Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency
ABSTRACT 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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ABSTRACT: Narcolepsy is linked to a widespread loss of neurons containing the neuropeptide hypocretin (HCRT), also named orexin. A transgenic (TG) rat model has been developed to mimic the neuronal loss found in narcoleptic humans. In these rats, HCRT neurons gradually die as a result of the expression of a poly-glutamine repeat under the control of the HCRT promoter. To better characterize the changes in HCRT-1 levels in response to the gradual HCRT neuronal loss cerebrospinal fluid (CSF) HCRT-1 levels were measured in various age groups (2-82 weeks) of wild-type (WT) and TG Sprague-Dawley rats. TG rats showed a sharp decline in CSF HCRT-1 level at week 4 with levels remaining consistently low (26%+/-9%, mean+/-S.D.) thereafter compared with WT rats. In TG rats, HCRT-1 levels were dramatically lower in target regions such as the cortex and brainstem (100-fold), indicating decreased HCRT-1 levels at terminals. In TG rats, CSF HCRT-1 levels significantly increased in response to 6 h of prolonged waking, indicating that the remaining HCRT neurons can be stimulated to release more neuropeptide. Rapid eye movement (REM) sleep in TG rats (n=5) was consistent with a HCRT deficiency. In TG rats HCRT immunoreactive (HCRT-ir) neurons were present in the lateral hypothalamus (LH), even in old rats (24 months) but some HCRT-ir somata were in various stages of disintegration. The low output of these neurons is consistent with a widespread dysfunction of these neurons, and establishes this model as a tool to investigate the consequences of partial hypocretin deficiency.Neuroscience 09/2007; 148(1):34-43. DOI:10.1016/j.neuroscience.2007.05.029 · 3.33 Impact Factor
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ABSTRACT: Excessive daytime sleepiness is a common symptom in Prader Willi syndrome (PWs). Sleep disordered breathing (SDB) and narcoleptic traits such as REM sleep onsets (SOREMPs) have been reported in these subjects. We evaluated nighttime and daytime sleep patterns in patients with PWs in order to clarify the nature of their hypersomnia. We performed overnight continuous EEG-polysomnographic studies (with breathing monitoring included) in 14 subjects (6 M,8 F; mean age 17 years, range 8-37) affected by PWs unselected for sleep disturbances. Ten patients underwent a Multiple Sleep Latency Test (MSLT) the day following the nocturnal sleep studies. Patients assessment was completed by means of immunogenetic characterization. Nocturnal polysomnographic investigation documented sleep related breathing abnormalities such as central apneas, hypopneas or hypoventilation which mainly occurred during REM sleep in 8 subjects and did not cause sleep disruption. Only 4 subjects presented an increase in the Respiratory Disorder Index (RDI) slightly above the normal limits. In 8 subjects out of 10, with and without SDB, the mean daytime sleep latency could be considered abnormal according to the Tanner staging of pubertal development. Five patients showed at least two SOREMPs at MSLT. Subjects with and without SOREMPs had, respectively, a mean age of 18.6 SD 7.9 (4 M, 1 F) and 14.5 SD 2.9 (4 F, 1 M). The paternal deletion:uniparental dysomy ratio at genotypic characterization was 4:1 and 3.5:1 in subjects with and without SOREMPs, respectively. No patient presented DR-15 nor Dq-6. Excessive sleepiness is a frequent disturbance in PWs. Subgroups of PW patients show hypersomnolence and SOREMPs. Sleep disordered breathing appears to have a limited role in the genesis of hypersomnia which not seems on the other hand attributable to the coexistence of narcolepsy phenotype. Hypersomnia in PW syndrome is likely to mainly be attributable to a primary hypothalamic dysfunction. The potential interacting role of other factors such as subjects age, sex and genetic pattern is suggested and deserve further investigation.Clinical Neurophysiology 06/2001; 112(5):800-5. DOI:10.1016/S1388-2457(01)00483-7 · 2.98 Impact Factor
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ABSTRACT: Paramedian thalamic stroke (PTS) is a cause of organic hypersomnia, which in the absence of systematic sleep-wake studies has been attributed to disruption of ascending activating impulses and considered a "dearoused" state. However, an increasing mount of data suggests a role of the thalamus in sleep regulation and raises the possibility that a sleep disturbance contributes to hypersomnia in PTS. We evaluated 12 patients with magnetic resonance imaging-proven isolated PTS and hypersomnia with 10 to >20 hours of sleep behavior per day. Nocturnal polysomnographic findings paralleled the severity of hypersomnia. All subjects had increased stage 1 NREM sleep, reduced stage 2 NREM sleep, and reduced numbers of sleep spindles. In patients with severe hypersomnia, slow-wave (stages 3-4) NREM sleep was often reduced, but there were no major REM sleep alterations. Daytime sleep behavior was associated mostly with stage 1 sleep by electroencephalogram; there was no correlation between hypersomnia and results of nap tests. We conclude that hypersomnia following PTS is accompanied by deficient arousal during the day and insufficient spindling and slow-wave sleep production at night. These observations support the hypothesis of a dual role of the paramedian thalamus as "final common pathway' for both maintenance of wakefulness and promotion of NREM sleep.Annals of Neurology 04/1996; 39(4):471-80. DOI:10.1002/ana.410390409 · 11.91 Impact Factor