Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency

Narcolepsy: A Clinical Guide 01/2010; DOI: 10.1007/978-1-4419-0854-4_14


Human narcolepsy is a chronic sleep disorder affecting 1:2,000 individuals. The disease is characterized by excessive daytime
sleepiness (EDS), cataplexy, and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations.
Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy–cataplexy is linked to hypocretin ligand deficiency
in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602).

The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e., symptomatic narcolepsy).
We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which
are also associated with a significant underlying neurological disorder that accounts for EDS and temporal associations. To
date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported,
inherited disorders (n = 38), tumors (n = 33), and head trauma (n = 19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis,
one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n = 6), encephalitis (n = 4) and degeneration (n = 1), and heredodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is
also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult
to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable
cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences
of the narcoleptic symptoms are parallel with the rise and fall of the causative disease.

A review of these cases (especially those with brain tumors) illustrates a clear picture that the hypothalamus is most often
involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be
often associated with nonhypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of
symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n = 5), head trauma (n = 3), vascular disorders (n = 5), encephalopathies (n = 3), degeneration (n = 30), demyelinating disorder (n = 7), genetic/congenital disorders (n = 11), and others (n = 2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS
in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the
hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction)
appeared, but they are not linked with hypocretin ligand deficiency.

Recently, the new possible pathophysiology of symptomatic narcolepsy in patients with MS and its related disorders was revealed.
These cases often show unique bilateral symmetric hypothalamic lesions associated with significant hypocretin ligand deficiency.
We found that these patients often share the clinical characteristics of neuromyelitis optica (NMO), including optic neuritis
or spinal cord lesions and the detection of NMO-IgG (or anti-aquaporin-4 [AQP4] antibodies). AQP4 is highly expressed in the
hypothalamic periventricular regions, an immune attack to AQP4 may thus possibly be responsible for the bilateral and hypothalamic
lesions and hypocretin deficiency in narcolepsy/EDS associated with these inflammatory demyelinating diseases.

In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency
in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually
selected for CSF hypocretin measures.

Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels, with central nervous
system interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in
symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

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