10 Chapter 1 The narcolepsy phenotype was initially described in 1877 by Dr. Carl Friedrich Otto Westphal and first named narcolepsy in 1880 by Dr. Jean Baptiste Gélineau as a syndrome with frequent daytime sleep attacks. Both doctors detailed periods of muscle atonia with preserved consciousness triggered by strong emotions [1-3], a phenomenon termed cataplexy by Dr. Richard Henneberg in 1916 [4, 5]. Excessive daytime sleepiness typically manifests as a diurnal inability to maintain wakefulness, and generally co-occurs with daytime vigilance complaints [6]. The combination of excessive daytime sleepiness and cataplexy has since been pathognomonic for the narcolepsy diagnosis (type 1). Narcolepsy without cataplexy (type 2) and idiopathic hypersomnia are later defined diagnostic entities within the central disorders of hypersomnolence domain and present with excessive daytime sleepiness in absence of cataplexy [7]. This thesis focusses on unravelling the pathophysiologies of the narcolepsies and idiopathic hypersomnia (the past), the effects of narcolepsy on brain structure and functioning (the present), and improving classification and disease management of central disorders of hypersomnolence (the future). Diagnostic differentiation and clinical presentation The American Academy of Sleep Medicine (AASM) currently identifies narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia as the three chronic central disorders of Hypersomnolence [8, 9]. Detailed diagnostic criteria of the third edition of the International Classification of Sleep Disorders (ICSD-3) are described in Box 1 [8]. Diagnostic differentiation is based on the combination of medical history taking and ancillary findings of a nocturnal polysomnography and daytime multiple sleep latency test (MSLT), commonly known as a napping test. Polysomnography is primarily used to rule out potential sleep disturbances and evaluate sleep duration, whereas the MSLT is employed to assess the severity of daytime sleepiness and the presence of sleep-onset rapid eye movement periods (SOREMPS), which are indicative of the narcolepsy diagnoses. Narcolepsy type 1 diagnosis can also be confirmed through hypocretin-1 deficiency via lumbar puncture (further details discussed in the pathophysiology section). The diagnostic criteria for narcolepsy type 1 have recently been revised in the ICSD-3 Text Revision, where a nocturnal SOREMP during the polysomnography in combination with typical cataplexy suffices for the diagnosis narcolepsy type 1 [9]. Within this thesis the original ICSD-3 criteria were used [8].
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