosuppression; watch for IRIS
Neurosyphilis: Argyll Robertson pupil (accommodates but does NOT react) + tabes dorsalis + general paresis; CSF VDRL specific but NOT sensitive; treat with IV penicillin G × 14 days — oral/IM benzathine does NOT penetrate CNS
Sporadic CJD: RPD + myoclonus + cerebellar/visual/pyramidal; MRI DWI cortical ribboning + basal ganglia (pulvinar sign in variant CJD); EEG periodic sharp wave complexes (1 Hz); CSF RT-QuIC (most sensitive/specific) > 14-3-3 + tau; fatal, no treatment
Lyme neuroborreliosis: BILATERAL CN VII palsy + painful radiculopathies + lymphocytic meningitis; ELISA + Western blot; CSF Lyme antibody index. Per 2020 AAN/ACR/IDSA: meningitis, cranial neuritis, and radiculoneuritis can be treated with oral doxycycline OR IV ceftriaxone/cefotaxime/penicillin G × 14–21 days; reserve IV therapy for parenchymal brain/spinal cord involvement or inability to take oral therapy.

🔍 Buzzwords & Pathognomonic FindingsClinical / CSF · Imaging / pathology · Treatment

Clinical / CSF

Fever + meningismus + AMS triad + photophobia → bacterial meningitis
Argyll Robertson pupil (accommodates, does NOT react to light) → neurosyphilis (tabes dorsalis)
Bilateral CN VII palsy + tick exposure + erythema migrans → Lyme neuroborreliosis
Fever + focal seizures + behavioral change + temporal lobe signs → HSV-1 encephalitis
Fever + flaccid asymmetric paralysis (polio-like) + parkinsonism → West Nile virus
HZ ophthalmicus → delayed contralateral hemiparesis → VZV vasculopathy
CSF lymphocytic + very low glucose + very high protein, subacute course → TB or fungal meningitis
CSF India ink + cryptococcal antigen + HIV CD4 <100 → cryptococcal meningitis
CSF RT-QuIC positive + 14-3-3 + tau elevated → sporadic CJD
Rapidly progressive dementia + myoclonus + startle → CJD
CSF VDRL reactive (specific not sensitive) → neurosyphilis
Tabes dorsalis: sensory ataxia + lancinating pains + dorsal column atrophy → tertiary syphilis

Imaging / pathology

Bilateral asymmetric temporal + insular + orbitofrontal T2/FLAIR/DWI hyperintensity with gyral enhancement → HSV-1 encephalitis
Basal meningeal enhancement + hydrocephalus + basal ganglia infarcts → TB meningitis
Multiple ring-enhancing lesions at basal ganglia + GW junction in HIV → toxoplasmosis
Single periventricular homogeneous-enhancing lesion in HIV, thallium-avid → PCNSL (EBV-driven)
Ring-enhancing lesion with restricted diffusion in CENTER + dark T2 capsule → pyogenic brain abscess
“Star of Jerusalem” scolex within cyst at GW junction; multistage (vesicular → colloidal → granular → calcified) → neurocysticercosis
Multifocal subcortical white matter T2 hyperintensities, NO mass effect, NO enhancement → PML (JC virus)
DWI cortical ribboning + basal ganglia hyperintensity → sporadic CJD
Pulvinar sign (bilateral posterior thalamic DWI hyperintensity) → variant CJD
EEG periodic sharp wave complexes at ~1 Hz → sporadic CJD
Spongiform vacuolation + prion protein deposition on biopsy → CJD
Monophasic large confluent post-viral demyelinating lesions in child → ADEM

Treatment / pearls

Vancomycin + ceftriaxone + dexamethasone BEFORE/WITH first dose → empiric bacterial meningitis (suspected pneumococcal)
Add ampicillin for age ≥50 / immunocompromised / pregnant → Listeria coverage
IV acyclovir 10 mg/kg q8h × 14–21 days, do NOT wait for PCR → HSV encephalitis
RIPE × 12 months + adjunctive dexamethasone → TB meningitis
Amphotericin B + flucytosine induction → fluconazole + SERIAL LPs for ICP → cryptococcal meningitis in HIV
Pyrimethamine + sulfadiazine + leucovorin (empiric, then reassess at 2 wk) → CNS toxoplasmosis
Albendazole + steroids (steroids BEFORE antiparasitic); add praziquantel if >2 viable cysts → neurocysticercosis (calcified lesions → symptomatic only)
IV penicillin G × 14 days (oral/IM does NOT penetrate CNS) → neurosyphilis
Oral doxycycline OR IV ceftriaxone/cefotaxime/penicillin G × 14–21 days → Lyme meningitis / cranial neuritis / radiculoneuritis (2020 AAN/ACR/IDSA); reserve IV therapy for parenchymal brain/cord disease
Reverse immunosuppression (stop natalizumab, restart ART) → PML — watch for IRIS
Rifampin or ciprofloxacin or ceftriaxone for close contacts → N. meningitidis chemoprophylaxis
Steroids/IVIG for monophasic post-viral demyelination → ADEM

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

Clinical Pearl

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 2 g IV q12h + vancomycin 15–20 mg/kg IV q8–12h (target trough 15–20 mcg/mL) + dexamethasone 0.15 mg/kg IV q6h × 4 days
Adults ≥50 yr / Immunocompromised / Pregnant	S. pneumoniae, Listeria, gram-negatives	Above regimen + ampicillin 2 g IV q4h for Listeria coverage (cephalosporins do NOT cover Listeria)
Hospital-acquired / post-neurosurgical / penetrating trauma / CSF shunt	S. aureus (incl. MRSA), Pseudomonas, gram-negatives, coag-neg Staph	Vancomycin 15–20 mg/kg IV q8–12h + cefepime 2 g IV q8h OR meropenem 2 g IV q8h (covers Pseudomonas + MRSA + gram-negatives)

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. Status epilepticus in CNS infection: treat per status protocol — levetiracetam 60 mg/kg IV load or fosphenytoin 20 PE/kg; consider cEEG monitoring since patients are encephalopathic and seizures may be subclinical (nonconvulsive status epilepticus is common)
Cerebral infarction — vasculitis/vasospasm of perforating arteries

💎 Board Pearl

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

💎 Board Pearl

DWI is a key differentiator: pyogenic abscess usually shows central restricted diffusion; necrotic tumors usually do not — characteristic but NOT pathognomonic (some metastases / high-cellularity tumors can restrict)
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 regimens by source:
- Community / contiguous (sinusitis, otitis, dental): ceftriaxone 2 g IV q12h + metronidazole 500 mg IV q8h ± vancomycin (if S. aureus suspected)
- Hematogenous (endocarditis): add vancomycin 15–20 mg/kg IV q8–12h for S. aureus coverage
- Post-neurosurgical / penetrating trauma: vancomycin + cefepime 2 g IV q8h OR meropenem 2 g IV q8h (Pseudomonas + MRSA + gram-negatives)
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

⚠ Warning

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
Dose by IDEAL BODY WEIGHT in obese patients; infuse over ≥1 hour with pre-hydration to prevent crystalline nephropathy
Untreated mortality: 70%; with acyclovir: ~20%
Adverse effects: nephrotoxicity (crystalluria — ensure adequate hydration), thrombocytopenia, neurotoxicity (especially in renal impairment)
Repeat PCR at end of treatment — if still positive, extend course

Post-HSV Anti-NMDAR Encephalitis

⚠ Warning

Post-HSV anti-NMDAR encephalitis: ~20–30% of patients (especially children) develop autoimmune anti-NMDAR encephalitis weeks after HSV recovery (median ~27 days). New movement disorder (orofacial dyskinesia, chorea) or psychiatric symptoms post-treatment → send CSF NMDAR antibodies; treat with immunotherapy (steroids, IVIg, PLEX, rituximab) — do NOT assume HSV relapse.

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)

💎 Board Pearl

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
Post-HSV anti-NMDAR encephalitis: ~20–30% develop autoimmune anti-NMDAR encephalitis weeks (median ~27 days) after HSV recovery — new dyskinesia or psychiatric symptoms = send CSF NMDAR Ab and treat with immunotherapy, not more acyclovir
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); induction: ganciclovir 5 mg/kg IV q12h + foscarnet 60–90 mg/kg IV q12h × 2–3 weeks, then maintenance until immune reconstitution
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. PEP (immunocompetent): HRIG 20 IU/kg infiltrated around wound (remainder IM distant from vaccine site) + rabies vaccine on days 0, 3, 7, 14; add day 28 if immunocompromised
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)
HHV-6 (post-transplant limbic encephalitis)	Acute amnestic syndrome + mesial temporal seizures in allogeneic stem-cell / bone-marrow transplant recipients (usually within 60 d post-transplant)	MRI: bilateral hippocampal T2/FLAIR hyperintensity (HSV-mimic but typically NO hemorrhage); CSF HHV-6 PCR positive; treat with foscarnet ± ganciclovir
Bartonella henselae (cat-scratch)	Kitten/cat exposure → regional lymphadenopathy; rare CNS: encephalopathy, seizures, status epilepticus, neuroretinitis with optic-disc swelling + “macular star” on fundoscopy	Bartonella IgM/IgG serology; CSF often normal; treat doxycycline + rifampin for CNS disease

Rhombencephalitis (Brainstem Encephalitis) — Differential

Infectious (most common): Listeria monocytogenes (#1 — deli meats, soft cheeses, raw milk; pregnant women, >65 y, immunocompromised), enterovirus 71 (children, hand-foot-mouth outbreaks), HSV (less common), tuberculosis (basal meningitis pattern).
Autoimmune: Behçet disease (most common autoimmune cause; oral/genital ulcers, uveitis, brainstem & basal ganglia lesions), CLIPPERS (corticosteroid-responsive, pontine punctate “peppering” enhancement), neurosarcoidosis, anti-MOG, NMOSD.
Paraneoplastic: SCLC — anti-Hu, anti-Ri (oculomotor abnormalities + ataxia + opsoclonus), anti-Ma2 (testicular germ-cell tumors; brainstem + diencephalon), anti-Yo (ovarian/breast, cerebellum-predominant).

💎 Board Pearl — Listeria Rhombencephalitis

Biphasic illness: prodromal fever/headache → cranial neuropathies (V, VII, IX–X) + ataxia + altered consciousness after a few days.
CSF often only mildly inflammatory (sometimes lymphocytic) — gram stain low sensitivity. Blood cultures positive in ~60%.
Treatment: ampicillin 2 g IV q4h + gentamicin (synergy) × ≥3 weeks. TMP-SMX is second-line for penicillin allergy. Empiric ampicillin should be added to standard meningitis regimens in pregnant, elderly, or immunocompromised patients.

💎 Board Pearl

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

COVID-19 Neurologic Complications

Spectrum of Neurologic Involvement

Category	Manifestations	Key Points
Encephalopathy / Delirium	Most common neuro complication of hospitalized COVID; toxic-metabolic + hypoxic + cytokine-mediated	Independent predictor of in-hospital mortality; often outlasts respiratory illness
Ischemic stroke	Large-vessel occlusion in younger patients; hypercoagulable state (elevated D-dimer, antiphospholipid antibodies); cryptogenic mechanism common	Stroke risk highest in first 2 weeks; consider COVID in young stroke during outbreak
Hemorrhagic stroke / ICH	Associated with anticoagulation, endothelial injury, severe disease (ECMO)	Higher mortality than COVID-related ischemic stroke
Anosmia / ageusia	Often early/isolated symptom; due to olfactory epithelium ACE2 expression; usually resolves but persistent in ~10–20%	Highly suggestive of COVID in early pandemic; persistence >6 months suggests long COVID
Guillain-Barré syndrome	Post-infectious (typically 1–4 weeks after); AIDP > AMAN; Miller Fisher variant reported	Standard treatment with IVIg or PLEX
ADEM-like / acute necrotizing encephalopathy	Multifocal demyelinating lesions; hemorrhagic ANE with bilateral thalamic involvement reported	Treat with high-dose steroids ± IVIg/PLEX
Encephalitis / meningoencephalitis	Rare direct CNS infection; CSF SARS-CoV-2 PCR usually negative; often parainfectious/autoimmune	Consider autoimmune encephalitis workup (NMDAR, others)
Post-COVID cognitive symptoms ("brain fog")	Attention, working memory, processing speed deficits; fatigue; dysautonomia (POTS); persists months	Component of long COVID / PASC; multidisciplinary rehab
Critical illness neuromyopathy	ICU-acquired weakness in prolonged ventilation; superimposed on COVID myopathy	Common in survivors of severe COVID requiring prolonged ICU stays

💎 Board Pearl

Encephalopathy is the #1 COVID neuro complication — independent mortality predictor
Young patient with large-vessel stroke + COVID — consider hypercoagulable state; check antiphospholipid antibodies
Anosmia/ageusia often early and isolated — due to olfactory epithelium involvement, not direct CNS invasion
Post-COVID cognitive symptoms are part of long COVID / PASC and may persist months — rule out treatable causes (depression, sleep disorder, dysautonomia)

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: pyrimethamine 200 mg PO load, then 50–75 mg/day + sulfadiazine 1,000–1,500 mg PO q6h + leucovorin 10–25 mg/day for ≥6 weeks induction (2-week empiric trial is for assessing response, NOT the full course); alternative: TMP-SMX or pyrimethamine + clindamycin (sulfa allergy)	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 5 mg/kg IV q12h + foscarnet 60–90 mg/kg IV q12h induction

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

💎 Board Pearl

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

💎 Board Pearl

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)	INH 5 mg/kg/day (max 300 mg) + Rifampin 10 mg/kg/day (max 600 mg; some advocate 15–20 mg/kg for CNS penetration) + Pyrazinamide 25 mg/kg + Ethambutol 15–20 mg/kg	2 months
Continuation phase	Rifampin + Isoniazid (same doses)	7–10 months
Total duration	9–12 months (longer than pulmonary TB)	—
Adjunctive dexamethasone (Thwaites regimen)	0.3–0.4 mg/kg/day IV tapered over 6–8 weeks — proven mortality benefit	Started with anti-TB therapy
Pyridoxine (B6)	25–50 mg/day — always co-administer with INH to prevent peripheral neuropathy	Throughout INH course

💎 Board Pearl

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	Penicillin allergy evaluation and desensitization is preferred per CDC. Alternative (limited data): ceftriaxone 1–2 g daily IM or IV × 10–14 days
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

💎 Board Pearl

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

Lyme Neuroborreliosis

Clinical Features

Manifestation	Details
Cranial neuritis	Facial palsy (CN VII) — often bilateral (Lyme is a leading cause of bilateral facial palsy); other CN involvement less common
Bannwarth syndrome	Painful meningoradiculitis — severe radicular pain (often nocturnal) + lymphocytic meningitis ± cranial neuritis; classic European presentation
Lymphocytic meningitis	Subacute headache, mild meningismus, photophobia
Encephalomyelitis (rare)	Parenchymal CNS involvement: white matter lesions, myelopathy, encephalopathy
Peripheral neuropathy	Mononeuropathy multiplex, plexopathy, distal axonopathy (late/chronic)

Diagnosis

CSF: lymphocytic pleocytosis (typically 100–200 cells), elevated protein, normal glucose
Intrathecal antibody production (CSF:serum Borrelia antibody index >1) — key for parenchymal CNS Lyme
Serum two-tier testing: ELISA → Western blot (or modified two-tier with two EIAs)
CSF Borrelia PCR — low sensitivity (~20–30%)

Treatment

Manifestation	Regimen
Cranial neuritis (incl. isolated facial palsy), meningitis, radiculoneuritis (non-parenchymal)	Doxycycline 100 mg PO BID × 14–21 days OR Ceftriaxone 2 g IV daily / cefotaxime / IV penicillin G × 14–21 days — oral doxycycline now considered equivalent to IV for non-parenchymal CNS Lyme (2020 AAN/ACR/IDSA)
Parenchymal brain/spinal cord involvement (encephalomyelitis)	IV therapy required: Ceftriaxone 2 g IV daily × 14–28 days (alternatives: cefotaxime, IV penicillin G)
Children <8 yr / pregnancy	Amoxicillin or ceftriaxone (avoid doxycycline in young children for prolonged courses)

💎 Board Pearl

Bilateral facial palsy + tick exposure / endemic area = Lyme until proven otherwise (other causes: sarcoid, GBS, HIV seroconversion)
Bannwarth syndrome: painful radiculitis + lymphocytic CSF + cranial neuritis = classic European neuroborreliosis
Intrathecal antibody index >1 is the gold-standard CSF finding (more reliable than CSF PCR)
Per 2020 AAN/ACR/IDSA: oral doxycycline OR IV ceftriaxone/cefotaxime/penicillin G × 14–21 d is acceptable for meningitis, cranial neuritis, and radiculoneuritis; reserve IV therapy for parenchymal CNS disease

Whipple Disease (CNS)

Clinical Features

Causative organism: Tropheryma whipplei (gram-positive actinomycete)
Systemic: chronic diarrhea, malabsorption, weight loss, arthralgias, lymphadenopathy — may precede CNS by years
CNS Whipple: cognitive decline / dementia, supranuclear gaze palsy (especially vertical), myoclonus, ataxia, seizures, hypothalamic dysfunction
Oculomasticatory myorhythmia (slow, rhythmic convergence of eyes synchronized with mandibular contraction) — pathognomonic; also oculo-facial-skeletal myorhythmia

Diagnosis

Small bowel biopsy: PAS-positive macrophages
CSF / brain biopsy: PCR for T. whipplei; PAS-positive inclusions
MRI: nonspecific T2 hyperintensities in mesial temporal lobes, hypothalamus, basal ganglia, brainstem; may enhance

Treatment

Induction: Ceftriaxone 2 g IV daily × 2–4 weeks (alternative: IV penicillin G + streptomycin)
Maintenance: TMP-SMX DS PO BID × 1–2 years (CNS-penetrating; sulfa allergy → doxycycline + hydroxychloroquine)
IRIS can occur after starting treatment — may require steroids

💎 Board Pearl

Oculomasticatory myorhythmia is pathognomonic for CNS Whipple — nothing else causes it
Whipple is a classic treatable CJD mimic — must exclude in rapidly progressive dementia with movement disorder
Dementia + supranuclear vertical gaze palsy + myoclonus + GI symptoms = think Whipple (not just PSP)

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: liposomal amphotericin B 3–4 mg/kg/day IV + flucytosine 25 mg/kg PO QID (100 mg/kg/day) × 2 weeks → Consolidation: fluconazole 800 mg/day × 8 weeks → Maintenance: fluconazole 200 mg/day until immune reconstitution. Serial LPs to keep OP <20 cmH2O (remove 20–30 mL CSF; VP shunt if refractory).
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

Clinical Pearl

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)	1–2 viable parenchymal cysts: albendazole monotherapy 15 mg/kg/day PO divided BID (max 1,200 mg/day) × 10–14 days + corticosteroids started BEFORE antiparasitic + AED. >2 viable parenchymal cysts: albendazole + praziquantel 50 mg/kg/day + steroids. Single enhancing lesion: IDSA/ASTMH suggests albendazole + steroids (NOT steroids alone). Calcified lesions: NO antiparasitic — symptomatic/seizure management only. Image eyes before treatment (ocular cysts contraindicate antiparasitics).
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 immediately (superior to quinine), then full oral follow-on therapy once parasitemia ≤1% and patient can tolerate PO. Exchange transfusion is NO LONGER recommended as adjunctive therapy (no proven benefit per CDC).
Toxoplasmosis	See HIV section; also congenital toxoplasmosis: chorioretinitis + intracranial calcifications + hydrocephalus	Serology; imaging; PCR	Pyrimethamine 200 mg PO load → 50–75 mg/day + sulfadiazine 1,000–1,500 mg PO q6h + leucovorin 10–25 mg/day × ≥6 weeks induction; maintenance until immune reconstitution
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

💎 Board Pearl

Neurocysticercosis: 1–2 viable cysts → albendazole + steroids (steroids before antiparasitic); >2 viable cysts → albendazole + praziquantel + steroids; single enhancing lesion → albendazole + steroids (NOT steroids alone); calcified lesions → symptomatic only
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 PrP^C → PrP^Sc 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 PrP^Sc; 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 PrP^Sc 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, PrP^Sc 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

💎 Board Pearl

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

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