Patients with narcolepsy type 1 have cataplexy and little or no orexin in cerebrospinal fluid narcolepsy type 2 is a diagnosis of exclusion requiring ancillary tests ruling out other causes of EDS. Narcolepsy arises from the interaction of genetic and environmental factors, which lead to an immune-mediated selective loss or dysfunction of orexin neurons in the lateral hypothalamus. Narcolepsy is a rare and often disabling hypothalamic disorder that presents with sleep–wake dysregulation (excessive daytime sleepiness (EDS), cataplexy, hallucinations, sleep paralysis and disturbed sleep) and motor, cognitive, psychiatric, metabolic and autonomic disturbances. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed. The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep–wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the ‘narcoleptic borderland’, including narcolepsy type 2 (NT2). This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1.

Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset cerebrospinal fluid orexin deficiency and positivity for HLA-DQB1*06:02. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep–wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. The cause of human narcolepsy remains unknown, however an autoimmune process in most probable acting on a highly genetic background with environmental factors such as streptococcal infections, and H1N1 AS03-adjuvanted vaccine named Pandemrix.Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus.

The deficiency of the hypocretin system is well-established in human narcoleptics with a reduction of cerebrospinal fluid hypocretin levels in relation with an early loss of hypocretin neurons. In contrast, a low hypocretin-1/orexin-A levels (values below 110 pg/mL) in the cerebrospinal fluid was highly specific for narcolepsy with cataplexy and was included in the recent diagnostic criteria for narcolepsy.

HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document mean sleep latency below 8 min and at least two sleep-onset REM periods. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and weight gain.

The main features are excessive daytime sleepiness and cataplexy or sudden less of muscle tone triggered by emotional situations. Narcolepsy with cataplexy or narcolepsy type 1 in a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000.

Narcolepsy with cataplexy stage 1