Episodic sleeping sickness is the most common cause of chronic narcolepsy, with an incidence ratio of approximately 1 in 2000; approximately half of patients are undiagnosed because clinicians are unfamiliar with the clinical manifestations of the disease. To further assist clinicians in identifying and diagnosing the disease, Professor Scammel from Harvard University authored a review detailing the clinical management of the disease, which was published in a recent issue of NEJM. Clinical presentation Patients usually present between the ages of 10 and 20 years with sudden onset of persistent daytime sleepiness; in most patients, the sleepiness is so severe that it makes it difficult to study, work, and perform other activities. Sleepiness in patients with episodic sleeping disorder occurs daily and at night with adequate sleep; these patients may seem particularly refreshed after waking up at night or after a short nap, but may feel sleepy again after 1 to 2 hours. Sudden collapse episodes are another feature of episodic sleep disorders, characterized by impaired rapid eye movement (REM) sleep regulation and complete or partial muscle paralysis. Sudden-onset episodes are usually triggered by strong emotional triggers (Figure 1); mostly positive emotions, but sometimes also by strong negative emotions. The seizures usually last for many seconds and first involve the face and neck (partial sudden onset) and then extend to the trunk and limbs (full onset), without involvement of the respiratory muscles. Sudden collapse attacks are diagnostically significant, especially in patients with type I. Another symptom is sleep paralysis, which occurs when the patient has just woken up and occasionally during sleep. It is accompanied by a pre-sleep hallucination, typically consisting of seeing a stranger in the bedroom or a person being attacked by an animal; it usually lasts for 1 to 2 minutes. In addition, patients with episodic sleep disorder have other problems, including excess weight, obstructive sleep apnea syndrome, periodic limb movement disorder (nocturnal myoclonus), sleepwalking, and REM sleep behavior disorder, and depression. Diagnosis and differential diagnosis The diagnosis of episodic sleep disorder is usually history dependent, but confirming the diagnosis requires an overnight polysomnogram as well as multiple sleep latency tests. Overnight sleep monitoring can help identify other causes of daytime sleepiness. Patients with episodic sleeping sickness usually present with fragmented light sleep and premature entry into REM sleep (less than 15 minutes after falling asleep). During multiple sleep latency tests, patients sleep for 20 minutes every 2 hours, usually starting at 8 am and continuing until 5-6 pm. Patients with episodic sleeping sickness usually fall asleep within 8 minutes, while healthy people usually fall asleep for more than 15 minutes. In addition, patients with episodic sleeping sickness usually have at least 2 REM sleep episodes during the day, whereas healthy individuals hardly ever have REM sleep during the day. Before performing multiple sleep latency tests, all sleep-disrupting medications need to be discontinued and patients need to be assured of good nighttime sleep in the week prior to the test. Episodic sleeping sickness needs to be differentiated from other sleep disorder disorders (see summary). Summary: Differential diagnosis of chronic daytime sleepiness 1. Sleep deprivation: decreased sleep on weekdays and increased sleep on weekends as well as holidays. 2, obstructive sleep apnea syndrome: snoring, apnea episodes, tonsillar and tongue hypertrophy, excessive uvula, obesity. 3, episodic sleep disorder: sudden collapse episodes, hallucinations before falling asleep, sleep paralysis, fragmentary sleep. 4.Sleep phase lapse syndrome: daytime sleepiness and nighttime wakefulness. 5, Periodic limb movement disorder: kicking movements affect the patient’s sleep, usually with restless leg syndrome, iron deficiency, uremia and neuropathy. 6.Shift sleep disorder: sleepiness at night during the night shift and sleep deprivation during the day. 7, use of sedative drugs: anti-insomnia drugs, anesthetics, sedatives, anticonvulsants, antipsychotics, antidepressants, antihistamines. 8.Idiopathic hypersomnia: sleeping too long at night and having difficulty waking up from sleep. 9, depression: increased time in bed, but multiple sleep latency tests show little functional sleep. 10.Other diseases: hypothyroidism, Parkinson’s disease, PraderCWilli syndrome, ankylosing muscular dystrophy. Pathological and genetic features Two types of episodic sleep disorders have been identified: type I episodic sleep disorder is characterized by bursting episodes and very low levels of appetitin A in the cerebrospinal fluid, whereas patients with type II episodic sleep disorder usually do not have bursting episodes and have normal appetitin A levels. This distinction suggests that the two types may have different underlying etiologies; type I patients are usually more drowsy and exhibit other symptoms and are easier to diagnose, whereas type II patients may have multiple false-positive or false-negative sleep latency tests. Type I episodic sleeping sickness is due to a severe loss of appetite-producing neurons. These neurons are not significantly damaged in type II episodic sleep disorder, but their exact cause is not known. The HLA-DQB1*06:02 gene is carried by more than 98% of patients with type I; it is also carried by some type II patients. Polymorphisms in other genes, including DQA1*01:02, the HLA-DQ allele, HLA-DP and TCRA, TCRB, P2RY11, EIF3G, and ZNF365, are also associated with type I patients with episodic sleeping disorder. Symptoms of onset sleeping sickness usually strike in late spring, suggesting that the disease may be associated with winter infections. For example, high titers of antibodies to lysozyme streptococcus O can be detected in patients after the onset of the disease, and the incidence of episodic sleeping sickness increases significantly during the H1N1 influenza epidemic. These phenomena also suggest that immune mechanisms may be involved in the development of episodic sleeping sickness; infection may trigger a T-cell response, leading to an inflammatory response that further damages appetite-producing neurons. In addition, in rare cases, episodic sleeping sickness can also occur as part of a more widespread hypothalamic injury; for example, nodal disease, demyelination, stroke, tumor or paraneoplastic syndromes. Neurobiological features Appetitin neurons are activated during the waking state, releasing appetitin and stimulating target neurons to maintain and promote the waking state; including the cortex, basal forebrain, brainstem and hypothalamus (Figure 2). Appetitin has a sustained effect on target neurons and helps maintain the arousal state throughout the day. Impaired appetitin signaling leads to impaired activity in these brain regions, resulting in episodes of narcolepsy. Figure 2 Neurobiological mechanisms of episodic sleepiness. Under normal conditions, appetite-producing neurons help maintain wakefulness by stimulating a series of wake-promoting neurons, including those in the cortex, brainstem, and basal forebrain (Figure A). In patients with episodic sleeping sickness, appetite-producing neurons are lost, resulting in drowsiness. These neurons also excite brainstem nuclei that inhibit REM sleep (Figure B). Strong emotional stimulation activates medial prefrontal cortex neurons by excitating appetite-producing neurons and the amygdala. In patients with episodic sleep disorder, damage to appetite-producing neurons and disruption of the function of this pathway leads to activation of the downstream pathway, which inhibits motor neurons and leads to partial or complete sudden-onset seizures. Emotionally triggered sudden-onset seizures may result in muscle paralysis through the medial prefrontal cortex and amygdala activation of pontine circuits. Appetitive signals also enhance metabolism, sympathetic tone, and rewarding behavior. Disturbances in these pathways may contribute to the development of obesity and depression. Treatment Episodic sleeping disorders are treated with a combination of behavioral and pharmacological treatments. Patients’ daytime sleepiness is usually partially relieved by adequate quality nighttime sleep and a 15-20 minute afternoon nap. However, most patients also require wake-promoting medications (see table below). Future research directions Although some progress has been made in the past in terms of pathogenesis and treatment, many questions remain to be addressed. Researchers are currently attempting to elucidate the pathogenesis of appetite-producing neuronal injury and how these neuronal injuries lead to sleepiness, sudden onset seizures, and obesity. Reconstruction of the appetitol signaling pathway in the brain may be an ideal therapeutic approach, but it is currently difficult to implement because appetitol does not cross the blood-brain barrier directly, and research is developing small molecule appetitol receptor agonists.