The need for developing a case definition for narcolepsy as an adverse event following immunization (AEFI):
1.1.1. General Introduction
Narcolepsy is a sleep disorder primarily characterized by excessive daytime sleepiness and cataplexy – episodes of muscle weakness brought on by emotions [1]. Additional symptoms may comprise hypnagogic hallucinations (vivid dream-like experiences occurring during the transition between wakefulness and sleep), sleep paralysis (episodes of inability to move during the onset of sleep or upon awakening, lasting for a few seconds or minutes), fragmented nocturnal sleep, as well as impaired ability for sustained attention and non-sleep symptoms such as obesity, anxiety, cognitive and emotional disturbances, and behavioral problems and precocious puberty in children [2], [3], [4], [5], [6], [7]. Excessive daytime sleepiness can occur in other disorders [8], but most patients suffering from narcolepsy experience their unwanted sleep episodes as short and refreshing [3], [4]. Cataplexy consists of brief episodes of muscle weakness without altered consciousness, usually triggered by emotions. Cataplexy constitutes a virtually pathognomonic symptom for narcolepsy [1], although it must be separated from a specific feeling of muscle weakness with emotions in normal subjects [4]. Cataplexy may rarely occur in some other disorders which are easily distinguished from narcolepsy, such as Niemann-Pick type C, Coffin-Lowry syndrome, and Norrie Disease [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. Given its specificity, determining of cataplexy is of paramount importance, although an objective test is not available [9] as of yet.
1.1.2. Diagnosis of narcolepsy
Formally, the diagnosis of narcolepsy can be made on clinical grounds [1]. However, particularly when cataplexy is absent, the diagnosis must be supported by additional polysomnographic testing and/or by the measurement of the neuropeptide hypocretin-1 (also called orexin A) in the cerebrospinal fluid (CSF) obtained by lumbar puncture [1]. A very low or undetectable hypocretin-1 level (<110 pg/ml) is the most specific finding in narcolepsy in general. For narcolepsy with cataplexy it also is highly sensitive: more than 90% of unambiguous cases are hypocretin deficient, making this neuropeptide a valuable diagnostic biomarker [20], [21]. For narcolepsy without cataplexy it is much less sensitive, with up to 20% of cases hypocretin-1 deficient [21], [22], [23], [24]. Intermediate levels of CSF hypocretin-1 (between 110 and 200 pg/ml) may not always suggest a diagnosis of narcolepsy, as they may also be observed in other neurologic conditions, tumors, infections, acute traumatic brain injury, and syndromic/genetic cases [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. Importantly however, these conditions are unlikely to lead to diagnostic confusion, since they have substantially different symptoms compared to narcolepsy. CSF hypocretin-1 measurement is the most precise diagnostic tool available in narcolepsy with cataplexy [1], [21], [37], and will be incorporated in the upcoming 3rd edition of the International Classification of Sleep Disorders (ICSD) as preferential and not only alternative criterion [1].
The main polysomnographic test is the Multiple Sleep Latency Test (MSLT), typically showing a short mean sleep latency (SL, ≤8 min) and ≥2 Sleep Onset Rapid Eye Movement Periods (SOREMPs) [1]. With such cut-offs, the MSLT sensitivity is 94.5% but the specificity is only 73.3% [38], [39].
1.1.3. Demographics and diagnostic rate
Narcolepsy with cataplexy has an estimated prevalence of 2–5/10,000 [40] and an average incidence of 7.4 per million person-years [41]. More than 50% of cases appear to have disease onset before 18 years of age [42]. Onset as late as 70 years of age is rare but has been described [4], [43]. Bimodal peaks have been reported, with one around 15 years of age (range 10–19 years) and the other around 35 years [44]. Onset of the disease can be insidious (over years) or acute (within weeks or even days). Acute onset is most often reported in children, especially for narcolepsy with cataplexy associated with a large BMI increase close to the onset of narcoleptic symptoms. Cataplexy develops in 5–8% of patients as an initial symptom but usually either together with excessive daytime sleepiness or within on average 6 years after the onset of sleepiness [4], [45], [46], [47]. Significant sex differences are not observed, although a slight male predominance was reported, while females showed a slightly earlier manifestation of symptoms in one German study [47]. As with many other rare diseases, narcolepsy is often overlooked or misdiagnosed, leading to an estimated mean diagnostic delay of 8 years, ranging from a few weeks to 60 years after the onset of clinical symptoms [48]. The delay between excessive daytime sleepiness and cataplexy onset may contribute to diagnostic delay [47]. In clinical practice, recognition of childhood cases is increasing, perhaps because of better awareness of the disease in the general population and in medical community [5], [48], [49], [50], [51]. Recognition of the disease in children is particularly challenging, since a wide range of daytime sleep requirements is often considered normal, cataplexy in children presents with atypical features [51], and there is a lack of objective pediatric diagnostic criteria [1].
