A 58-year-old man presents with 6 months of progressive insomnia, vivid hallucinations, confusion, and profuse sweating. Examination reveals continuous spontaneous muscle twitching that persists even during attempted sleep, along with tachycardia and hypertension. EMG shows high-frequency motor unit discharges (150–300 Hz). Overnight EEG shows the pattern marked **B** in the diagram — loss of normal sleep architecture with continuous mixed wake-like and drowsy rhythm without clear NREM or REM stages. Anti-CASPR2 IgG antibodies are detected. Which of the following is the most likely diagnosis?
A. Delirium tremens with secondary myoclonus
B. Fatal familial insomnia (PRNP mutation with thalamic atrophy)
C. Morvan syndrome (anti-CASPR2 autoimmune encephalitis)
D. Creutzfeldt-Jakob disease with limbic involvement
Explanation
Why Morvan syndrome (anti-CASPR2 autoimmune encephalitis) is right
Morvan syndrome is a rare autoimmune encephalitis caused by IgG antibodies against CASPR2 (contactin-associated protein-like 2), a component of the VGKC complex. The clinical triad of agrypnia excitata (severe insomnia with loss of sleep architecture—the pattern marked B), neuromyotonia (continuous spontaneous muscle twitching with myokymic and neuromyotonic discharges on EMG), and dysautonomia (hyperhidrosis, tachycardia, hypertension) is pathognomonic. CASPR2 is expressed at juxtaparanodes of peripheral nerves and in limbic/thalamic neurons, explaining both the peripheral motor manifestations and the central sleep/limbic dysfunction. The EEG pattern B (loss of normal sleep stages with continuous mixed wake-like rhythm) is the hallmark of agrypnia excitata and is diagnostic when paired with anti-CASPR2 serology. [Brain 2012 Irani CASPR2; Harrison's 21e Autoimmune Encephalitis]
Why each distractor is wrong
Fatal familial insomnia (PRNP mutation with thalamic atrophy): While FFI also presents with agrypnia excitata and a similar EEG pattern (B), it is a genetic prion disease (PRNP mutation) with progressive thalamic atrophy on MRI. The absence of anti-CASPR2 antibodies, the presence of neuromyotonia with myokymic discharges, and the acute/subacute onset with autoimmune features (positive serology) distinguish Morvan syndrome. FFI typically shows a more insidious course and lacks the prominent peripheral motor manifestations.
Delirium tremens with secondary myoclonus: Delirium tremens is an acute withdrawal syndrome in chronic alcohol users, characterized by autonomic hyperactivity, hallucinations, and tremor—not the sustained myokymia or the specific agrypnia excitata EEG pattern B. It does not produce anti-CASPR2 antibodies and resolves with benzodiazepines and supportive care, not immunotherapy.
Creutzfeldt-Jakob disease with limbic involvement: While CJD can present with cognitive decline, myoclonus, and sleep disturbance, it is a rapidly progressive neurodegenerative prion disease with characteristic MRI findings (cortical ribboning, basal ganglia hyperintensity on DWI/FLAIR) and CSF biomarkers (14-3-3, RT-QuIC). It does not produce anti-CASPR2 antibodies and lacks the specific neuromyotonic discharges and dysautonomic features of Morvan syndrome.
High-YieldNEET PG
Morvan syndrome = anti-CASPR2 autoimmune encephalitis with the triad of agrypnia excitata (loss of sleep architecture on EEG), neuromyotonia (myokymic discharges on EMG), and dysautonomia; requires aggressive immunotherapy and screening for thymoma.
