385.1 🎓 醫孞生版

385.1.0.1 📌 䞀頁重點

385.1.0.1.1 Prion Diseases

385.1.1 Pathophysiology

  • Prion protein (PrPC normal cellular) misfolds to PrPSc (scrapie)
  • Templates further misfolding (self-propagating)
  • Aggregates → neuronal death
  • Resistant to standard sterilization

385.1.2 Classification

Sporadic (~ 85%): - Sporadic CJD (sCJD) — most common - Variably protease-sensitive prionopathy

Genetic (~ 15%): - Familial CJD (fCJD) — PRNP mutations - Gerstmann-StrÀussler-Scheinker (GSS) — ataxia + late dementia - Fatal familial insomnia (FFI) — insomnia, autonomic, motor

Acquired (rare): - Variant CJD (vCJD) — bovine spongiform encephalopathy (BSE, “mad cow”) - Iatrogenic CJD — dural grafts, growth hormone (historical), neurosurgery instruments - Kuru — historic, Papua New Guinea (ritualistic cannibalism)

385.1.3 Sporadic CJD Features

  • Mean onset 65 (range 40-90)
  • Rapid progression (median survival 4-7 months from onset)
  • Rapidly progressive dementia
  • Myoclonus (startle myoclonus characteristic)
  • Cerebellar signs (ataxia)
  • Visual changes (Heidenhain variant)
  • Behavioral changes
  • Pyramidal + extrapyramidal signs
  • Akinetic mutism (terminal)

385.1.4 Variant CJD (vCJD)

  • BSE-related
  • Younger (mean 28)
  • Longer course (~ 14 months)
  • Psychiatric symptoms early
  • Painful dysesthesia
  • Pulvinar sign on MRI (bilateral thalamic)
  • Tonsillar biopsy can detect PrPSc

385.1.5 Diagnosis

MRI (very useful): - Cortical ribboning on DWI (cortex bright) - Basal ganglia hyperintensity on DWI/FLAIR - Distribution variable

EEG: - Periodic sharp wave complexes (PSWCs) in sCJD (late, ~ 65% sensitive) - Other patterns variable

CSF: - RT-QuIC (real-time quaking-induced conversion) — most accurate, > 95% sensitivity + specificity - 14-3-3 protein — sensitive but less specific - Total tau ↑ — supportive - Normal cells + glucose + mild protein

Brain biopsy/autopsy: - Spongiform vacuolation - PrPSc immunostaining - Gold standard

385.1.6 Treatment

  • No effective treatment
  • Supportive
  • Anti-prion drugs (quinacrine, doxycycline) tried — unsuccessful
  • Investigational antisense (PRN100, BIIB104)
385.1.6.0.1 HIV-Associated Neurocognitive Disorder (HAND)

385.1.7 Classification (Frascati Criteria 2007)

  • Asymptomatic neurocognitive impairment (ANI)
  • Mild neurocognitive disorder (MND)
  • HIV-associated dementia (HAD) — severe

385.1.8 Epidemiology

  • Even on cART
  • 20-50% have some HAND
  • HAD < 5% on cART

385.1.9 Features

  • Subcortical pattern: psychomotor slowing, attention, executive
  • Motor: bradykinesia, gait
  • Behavioral: apathy, depression

385.1.10 Treatment

  • cART (some agents better CNS penetration — CHARTER score)
  • Supportive
385.1.10.0.1 Neurosyphilis
  • Tabes dorsalis
  • General paresis
  • Meningovascular
  • Asymptomatic on LP
  • Tests: VDRL CSF, treponemal serum
  • Treatment: IV penicillin G 18-24 million units/day × 10-14 days
385.1.10.0.2 Whipple Disease (CNS)
  • Tropheryma whipplei
  • Oculomasticatory myorhythmia (pathognomonic!)
  • Dementia, ataxia, ophthalmoplegia
  • Often GI symptoms
  • PCR or biopsy
  • Treatment: ceftriaxone + TMP-SMX or doxycycline + hydroxychloroquine
385.1.10.0.3 Autoimmune Encephalitis
  • See Ch389 (Neuroimmunology)
  • Subacute cognitive decline + psychiatric + seizures
  • Antibody-mediated:
    • Anti-NMDA-R (young women, paraneoplastic ovarian teratoma; psychiatric → seizures → movement → autonomic)
    • Anti-LGI1 (faciobrachial dystonic seizures + amnesia + hyponatremia)
    • Anti-CASPR2
    • Anti-GAD65
  • Treatment: immunotherapy
385.1.10.0.4 Paraneoplastic Limbic Encephalitis
  • Onconeural antibodies (Hu, Ma2, CV2, others)
  • Underlying cancer (SCLC, testicular, breast, ovarian)
  • Treat cancer + immunotherapy
385.1.10.0.5 Toxic / Metabolic / Nutritional
  • B12 deficiency — subacute combined degeneration + cognitive
  • Wernicke-Korsakoff — thiamine
  • Heavy metals — lead, mercury, arsenic
  • Hepatic encephalopathy
  • Uremic encephalopathy
  • Hypothyroidism (myxedema dementia)
  • Hyperparathyroidism
  • Hashimoto encephalopathy (steroid-responsive)
  • CO poisoning
  • Alcohol-related dementia
  • Substance-induced
385.1.10.0.6 Leukodystrophies (Adult-Onset)
  • Adult-onset metachromatic leukodystrophy
  • Adrenoleukodystrophy (X-linked)
  • Cerebrotendinous xanthomatosis
  • CADASIL (see Ch383)
385.1.10.0.7 Mitochondrial Diseases
  • MELAS, MERRF
  • Maternal inheritance
  • Multisystem (lactic acidosis, stroke-like episodes)
  • mtDNA testing
385.1.10.0.8 Neurometabolic
  • Wilson disease (always test in young < 40 with movement + cognitive)
  • Niemann-Pick C
  • Storage diseases
  • Various
385.1.10.0.9 Approach to Rapidly Progressive Dementia
  • Workup more extensive
  • Consider CJD, autoimmune, infectious, metabolic, paraneoplastic, vascular (multi-infarct), neoplastic, toxic, structural
  • LP, MRI, EEG, autoimmune/paraneoplastic panels, B12, thyroid, syphilis, HIV
  • Treatable etiologies first!

385.1.10.1 🩺 床邊速查

  • Prion (sCJD): rapid dementia + myoclonus + ataxia + visual + behavioral
  • CJD diagnosis: MRI (cortical ribbon, BG bright) + RT-QuIC + 14-3-3
  • No treatment for prion
  • vCJD: BSE, younger, psychiatric, pulvinar sign
  • HAND: subcortical, on cART
  • Neurosyphilis: VDRL CSF, IV penicillin
  • Whipple CNS: oculomasticatory myorhythmia pathognomonic
  • Autoimmune encephalitis: anti-NMDA-R, anti-LGI1 → immunotherapy
  • Treatable causes of dementia must rule out