Central Disorders of Hypersomnolence.

PURPOSE OF REVIEW: This article discusses the central disorders of hypersomnolence, a group of disorders resulting in pathologic daytime sleepiness, particularly narcolepsy type 1 and narcolepsy type 2, idiopathic hypersomnia, and Kleine-Levin syndrome. Disease features, diagnostic testing, epidemiology, pathophysiology, and treatment are reviewed. RECENT FINDINGS: Increasing evidence implicates autoimmunity in narcolepsy type 1, including a strong association with human leukocyte antigen-DQB1*06:02, association with a polymorphism in the T-cell receptor alpha locus in genome-wide association, and the identification of autoreactive T cells in patients with this type of narcolepsy. In contrast, the cause or causes of narcolepsy type 2 and idiopathic hypersomnia are unknown. Multiple treatment options exist, including two medications approved for the treatment of narcolepsy by the US Food and Drug Administration (FDA) in 2019. These include solriamfetol, a dopamine- and norepinephrine-reuptake inhibitor, and pitolisant, an H3-inverse agonist/antagonist that increases histaminergic neurotransmission. SUMMARY: The central disorders of hypersomnolence all cause severe sleepiness but can be differentiated based on ancillary symptoms, diagnostic testing, and pathophysiology. It is important that these disorders are identified because multiple treatments are available to improve functioning and quality of life.

Impact of autoimmune comorbidity on fatigue, sleepiness and mood in myasthenia gravis.

BACKGROUND: Disease burden in myasthenia gravis (MG) and in other autoimmune disorders is often determined by common accompanying symptoms such as fatigue, sleepiness and mood disturbances. Many MG patients have a second autoimmune disease, but it is unclear whether autoimmune comorbidities add to the severity of fatigue, sleepiness and mood disturbances. METHODS: We ascertained the presence of autoimmune comorbidities in 69 well-characterized MG patients. To assess fatigue, sleepiness and mood disturbances, we applied the Fatigue Severity Scale (FSS), the Fatigue Impact Scale (FIS), the Epworth Sleepiness Scale (ESS), as well as the Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) to all patients. RESULTS: Thirteen MG patients had concomitant autoimmune thyroid disease (AITD), including 1 patient with rheumatoid arthritis as third autoimmune disease. Fatigue (68.1%), excessive daytime sleepiness (14.5%), moderate-severe depression (20.3%) and anxiety (26.1%) were common, but MG patients with and without autoimmune comorbidities had similar FSS, FIS, ESS, BDI and STAI scores. The presence of autoimmune comorbidities was not associated with altered clinical and immunological MG characteristics, but MG patients with autoimmune comorbidities have more often been treated with corticosteroids than patients without autoimmune comorbidities (92.3% vs. 60.7%; p = 0.03). CONCLUSIONS: While many MG patients were affected by fatigue, sleepiness, depression and anxiety, the present study does not suggest that coexisting autoimmune diseases substantially contribute to the magnitude of these cumbersome comorbid symptoms. However, the higher frequency of steroid treatment may have counterbalanced the effects of the autoimmune comorbidity.

Neurobiological Basis of Hypersomnia.

Narcolepsy is the most well-characterized hypersomnia in both clinical and basic research fields. Narcolepsy is caused by degeneration of hypocretin-producing neurons in the hypothalamus. Although hypocretin receptor antagonists have been developed as sleep-inducing drugs, a high dose of suvorexant, a hypocretin receptor antagonist, inhibits gene expression of prepro-hypocretin to induce narcoleptic attack in wild-type mice. Prostaglandin D2 is the most potent endogenous sleep-promoting substance. Overproduction of prostaglandin D2 is involved in hypersomnia in patients with mastocytosis and African sleeping sickness or in mice after a pentylenetetrazole-induced seizure. Commercialized sleep-promoting supplements also may induce hypersomnia in humans.

[Metal implant sensitivity: clinical and histological presentation]. / Klinik und Histologie Metallimplantat-assoziierter Hauterscheinungen.

Metal implant sensitivity (intolerance) can cause pain, reduced mobility, loosening of the implant and skin rashes. Knowledge of differential diagnoses, histology and appropriate diagnostics are essential for proper diagnosis. To outline typical clinical signs and histology in metal-implant-associated skin lesions we present three exemplary patients from our implant allergy outpatient department and give an overview of the current literature regarding metal implant sensitivity. In patients with a negative patch test the lymphocyte transformation test may reveal metal sensitization. Even "pure" titanium alloys may contain traces of nickel. The histology of implant-associated skin reactions goes from teleangiectatic postimplantation erythema to eczema and vasculitis. Based on the synopsis of history, clinical picture, allergological testing and histology, metal implant sensitivity can be diagnosed more precisely.

[Metal implant allergy update]. / Update Metallimplantatallergie.

Intolerance reactions to metal implants may also be caused by metal allergy. A differential diagnostic workup must be performed based on the complaints of the patient. For patch testing the standard series with its nickel, cobalt, chromium preparations is used. There is no consensus regarding implant metal test series or, for example, bone cement test series; however, progress is being made. The combination of several diagnostic tools including histology is useful. The lymphocyte transformation test (LTT) must be performed by experienced laboratories and results must be carefully evaluated. New insights into pathomechanisms of intolerance reactions to metal implants and identification of potential biomarkers are expected.

Excessive daytime sleepiness and antipathogen drug consumption in the elderly: a test of the immune theory of sleep.

The evolutionary reasons for sleep remain controversial. The immune theory of sleep suggests that sleep is essential to the immune system, allowing organisms to allocate more energy to their immunity. This hypothesis was tested by exploring the links between excessive daytime sleepiness (EDS) and vulnerability to infectious diseases in a large (n = 9294) cohort of elderly individuals, with information on socio-demographics, daily habits, and medical characteristics. At the two-year and four-year follow-ups, we obtained individual data from the national healthcare insurance about all medications prescribed to the participants between 2001 and 2003 (n = 2865). We found an independent positive association between EDS and the consumption of some anti-pathogen drugs. This relationship was mostly explained by fungal and parasitic infections rather than by viral and bacterial ones. These results, although based on correlations, are consistent with the idea that EDS as a proxy of altered sleep quality/quantity may affect the efficiency of the immune system, and hence vulnerability to infections.

Self-perceived sleep quality and quantity in adults with asthma: findings from the costeAsma study

Background and Objective: Nocturnal asthma symptoms are associated with poor sleep quality, excessive daytime sleepiness, and poor daytime functioning. The aim of this study was to describe self-perceived sleep quality and quantity in asthmatic adults in a real-world setting according to different determinants of patient health status. Methods: A cross-sectional, observational, seasonal, multiwave survey was designed. Allergists nationwide were asked to consecutively survey adult asthmatics aged 18 to 65 years, evenly distributed by seasons and asthma severity (Global Initiative for Asthma criteria). Sleep quality and quantity were assessed using the self-administered Medical Outcomes Study (MOS) Sleep Scale. The Asthma Control Test was applied to ascertain the degree of asthma symptom control. Results: A total of 1098 individuals (58.7% females, 41.2 [13.6] years) were analyzed. Asthma severity was associated with poor sleep quality and quantity; patients with more severe disease scored higher on the MOS Sleep Scale (P<.001) and also reported significantly fewer daily average hours of sleep (0.3-0.5 hours, P<.001). Level of symptom control and asthma severity were both associated with poor sleep quality and quantity, with the following mean MOS sleep problem index scores: 25.3 (fully controlled asthma), 26.4 (controlled), 32.6 (partly controlled), and 44.6 (uncontrolled) (P<.001), and 48.4 (severe asthma), 39.0 (moderate), 32.6 (mild), and 26.5 (intermittent) (P<.001). Sex was significantly associated with the summary MOS sleep problem index. Conclusions: Sleep quality and quantity was significantly associated with poor health status in asthmatic patients. Guidelines should recommend asking about nocturnal asthma symptoms and encourage clinicians to take a global sleep history. Better control of nocturnal asthma symptoms could lead to improved sleep quality and a decrease in daytime sleep-related symptoms (AU)

Introducción y Objetivo: Los síntomas nocturnos de asma, están asociados con la calidad de la falta de sueño, somnolencia diurna excesiva y mal funcionamiento durante el día. El objetivo de este estudio fue describir la calidad y cantidad del sueño percibida por el paciente asmático en un emplazamiento de vida real según diferentes determinantes del estado de salud del paciente. Métodos: Se diseñó una encuesta de corte transversal, observacional, en olas estacionales. Se les pidió a alergólogos de todo el país que realizaran una encuesta de forma consecutiva a asmáticos de 18-65 años, distribuido por estaciones y gravedad (criterios GINA). Cantidad y calidad del sueño se evaluaron utilizando la escala autoadministrada de sueño MOS-sleep scale. La escala ACT se aplicó para determinar el grado de control de síntomas asmáticos. Resultados: Un total de 1.098 sujetos [58,7% mujeres, 41,2 (13,6) años] se incluyeron en el análisis. La gravedad del asma se relacionó con calidad/cantidad de falta de sueño, con puntuaciones más altas en los pacientes más graves (p<0,001), que tenían significativamente menos horas promedio diarias de sueño: 0,3-0,5 horas (p< 0,001). El grado de control de síntomas y nivel de severidad se asociaron con problemas de sueño: 25,3 (control total), 26,4 (controlada), 32,6 (parcialmente controlada) y 44,6 (no controlada); p<0,001 y 48,4 (grave), 39,0 (moderado), 32,6 (leve) y 26,5 (intermitente), p<0,001. En nuestro estudio, el género se asoció significativamente con la puntuación resumen del índice de sueño. Conclusión: La cantidad y calidad del sueño se asoció significativamente con el estado de salud de los pacientes asmáticos. Las guías deberían recomendar preguntar tanto por los síntomas de asma nocturno como asesorar a los clínicos acerca de hacer una historia global de sueño Un mejor control de la sintomatología nocturna del asma podría conllevar a una mejor calidad del sueño y una disminución en los síntomas relacionados con el sueño durante el día (AU)

Atypical Bickerstaff brainstem encephalitis: ataxic hypersomnolence without ophthalmoplegia.

OBJECTIVE: Clinical and immunological evaluation of 'incomplete' Bickerstaff brainstem encephalitis (BBE). METHODS: We studied two patients with postinfectious brainstem syndromes who presented at National University Hospital Singapore. Laboratory work-up included measurement of antiganglioside antibodies. RESULTS: Both patients displayed hypersomnolence and cerebellar-like ataxia in the absence of external ophthalmoplegia and carried high serum titres of IgG anti-GQ1b antibodies, strongly indicative of BBE. CONCLUSIONS: Ophthalmoplegia can be absent or incomplete in BBE, and the absence of this clinical feature should not exclude BBE from the clinicians' differential. Such cases of incomplete BBE could be defined as 'ataxic hypersomnolence without ophthalmoplegia'.

A patient with anti-aquaporin 4 antibody presenting hypersomnolence as the initial symptom and symmetrical hypothalamic lesions.

Here we report a case with positive serum anti-aquaporin 4 (AQP4) antibody who presented with hypersomnolence, symmetrical hypothalamic lesions and a reduced CSF orexin (hypocretin) level without optic nerve and spinal cord lesions on MRI. All of the symptoms, MRI finding and CSF orexin level improved simultaneously after steroid therapy. AQP4 is a member of the AQP superfamily which is strongly expressed in the hypothalamus where orexin (hypocretin)-containing neurons are primarily concentrated. Although there have been only a few reports similar to our case, the present case suggests a close relationship between the positive serum anti-AQP4 antibody and symmetrical hypothalamic lesions with hypersomnolence and without optic /spinal lesion, which is improved by steroid treatment.

Sleep measures and morning plasma TNF-alpha levels in children with sleep-disordered breathing.

BACKGROUND: Sleep disordered breathing in children is associated with severity-dependent increases in excessive daytime sleepiness (EDS). TNF-alpha is an inflammatory cytokine that has been implicated in EDS. Since, at any given level of apnea-hypopnea index, there is significant variability in EDS, we hypothesized that morning tumor necrosis factor (TNF)-alpha plasma levels may provide a biologic correlate of EDS. METHODS: Children being evaluated for sleep disordered breathing underwent a blood draw after nocturnal polysomnography, and TNF-alpha plasma concentrations were assayed using ELISA. In a subset of 15 children with sleep disordered breathing and in 15 matched control subjects, whole blood cultures in the presence of lipopolysaccharide and Multiple Sleep Latency Test were conducted. Furthermore, 22 children with obstructive sleep apnea had TNF-alpha levels assayed and underwent nocturnal polysomnography and Multiple Sleep Latency Test before and after adenotonsillectomy. RESULTS: In 298 children, morning TNF-alpha levels were globally increased in the presence of obstructive sleep apnea, particularly in more severe cases, and correlated with obstructive apnea-hypopnea index and sleep pressure score, a measure of respiratory-induced sleep fragmentation, but not with nadir Sa02. A stepwise logistic regression analysis revealed that sleep pressure score and body mass index accounted for 36.2% of the adjusted variance in TNF-alpha levels (P < 0.0001). Furthermore, multiple sleep latencies were correlated with whole blood culture-derived TNF-alpha levels (n = 15), and morning TNF-alpha levels decreased after adenotonsillectomy in 22 children. CONCLUSIONS: TNF-alpha levels are increased in pediatric obstructive sleep apnea, are primarily driven by sleep fragmentation and body mass index, and are closely associated with the degree of sleepiness, as measured by Multiple Sleep Latency Test. Furthermore, surgical treatment of obstructive sleep apnea results in significant reductions in TNF-alpha levels with reciprocal prolongations in sleep latency.

A 5th type of hypersensitivity reaction: does incidental recruitment of autoreactive effector memory T-cells in response to minute amounts of PAMPs or DAMPs, underlie inflammatory episodes in the seronegative arthropathies and acute anterior uveitis?

There are many documented associations of the HLA B27-related diseases--the seronegative arthropathies (SNAs) and acute anterior uveitis (AAU). However, to date no single pathogenic mechanism has been proposed which can account for more than a few of these associations. The hypothesis presented in this paper is that individual inflammatory episodes in the SNAs and HLA B27 AAU are initiated locally within the inflamed site, in response to tiny quantities of innately recognised molecules--pathogen associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). However, clinically significant responses to such small amounts of PAMPs/DAMPs only occur in those individuals who possess pre-existing tissue-specific autoreactive effector memory T-cells, which once recruited into the tissue where their autoantigen resides, can mediate inflammatory damage. The mechanism put forward here could explain much of the research evidence and distinguishing clinical features of the HLA B27-associated diseases. These include: the well documented involvement of micro-organisms and tissue damage in these diseases; the more frequent involvement of certain organs compared with others; the often local and asymmetrical presentation of the SNAs/AAU, which contrasts with other autoimmune diseases that effect many sites in a more diffuse/symmetrical pattern; the fact that these diseases which are thought to be mediated by T-cells, are nonetheless refractory to treatment with T-cell activation blockers. Finally, if correct, the mechanism would define a 5th type of clinical hypersensitivity reaction, one manifested by an excessive reaction to small pro-inflammatory signals, in individuals who possess tissue-specific autoreactive effector memory T-cells.

Sleep duration and biomarkers of inflammation.

INTRODUCTION: Extremes of sleep duration have been associated with adverse health outcomes. The mechanism is unclear but may be related to increased inflammation. We sought to assess the association between sleep duration and inflammatory biomarkers. METHODS: A total of 614 individuals from the Cleveland Family Study completed questionnaires about sleep habits and underwent polysomnography. A morning fasting blood sample was assayed for 5 inflammatory cytokines. RESULTS: In this cohort, mean (SD) habitual sleep duration based on self-report was 7.6 (1.6) h and mean sleep duration by polysomnography (PSG) on the night prior to blood sampling was 6.2 (1.3) h. After adjusting for obesity and apnea severity, each additional hour of habitual sleep duration was associated with an 8% increase in C-reactive protein (CRP) levels (P=0.004) and 7% increase in interleukin-6 (IL-6) levels (P=0.0003). These associations were independent of self-reported sleepiness. In contrast, PSG sleep duration was inversely associated with tumor necrosis factor alpha (TNFa) levels. For each hour reduction in sleep, TNFalpha levels increased by 8% on average (P=0.02). Sleep duration was not associated with IL-1 or IL-10. CONCLUSIONS: Increases in habitual sleep durations are associated with elevations in CRP and IL-6 while reduced PSG sleep duration is associated with elevated TNFa levels. Activation of pro-inflammatory pathways may represent a mechanism by which extreme sleep habits affect health.

Inflammatory proteins in patients with obstructive sleep apnea with and without daytime sleepiness.

Excessive daytime sleepiness (EDS) is one of the most frequent symptoms in patients with obstructive sleep apnea syndrome (OSAS). However, not all patients with OSAS manifest EDS. The aim of this study was to assess whether differential circulatory levels of inflammatory mediators would account for differences in somnolence among patients with OSAS. Patients were prospectively recruited from referral patient cohort to the university hospital sleep center. A total of 50 consecutive patients with OSAS undergoing overnight polysomnography with or without EDS and 20 controls were evaluated. EDS was assessed using the Epworth sleepiness scale (ESS) and the multiple sleep latency test after overnight polysomnography. EDS was defined when the ESS was >10 and the mean sleep latency <10 min. Fasting blood was drawn in the morning after polysomnography. Circulating levels of tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), 8-isoprostaglandin F2alpha (8-iso-PGF2alpha), and P-selectin were measured with commercially available high sensitivity kits. Although patients with OSAS have elevated levels of ICAM-1, IL-6, and TNFalpha, there were no statistically significant differences in any of the inflammatory mediators between patients with EDS and without EDS. Emergence of EDS in the context of OSA does not appear to result from the selective increase of any particular somnogenic substance, i.e., TNFalpha, IL-6, ICAM-1, 8-iso-PGF2alpha, and P-selectin in the context of sleep-disordered breathing.

Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system.

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, 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 excessive daytime sleepiness (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 hererodegenerative 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 non-hypothalamic 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. 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 CNS 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.

Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia.

The discovery that hypocretins are involved in narcolepsy, a disorder associated with excessive daytime sleepiness, cataplexy, and unusually rapid transitions to rapid eye movement sleep, opens a new field of investigation in the area of disorders of sleep and activation. Hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) (also called orexin-A and orexin-B) are newly discovered neuropeptides processed from a common precursor. Hypocretin containing cells are located exclusively in the lateral hypothalamus, with widespread projections within the central nervous system. The role of the hypocretin system in other disorders causing excessive daytime sleepiness is more uncertain. This study reports the findings of a prospective study measuring cerebrospinal fluid concentrations of hypocretin-1 and hypocretin-2 in HLA DQB1*0602 positive narcolepsy with cataplexy, monosymptomatic narcolepsy, and primary hypersomnia. The results confirmed the previous observations, that hcrt-1 is deficient in narcolepsy and for the first time report very low levels of hcrt-1 in primary hypersomnia. It is also reported for the first time that there is a generalised defect in hcrt-2 transmission in all three of these clinical entities compared with controls.

[Disorders of awakening. Second part: secondary disorders]. / Troubles de l'éveil.

Secondary disorders of awakening should be distinguished from primary disorders, narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, the causes of which are still unknown despite regular progress in the knowledge of the pathophysiology of narcolepsy. By definition secondary disorders of awakening are due to clearly identified causes of various origins. Two main types of secondary disorders of awakening have been distinguished: those depending on more or less voluntary sleep curtailment or on psychotropic or non psychotropic medications and those consecutive to different disorders, respiratory, neurologic, traumatic, psychotropic, infectious, metabolic, endocrinologic, and insomnia. Some of these disorders, frequent or very frequent, are polysomnographically investigated, night and day, enabling to assess in each case the type and severity of sleepiness. Others are only clinically evaluated. Disorders of awakening secondary to neurologic conditions and to a lesser extent to infectious conditions offer a special opportunity to study the anatomical basis of these disorders. They are granted more space.

Narcolepsy and other non-SAS hypersomnia in sleep breathing disorders clinic.

Four of the 708 snorers (0.56%), referred to our sleep breathing disorders clinic for the past 2 years were diagnosed as having narcolepsy-cataplexy. Detecting HLA DRB1*1501/DQB1*0602 positive was informative for differentiating genuine narcolepsy from non-sleep apnea syndrome (non-SAS) hypersomnia in our clinic. A non-SAS obese boy, diagnosed as having essential hypersomnia syndrome, was found to be HLA DRB1*1502/DQB1*0601 positive. His hypocretin concentration was 206 pg/mL in the cerebrospinal fluid.

HLA class II analysis in Jewish Israeli narcoleptic patients.

HLA class II was investigated in eight Jewish narcoleptic patients, representing the total of such patients known in Israel at present, and in three patients suffering from sleep disturbances other than narcolepsy. All (11 out of 11) patients carried the serologic specificities DR2, DQ6 (DQ1). At the DNA level, all narcoleptics were found to be DRB1*1501, DQA1*0102, DQB1*0602 which indicates that the susceptibility gene may be located within the HLA class II region, DR, and/or DQ. As for the nonnarcoleptic patients with idiopathic hypersomnia, they carried different alleles of DR2 and DQ6, namely DRB1*1502, DQA1*0103, DQB1*0601. This study confirms that the incidence of narcolepsy in Israel is extremely low and that HLA class II genes or a gene(s) tightly linked to them are involved in the disease.