**1. Introduction**

Narcolepsy is a chronic and disabling disease, which, according to the International Classification of Sleep Disorders (ICSD-3), considered to be hypersomnias of central origin [1]. Narcolepsy presents with a variable combination of sleep–wake symtoms and motor, psychiatric, emotional, cognitive, metabolic and autonomic disturbances that reflect the hypothalamic origin of the disorder.

The leading symptoms are:


Other sleep–wake symptoms are fatigue, sleep paralysis, hypnagogic and hypnopompic hallucinations, nightmares, lucid dreams, enacted dreams, disrupted night-time sleep, restless legs syndrome or parasomnias.

The current International Classification of Sleep Disorders (ICSD-3) defines two types of narcolepsy:


If cataplexy develops over time or CSF orexin levels decrease to < 110 pg./ml, the diagnosis of NT2 must be change to NT1.

The main symptoms of NT1 are related to hypocretin/orexin (ORX) deficiency, due to the selective destruction, likely autoimmune in origin, of ORX-producing hypothalamic neurons. Likewise, hypocretin deficiency reduces the excitatory signal of the neurons responsible for the synthesis of neurotransmitters that promote wakefulness, such as noradrenaline (NA), dopamine (DA), serotonin (5-HT) and histamine.

Genetically, approximately 98% of patients with NT1 carry the HLA class II allele DQB1\*06:02; this allele is present in 50% of patients with NT2 and only 12–30% of the general population [2]. So far, no specific antibodies against ORX neurons have been detected. This could be due either to their location in a restricted area where there is a small number of damaged antibodies, or because the activation of specific T cells is negligible.

There is a clear variability in the evolution of the disease over time. On one hand, it is important to note that when a patient develops symptoms, the hypocretinergic neurons may already present irreversible damage; on the other hand, on average, there is a diagnostic delay of 10 years from the onset of symptoms. For this reason, it is still not possible to establish a concrete and extrapolable pattern. Some patients observed with severe narcolepsy and cataplexy show full symptomatology in the first days of the disease, while others develop a progressive course with excessive daytime sleepiness (EDS) as the initial symptom and followed by cataplexy after months or years of evolution.

Different hypotheses have been postulated regarding the pathophysiology of cataplexy. On one hand, there is a direct relationship between the brain areas responsible for inhibition of muscle tone in REM sleep and hypocretinergic neurons. The loss of these neurons would cause dissociated REM sleep (the atonia of the REM phase would appear during wakefulness) manifesting itself clinically as cataplexy or sleep paralysis [3]. Likewise, it has been proposed that hypocretin deficiency would facilitate sleep–wake transitions more frequently due to the instability of wake– sleep regulation mechanisms.

Pharmacotherapy in the treatment of narcolepsy is currently aimed at controlling the principal symptoms: EDS, cataplexy, sleep fragmentation, sleep paralysis and hypnagogic and hypnopompic hallucinations, but are not intended to cure the disease. However, the treatment does manage to significantly improve quality of life.

The following is a detailed breakdown of the different existing treatments and the promising future lines that are being developed for the treatment of Narcolepsy.
