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PubMed2005

A pilot tolerability and efficacy trial of sodium oxybate in ethanol-responsive movement disorders.

Sodium oxybate is currently approved in the United States exclusively for the treatment of cataplexy in narcoleptic patients. In a prior article published in this journal, we reported a patient with severe posthypoxic myoclonus whose myoclonus improved with ethanol and also with treatment with sodium oxybate. We extend this preliminary observation to five other patients with ethanol-responsive movement disorders in an open-label, dose-titration, add-on, 8-week trial. All five patients (one with severe alcohol-responsive posthypoxic myoclonus, two with epsilon-sarcoglycan-linked myoclonus-dystonia, and two with essential tremor) experienced improvement from baseline of 50% or greater as measured by blinded videotape review. Tolerability was satisfactory, with dose-dependent sedation as the most common side effect. Further studies of this drug in hyperkinetic movement disorders are warranted.

Adjuvants, Anesthesia↗

PubMed2000

Linkage of human narcolepsy with HLA association to chromosome 4p13-q21.

Although narcolepsy is highly associated with human leukocyte antigen (HLA) DQ6/DQB1*0602 and/or DR2/DRB1*1501, most individuals with the HLA haplotype are free of narcolepsy. This indicates that HLA alone makes a relatively small contribution to the development of narcolepsy and that a non-HLA gene(s) can contribute to the genetic predisposition even in narcoleptic cases with HLA association. We conducted a genome-wide linkage search for narcolepsy in eight Japanese families with 21 DR2-positive patients (14 narcoleptic cases with cataplexy and 7 cases with an incomplete form of narcolepsy). A lod score of 3.09 suggested linkage to chromosome 4p13-q21. A lod score of 1.53 was obtained at the HLA-DRB1 locus, though this lod score may be biased since all the affected patients and many of the family members were DR2-positive. No other loci including hypocretin, hypocretin receptor 1, and hypocretin receptor 2 had lod scores greater than 1.0. The present study suggests that chromosome 4p13-q21 contains a second locus for HLA-associated human narcolepsy.

Chromosome Mapping↗

PubMed2000

Workshop I: Parkinson's disease and sleep--results of the group discussion.

The group agreed on the facts that unwanted sleep onset has been observed after non-ergot as well as ergot dopamine agonists, that patients on these drugs need to be warned, that patients who have experienced sleepiness already must not drive a car unless the dosage is lowered and sleepiness has vanished, that a genetic predisposition for narcoleptic cataplexy has to be ruled out, that predictors of so-called sleep attacks need to be explored individually with the help of sleepiness scales and collectively in a careful study, respectively.

Causality↗

PubMed2003

Polymorphisms of the tumor necrosis factor receptors: no association with narcolepsy in German patients.

Narcolepsy is a debilitating sleep disorder characterized by daytime sleepiness and cataplexy. The strong association of narcolepsy with the HLA system suggests an autoimmune cause. Tumor necrosis factor is a cytokine involved in both regulation of immune mechanisms and sleep. Several studies were undertaken to determine a contribution of tumor necrosis factor and its receptors to the pathogenesis of narcolepsy. A significant increase in the 196R allele, a functionally relevant polymorphism in the TNFR2 gene, has been found in Japanese patients, indicating altered transduction of tumor necrosis factor signals. Here we explore polymorphisms in both tumor necrosis factor receptor genes as risk factors in a German population sample. Neither the polymorphism in the TNFR1 nor that in the TNFR2 gene was associated with narcolepsy. Our findings contrast to those previously published and thus provide evidence for genetic heterogeneity between different narcolepsy populations.

Germany↗

PubMed2004

Screening for candidate gene regions in narcolepsy using a microsatellite based approach and pooled DNA.

Narcolepsy is a complex sleep disorder characterized by excessive daytime sleepiness and cataplexy. Mutations in genes of the hypocretin (orexin) neurotransmitter system cause narcoleptic symptoms in animal models. The absence of hypocretin in the cerebrospinal fluid of human patients is hypothesized to originate from destruction of hypocretinergic cells in the hypothalamus, the cause of which remains unknown. Due to strong HLA association autoimmune models of narcolepsy pathogenesis are still mostly favored. Genetic predisposition factors other than HLA are likely to play a role in causing the disorder. We screened three sets of gene regions ( n=254) for association with narcolepsy using a microsatellite based approach and pooled DNA: genes related to immunity, particularly apoptosis; genes related to regulation of circadian rhythmicity; genes coding for several factors of neurotransmission. In relation to apoptosis an association was found for the BAG1 gene region. Interestingly, microsatellites representing four genomic regions related to neurotransmission revealed association with narcolepsy: COMT, DRD2, GABBR1, and HTR2A. These results, although exploratory and still to be confirmed in independent samples, support a complex pathogenetic model for narcolepsy, including disturbances of neurotransmission rather than involvement of autoimmunity.

Alleles↗

PubMed2003

[Niemann-Pick disease type C--a neurometabolic disease through disturbed intracellular lipid transport].

Niemann-Pick disease type C (NPC) is a rare, neurovisceral lipid storage disorder caused by genetic defects in lipid transporting proteins. It is distinct from Niemann-Pick types A and B (sphingomyelin lipidoses) and displays genetic (mutations in the NPC1 or NPC2[=HE1] gene), biochemical, and clinical heterogeneity. Late infantile to juvenile forms of NPC predominate and are characterised by atypical behaviour, ataxia, dysarthria, dysphagia, dystonia, cataplexy, vertical gaze palsy, splenomegaly, and dementia. In adult variants, psychosis and dementia are common, and dysarthria, ataxia, splenomegaly, and vertical gaze palsy are further facultative signs. Routine laboratory results including serum cholesterol are normal. In bone marrow smears, sea-blue histiocytes are often demonstrated and foam cells sometimes seen. The diagnosis is confirmed by detecting free cholesterol accumulation in perinuclear granules (lysosomes) and reduced cholesterol esterification after challenge with exogenous low-density lipoprotein in fibroblasts. Alternatively or additionally, mutational analysis can be performed. Treatment is restricted to symptomatic measures, since there is no specific therapy.

Adult↗

PubMed2004

[The neurotransmitter, hypocretin. An overview].

Hypocretins (orexins) are recently discovered excitatory neuropeptides produced only in the posterolateral hypothalamus. These neurotransmitters play a key role in sleep-waking regulation. In patients with narcolepsy and cataplexy, hypocretin neurotransmission is deficient, as demonstrated by low or undetectable levels of hypocretin-1 in the cerebrospinal fluid. The etiology of this deficiency is not clear. In most patients with other hypersomnolent syndromes or sleep-waking disturbances, hypocretin neurotransmission is normal. Other functions of the hypocretins include the regulation of food intake and of neuroendocrine mechanisms.

Animals↗

PubMed2000

[Narcolepsy. An illness in transition].

The signs of narcolepsy have been known since the last century and the tetrad of symptoms was described 50 years ago: excessive sleepiness, cataplexy, sleep paralysis, and hallucinations. Polysomnography typically shows decreased sleep and REM sleep latency, and laboratory testing reveals a high association with the human leucocyte antigens (HLA) DQB1*0602 and DQA1*102. Actual studies suggest disturbances in the orexin (hypocretin) neurotransmitter system. However, the exact pathophysiology is still unclear. In Germany, about 1500 patients diagnosed with narcolepsy are known. The prevalence in Caucasian populations is estimated at 50/100,000. Thus, the number of undiagnosed patients is likely to be high.

Cross-Sectional Studies↗

PubMed2005

Parkinsonism with excessive daytime sleepiness--a narcolepsy-like disorder?

BACKGROUND: Parkinsonian patients with excessive daytime sleepiness (EDS), hallucinations, REM sleep behavior disorder (RBD), short mean sleep latencies, and sleep-onset REM periods (SOREMP) on multiple sleep latency tests (MSLT) have been reported. In these patients a narcolepsy-like pathophysiology of sleep-wake disturbances has been suggested. PATIENTS AND METHODS: We studied 14 consecutive patients with Parkinsonism and EDS. Standard studies included assessment of duration and severity of Parkinsonism (Hoehn & Yahr score), Epworth sleepiness score (ESS), history of "REM-symptoms" (RBD/hallucinations/sleep paralysis/cataplexy-like episodes), polysomnography (PSG), MSLT, and measurement of cerebrospinal fluid (CSF) levels of hypocretin-1 (orexin A). RESULTS: There were 12 men and 2 women (mean age 69 years; range 54-82). The mean duration and the Hoehn&Yahr score were 6.3 years and 2.2, respectively. Diagnoses included idiopathic Parkinson's disease (IPD, n = 10), dementia with diffuse Lewy bodies (n = 3), and multisystem atrophy (n = 1). The ESS was > or = 10 in all patients (mean 12; range 10-18). "REM-symptoms" were reported by all but two patients (hallucinations: n = 9; RBD: n = 9). None of the patients reported cataplexy-like symptoms or sleep paralysis. On PSG sleep apnea (apnea hypopnea index > 10/h, n = 7), periodic limb movements during sleep (PLMS-index > 10/h, n = 6), and features of RBD (n = 5) were found. On MSLT mean sleep latency was < 5 minutes in 10 patients, and SOREMP were found in two patients. When compared with controls (n = 20, mean 497 pg/ml; range 350-603), CSF hypocretin-1 levels were normal in 8 patients and low in 2 patients (221 and 307 pg/ml, respectively). CONCLUSION: These findings do not support the hypothesis of a "final common pathway" in the pathophysiology of narcolepsy and Parkinsonism with EDS. Sleep apnea and PLMS may play a so-far underestimated role in the pathogenesis of EDS in Parkinsonian patients.

Aged↗

PubMed2025

Co-morbid monogenic disorders at chromosome region 1q2: LMNA- and FLG-related disorders in a patient referred for assessment of joint hypermobility.

The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next-generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery, hearing loss, asthma, retinopathy, myopia, atrial septal defect, narcolepsy with cataplexy, polyneuropathy, folliculitis, lichen simplex chronicus, atopic dermatitis, and hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants LMNA c.1262 T > C p.L421P [classified as likely pathogenic], FLG c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and FLG c.1501 C > T p. R501* [classified as pathogenic]. Mitochondria sequencing revealed a variant of uncertain significance (VUS), MT-ND2 m.5047 T > C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [LMNA and FLG] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.

Humans↗

PubMed2006

Differential diagnosis in hypersomnia.

Hypersomnia includes a group of disorders in which the primary complaint is excessive daytime sleepiness. Chronic hypersomnia is characterized by at least 3 months of excessive sleepiness prior to diagnosis and may affect 4% to 6% of the population. The severity of daytime sleepiness needs to be quantified by subjective scales (at least the Epworth sleepiness scale) and objective tests such as the multiple sleep latency test. Chronic hypersomnia does not correspond to an individual clinical entity but includes numerous different etiologies of hypersomnia as recently reported in the revised International Classification of Sleep Disorders. This review details most of those disorders, including narcolepsy with and without cataplexy, idiopathic hypersomnia with and without long sleep time, recurrent hypersomnia, behaviorally induced insufficient sleep syndrome, hypersomnia due to medical condition, hypersomnia due to drug or substance, hypersomnia not due to a substance or known physiologic condition, and also sleep-related disordered breathing and periodic leg movement disorders.

Chronic Disease↗

PubMed2003

Sleepiness and Unintended Sleep in Parkinson's Disease.

Patients with Parkinson's disease (PD) and parkinsonian syndromes (eg, dementia with Lewy bodies, multisystem atrophy, and Shy-Drager syndrome) suffer from daytime sleepiness. Sleepiness in PD is common (10% to 50% of patients) and very real, often approaching levels observed in the prototypical disorder of sudden-onset sleep, viz, and narcolepsy with cataplexy. Physicians need to be vigilant in assessing parkinsonian patients for sleepiness, because treatment can dramatically enhance quality of life and prevent the significant morbidity and mortality that attends daytime sleepiness. Men with advanced disease, cognitive impairment, drug-induced psychosis, and orthostatic hypotension are most at risk for developing pathologic sleepiness. Because primary sleep disorders can coexist with Parkinsonism (eg, sleep apnea, insufficient or interrupted sleep), these potential causes should be carefully assessed with polysomnography and treated appropriately. Dopaminomimetics may exacerbate sleepiness in a small subset of patients. The primary pathologies involved in Parkinsonism appear to be the greatest contributors to the development of daytime sleepiness. Sleepiness in Parkinsonism, especially a narcolepsy-like phenotype, may necessitate treatment with wake-promoting agents, such as bupropion, modafinil, or traditional psychostimulants.

Journal Article↗

PubMed1990

Prostaglandin E2 levels in cerebrospinal fluid of normal and narcoleptic dogs.

It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.

Animals↗

PubMed1993

Schizophrenia, narcolepsy, and HLA-DR15, DQ6.

A strong association between HLA-DR2, DQ1 and narcolepsy-cataplexy has been known since 1986. In 1990 a subdivision (HLA-DR15, DQ6) was shown to be equally associated. Narcolepsy symptoms include rapid eye movement (REM)-sleep intrusion hallucinations during the day. Some narcoleptics may be so hallucinated that they become delusional and receive a diagnosis of schizophrenia. Fifty-six inpatient schizophrenics and 56 normal controls were compared to see if there was an excess of the narcolepsy-associated antigens (NAA) among schizophrenics. Patients had frequency of the NAA 3.89 times higher than controls. After a subset was studied by night (n = 9) and day (n = 7) polysomnography, two patients were found to be true narcoleptics. Their psychosis improved with treatment for narcolepsy. When NAA(+) and NAA(-) schizophrenics were compared, the NAA(+) subgroup had significantly higher Brief Psychiatric Rating Scale (BPRS) scores and more hospitalizations. There were no effects attributable only to gender or race. We conclude that narcolepsy can simulate schizophrenia in some cases, and that even in nonnarcoleptic patients, the HLA-DR15,DQ6 antigens mark a group of severe schizophrenics that merits further study.

Adult↗

PubMed1977

Characteristics of the experimental reflex sleep induced by vago-aortic nerve stimulation.

1. Electrical stimulation of the baroceptive fibres of the vago-aortic trunks (VA St) reflexly induces, in the Ecéphale isolé (EI) cat preparation, a complete sleep cycle characterized by a progression of all stages of sleep previously described in chronic preparations (slow wave sleep, phasic slow wave sleep, paradoxical or REM sleep). Some qualitative and quantitative characteristics of this "vago-aortic" (VA) sleep are analysed and compared with those obtained in EI cats previously deprived of REM sleep. 2. VA sleep is not simply the consequence of chance occurrences, but the consequence of VA St. It is stimulus-bound, even if the interval between successive stimuli is as short as 7.5 min. Thus it is possible to impose an artificially regular cycle much shorter than the normal one. one. 3. VA St. precipitates the onset of the differrent sleep cycle episodes in the non-REM-deprived EI cat as well as in the REM-deprived EI cat. 4. REM sleep begins rapidly after stimulus onset, so that an experimental reflex REM narcolepsy may be obtained. This effect is particularly noteworthy in REM-deprived cats. In this situation, REM sleep episodes with cataplexy (muscular atonia and areflexia) can immediately follow the onset of stimulation.

Animals↗

PubMed1978

Some peculiar changes in the pattern of respiration connected with REM sleep. A preliminary report.

In the course of polygraphic studies of night sleep the authors recorded respiration through the right and left nostrils by means of two thermoelements. They observed a peculiar and unexpected phenomenon: during the REM sleep phase of the 3rd sleep cycle of 4 healthy persons with 6 full night recordings, respiration through the left nostril stopped, whereas it increased both in frequency and amplitude through the right nostril. This type of respiration continued until awakening. In 2 patients with narcolepsy-cataplexy and in 2 others with idiopathic hypersomnia (8 nights recorded) the same phenomenon was observed with the difference that respiration disappeared on the right side and was preserved on the left side. Furthermore, these changes occurred earlier than in healthy persons. The above changes could be explained by congestion of the venous plexi of the nose.

Adult↗

PubMed1984

Fragmentary pathological myoclonus in NREM sleep.

A 42-year-old patient is reported who presented with marked daytime sleepiness and in whom the only major nocturnal polysomnographic abnormality was intense fragmentary (partial) myoclonus occurring with equal frequency in all stages of NREM sleep associated with some degree of sleep fragmentation. The myoclonus was very brief (less than 150 msec duration), aperiodic and recurred in asynchronous and asymmetrical fashion over the legs, arms and face. It appears unrelated to the clinically similar physiological myoclonus of REM sleep. Other main sleep disorders such as periodic movements, restless leg syndrome, sleep apnea and narcolepsy-cataplexy were excluded by history and polysomnography.

Adult↗

PubMed1984

The structure of wakefulness and its relationship to daytime sleep in narcoleptic patients.

Seven patients with narcolepsy-cataplexy were continuously monitored during the day using polygraphy and videotape recording. The patients were free to do whatever they wanted while confined to a sitting-at-a-table situation. Daytime activity was evaluated by distinguishing between two polygraphically defined states, namely active wakefulness and quiet wakefulness. The data from the patients were compared with those from 7 normal subjects who were studied under the same experimental conditions. While all patients had recurrent daytime sleep episodes, none of the controls napped during the recording period. The narcoleptic patients showed an altered structure of wakefulness: they spent more of their time awake in the state of active wakefulness and less in quiet wakefulness than the control subjects. Moreover, the patients remained in the quiet state for shorter periods. Daytime sleep selectively diminished the state of quiet wakefulness, whereas it did not affect the amount of time spent in active wakefulness. In addition, in 3 patients there was a clear-cut alternation of periods of sustained wakefulness and transitional phases with a mixture of sleep and wakefulness which occurred rather regularly, suggesting an ultradian cycle of sleepiness.

Adult↗