A 32-year-old man presents with a 3-year history of irresistible daytime sleep attacks and sudden episodes of bilateral muscle weakness triggered by laughter at social gatherings. His wife reports he experiences vivid dream-like visions while falling asleep. Nocturnal polysomnography followed by Multiple Sleep Latency Test (MSLT) shows a mean sleep latency of 6 minutes with sleep-onset REM periods (SOREMPs) appearing within 15 minutes of sleep onset on 3 of 5 nap opportunities. The sleep architecture pattern marked **C** in the diagram is most consistent with this presentation. Which of the following best explains the underlying pathophysiology of the condition shown in **C**?
A. Autoimmune destruction of hypocretin/orexin-producing neurons in the lateral hypothalamus leading to dysregulated REM sleep
B. Periodic involuntary leg movements during sleep with associated cortical arousals and sleep fragmentation
C. Intermittent upper airway obstruction causing recurrent oxygen desaturations and fragmented sleep architecture
D. Excessive glutamatergic activity in the pedunculopontine tegmentum causing premature REM initiation
Explanation
Why option 1 is correct
Narcolepsy type 1 is fundamentally a disorder of REM regulation caused by autoimmune destruction of hypocretin/orexin-producing neurons in the lateral hypothalamus. This loss of hypocretin signaling (confirmed by CSF hypocretin-1 ≤110 pg/mL) removes the tonic inhibition of REM-promoting cholinergic neurons, resulting in dysregulated REM sleep that intrudes into wakefulness (causing cataplexy and sleep paralysis) and appears prematurely at sleep onset (SOREMPs). The strong HLA-DQB1*06:02 association (>95%) and temporal clustering after H1N1 infection and Pandemrix vaccination confirm autoimmune pathogenesis. The clinical tetrad—excessive daytime sleepiness, cataplexy (pathognomonic for type 1), sleep paralysis, and hypnagogic hallucinations—all reflect this fundamental defect in REM regulation. The MSLT findings (mean sleep latency ≤8 minutes + ≥2 SOREMPs) directly demonstrate the premature and intrusive REM sleep characteristic of this condition.
Why each distractor is wrong
Option 2 (Obstructive sleep apnea): This describes the pathophysiology of OSA (marked B in the diagram), not narcolepsy. OSA involves mechanical airway obstruction, not hypocretin deficiency, and does not produce SOREMPs or cataplexy. Patients with OSA have fragmented sleep due to arousals from hypoxemia, not REM dysregulation.
Option 3 (Restless leg syndrome): This describes the pathophysiology of RLS (marked D in the diagram), which involves periodic involuntary leg movements and iron metabolism abnormalities in the substantia nigra. RLS does not cause cataplexy, SOREMPs, or the characteristic sleep-onset REM intrusions seen in narcolepsy type 1.
Option 4 (Glutamatergic excess in pedunculopontine tegmentum): While the pedunculopontine tegmentum is involved in REM generation, excessive glutamatergic activity is not the primary pathophysiology of narcolepsy type 1. The fundamental defect is loss of hypocretin inhibition of REM-promoting circuits, not primary excitatory overactivity. This distractor conflates REM neurobiology with the specific autoimmune pathology of narcolepsy.
High-YieldNEET PG
Narcolepsy type 1 = hypocretin deficiency (autoimmune) + SOREMPs + cataplexy; type 2 = no cataplexy, normal hypocretin.
AASM ICSD-3; Kaplan & Sadock 11e
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