Narcolepsy: an interface among neurology, immunology, sleep, and genetics.

Narcolepsy is a primary disorder of the central nervous system resulting from genetic, environmental, and immunological interactions defined as excessive daytime sleepiness plus cataplexy, hallucinations, sleep paralysis, and sleep fragmentation. The pathophysiology is not entirely known, but the interaction among genetic predisposition, environmental exposition, and immune component with consequent hypocretin-1 deficiency is the model to explain narcolepsy type I. The mechanism of narcolepsy type II is less understood. There is a delay of over ten years for the diagnosis of narcolepsy around the world. Patients with narcolepsy have many comorbidities with a negative impact on quality of life. The treatment of narcolepsy must contain an educational approach for the family, coworkers, and patients. Scheduled naps and sleep hygiene are essential to minimize the dose of medications. Much progress has been seen in the pharmacological treatment of narcolepsy with new stimulants, different presentations of oxybate, and recent studies with orexin agonists. Narcolepsy is a rare disease that needs to be more understood and highlighted to avoid delayed diagnosis and severe disabilities in patients.

A narcolepsia é um distúrbio primário do sistema nervoso central resultante das interações genéticas, ambientais e imunológicas definidas como sonolência diurna excessiva mais cataplexia, alucinações, paralisia do sono e fragmentação do sono. A fisiopatologia não é completamente conhecida, mas a interação entre predisposição genética, exposição ambiental e componente imunológico com consequente deficiência de hipocretina-1 é o modelo para explicar a narcolepsia tipo I. O mecanismo da narcolepsia tipo II é menos compreendido. Há um atraso de mais de dez anos para o diagnóstico da narcolepsia em todo o mundo. Pacientes com narcolepsia apresentam muitas comorbidades com impacto negativo na qualidade de vida. O tratamento da narcolepsia deve conter uma abordagem educativa para a família, colegas de trabalho e pacientes. Cochilos programados e higiene do sono são importantes para minimizar a dose dos medicamentos. Muito progresso foi observado no tratamento farmacológico da narcolepsia com novos estimulantes, diferentes apresentações de oxibato e estudos recentes com agonistas de orexina. A narcolepsia é uma doença rara que precisa ser mais compreendida e destacada para evitar atrasos no diagnóstico e incapacidades graves nos pacientes.

Teaching video neuroimages: gelastic cataplexy as the first neurologic manifestation of Niemann-Pick disease type C.

A 10-year-old boy presented to our hospital with a 3-year history of fall attacks triggered by laughing, leading to a generalized loss of muscle tone without loss of consciousness (video). One year later, motor delayed skills started. Examination showed ataxia, moderate cognitive impairment, and vertical gaze palsy. EEG revealed diffuse slowing and disorganization of background rhythms. Molecular analysis disclosed heterozygosis p.P1007A and p.A1035V mutations, diagnostic of Niemann-Pick disease type C (NPC).

Traditional biomarkers in narcolepsy: experience of a Brazilian sleep centre.

UNLABELLED: This study was thought to characterized clinical and laboratory findings of a narcoleptic patients in an out patients unit at São Paulo, Brazil. METHOD: 28 patients underwent polysomnographic recordings (PSG) and Multiple Sleep Latency Test (MSLT) were analyzed according to standard criteria. The analysis of HLADQB1*0602 allele was performed by PCR. The Hypocretin-1 in cerebral spinal fluid (CSF) was measured using radioimmunoassay. Patients were divided in two groups according Hypocretin-1 level: Normal (N) - Hypocretin-1 higher than 110 pg/ml and Lower (L) Hypocretin-1 lower than 110 pg/ml. RESULTS: Only 4 patients of the N group had cataplexy when compared with 14 members of the L group (p = 0.0002). DISCUSSION: This results were comparable with other authors, confirming the utility of using specific biomarkers (HLA-DQB1*0602 allele and Hypocretin-1 CSF level) in narcolepsy with cataplexy. However, the HLADQB1*0602 allele and Hypocretin-1 level are insufficient to diagnose of narcolepsy without cataplexy.

Traditional biomarkers in narcolepsy: experience of a Brazilian sleep centre / Biomarcadores tradicionias em narcolepsia: experiência de um centro de sono brasileiro

This study was thought to characterized clinical and laboratory findings of a narcoleptic patients in an out patients unit at São Paulo, Brazil. METHOD: 28 patients underwent polysomnographic recordings (PSG) and Multiple Sleep Latency Test (MSLT) were analyzed according to standard criteria. The analysis of HLADQB1*0602 allele was performed by PCR. The Hypocretin-1 in cerebral spinal fluid (CSF) was measured using radioimmunoassay. Patients were divided in two groups according Hypocretin-1 level: Normal (N) - Hypocretin-1 higher than 110pg/ml and Lower (L) Hypocretin-1 lower than 110 pg/ml. RESULTS: Only 4 patients of the N group had cataplexy when compared with 14 members of the L group (p=0.0002). DISCUSSION: This results were comparable with other authors, confirming the utility of using specific biomarkers (HLA-DQB1*0602 allele and Hypocretin-1 CSF level) in narcolepsy with cataplexy. However, the HLADQB1*0602 allele and Hypocretin-1 level are insufficient to diagnose of narcolepsy without cataplexy.

Este estudo foi idealizado para avaliar as características clinicas e laboratoriais de uma população de narcolépticos atendidos num centro de referência na cidade de São Paulo (Brasil). MÉTODO: 28 pacientes realizaram polissonografia e teste de múltiplas latências do sono segundo critérios internacionais. O alelo HLADQB1*0602 foi identificado por PCR. A Hipocretina-1 no líquido cefalorradiano (LCR) foi mensurada por radioimunoensaio. Os pacientes foram divididos em 2 grupos conforme o nível de Hipocretina-1. Normal (N) - Hypocretin-1 >110pg/ml e baixa (B) - Hypocretina-1 <110pg/ml. RESULTADOS: Somente 4 pacientes do grupo N tinham cataplexia quando comparados com 14 pacientes do grupo B (p=0,0002). DISCUSSÃO: Estes resultados foram comparáveis com outros autores, confirmando a utilidade do uso de biomarcadores específicos (HLA-DQB1*0602 e nível da hipocretina-1 no LCR) em narcolepsia com cataplexia. Porém, o alelo HLADQB1*0602 e a dosagem da Hipocretina-1 são insuficientes para o diagnóstico da narcolepsia sem cataplexia.

Association of narcolepsy-cataplexy with HLA-DRB1 and DQB1 in Mexican patients: a relationship between HLA and gender is suggested.

BACKGROUND: Narcolepsy-cataplexy is characterized by excessive daytime sleepiness with recurrent episodes of irresistible sleep, cataplexy, hallucinations and sleep paralysis. Its aetiology is unknown, but it is positively associated with the human leukocyte antigens (HLA) in all studied populations. The purpose of the present study was to investigate the association of HLA class II DRB1/DQB1 alleles with narcolepsy-cataplexy in Mexican Mestizo patients. METHODS: This is a case-control study of consecutive patients and ethnically matched controls. We included 32 patients diagnosed with typical narcolepsy-cataplexy, of the National Institute of Neurology, of the Institute of Psychiatry and at the Center of Narcolepsy at Stanford University. As healthy controls, 203 Mexican Mestizos were included. DRB1 alleles were identified using sequence based typing. A PCR-SSOP reverse dot blot was used for DQB1 typing. Allele frequency was calculated by direct counting and the significance of the differences was assessed using the Yates Chi square. Odds ratio and confidence intervals were evaluated. RESULTS: HLA-DRB1*1501 (OR = 8.2; pc < 0.0001) and DQB1*0602 (OR = 8.4; pc < 0.0001) were found positively associated with narcolepsy. When deleting DQB1*0602+ patients from the analysis, DQB1*0301 was also found increased (OR = 2.7; p = 0.035; pc = NS). DQB1*0602/DQB1*0301 genotype was present in 15.6% of the cases (OR = 11.5; p = 0.00035), conferring a high risk. DRB1*0407 (OR = 0.2; p = 0.016 pc = NS) and DQB1*0302(OR = 0.4; p = 0.017, pc = NS) were found decreased in the patients. The gender stratification analysis showed a higher risk in females carrying DRB1*1501 (OR = 15.8, pc < 0.0001) and DQB1*0602 (OR = 19.8, pc < 0.0001) than in males (OR = 5.0 for both alleles; p = 0.012, pc = NS for DRB1 & p = 0.0012, pc = 0.017 for DQB1). The susceptibility alleles found in Mexicans with narcolepsy are also present in Japanese and Caucasians; DRB1*04 linked protection has also been shown in Koreans. A stronger HLA association is suggested in females, in accordance with the sexual dimorphism claimed previously. CONCLUSION: This knowledge may contribute to a better understanding of the disease pathogenesis in different populations. The evaluation of the risk to develop narcolepsy-cataplexy in carriers of the described alleles/genotypes may also be possible. A larger sample should be analysed in Mexican and in other Hispanic patients to confirm these results.

Characterization of the spontaneous and gripping-induced immobility episodes on taiep rats.

In 1989, we described a new autosomic-recessive myelin-mutant rat that develops a progressive motor syndrome characterized by tremor, ataxia, immobility episodes (IEs), epilepsy, and paralysis. taiep is the acronym of these symptoms. The rat developed a hypomyelination, followed by demyelination. At an age of 7-8 months, taiep rats developed IEs, characterized electroencephalographically by REM sleep-like cortical activity. In our study, we analyzed the ontogeny of gripping-induced IEs between 5 and 18 months, their dependence to light-dark changes, sexual dimorphism, and susceptibility to mild stress. Our results showed that IEs start at an age of 6.5 months, with a peak frequency between 8.5 and 9.5 months. IEs have two peaks, one in the morning (0800-1000 h) and a second peak in the middle of the night (2300-0100 h). Spontaneous IEs showed an even distribution with a mean of 3 IEs every 2 h. IEs are sexually dimorphic being more common in male rats. The IEs can be induced by gripping the rat by the tail or the thorax, but most of the IEs were produced by gripping the tail. Mild stress produced by i.p. injection of physiological saline significantly decreased IEs. These results suggested that IEs are dependent on several biological variables, which are caused by hypomyelination, followed by demyelization, which causes alterations in the brainstem and hypothalamic mechanisms responsible for the sleep-wake cycle regulation, producing emergence of REM sleep-like behavior during awake periods.

Sleep and EEG disturbances in a rat neurological mutant (taiep) with immobility episodes: a model of narcolepsy-cataplexy.

The electroencephalographic sleep patterns recorded during short periods of time (3 h) of a neurological mutant rat (taiep) were studied. This rat exhibits, among other signs, immobility episodes that are similar to those observed in narcolepsy-cataplexy. We describe findings of long term (6 months) electroencephalographic studies done in 9 mutant and 5 control rats. The mutant rats present electroencephalographic and behavioral disorders consisting of: (a) bursts of cortical waxing and waning waves occurring during the drowsy state; in some animals this activity represents up to 25% of the total drowsiness time; (b) shortened sleep time; (c) fragmented paradoxical sleep; (d) immobility episodes when the animals are subjected to an emotional excitement; and (e) electrographic activity of paradoxical sleep without atonia during the immobility episodes. These findings show that the taiep mutant shows several aspects of narcolepsy-cataplexy and it may represent an experimental model for the study of this pathology.

The neurobiology of narcolepsy-cataplexy syndrome.

The pathophysiology of narcolepsy is closely related to the abnormalities of REM sleep that are the electrophysiologic signature of the syndrome. Evidence from studies of canine narcolepsy and postmortem human narcoleptic brain tissue provide strong evidence that cholinergic and monoaminergic systems involved in REM sleep regulation are abnormal in narcolepsy but the primary neurochemical abnormality has not yet been determined. There is now conclusive evidence that a genetic basis is required for all or almost all cases of narcolepsy. In the vast majority of narcoleptics, a gene closely linked to the HLA-DR/DQ region appears to confer narcoleptic susceptibility, but the penetrance of the gene is low and additional environmental and perhaps genetic factors are required to express the disease. In a minority of narcoleptics, there may be a second autosomal dominant gene not linked to HLA-DR2 that facilitates the occurrence of narcolepsy. This gene may be related to the mu-immunoglobulin heavy-chain switch-like segment that has been implicated in canine narcolepsy. There appear to be at least two narcoleptic phenotypes associated with the narcoleptic susceptibility gene or genes: narcolepsy-cataplexy syndrome and monosymptomatic narcolepsy, or narcolepsy with REM sleep abnormalities but without cataplexy. Idiopathic hypersomnia without cataplexy or REM sleep abnormalities may represent a third phenotype, although most cases of idiopathic hypersomnia are probably unrelated to the HLA-D linked gene. The link between the genetic basis of narcolepsy and its neurochemical abnormalities is still entirely unknown. Although the hypothesis that a transient immune-mediated reaction leads to a permanent alteration of monoaminergic function is appealling, there is no direct evidence to support this hypothesis. Several important questions concerning the neurobiology of narcolepsy remain to be answered. What is the specific gene in the HLA-D region that is linked to human narcolepsy and what are the products or functions of the gene that predispose to narcolepsy? Does the human mu-switch region contain genetic material homologous to the 85-kb band linked to canarc-1 that predisposes to narcolepsy? What are the environmental factors required for expression of the disease in susceptible individuals and do they incite immunologic processes? Which of the neurochemical abnormalities are primary, which are secondary or compensatory, and how do they relate to the predisposing genetic and environmental elements? Additional familial, genetic, and neurochemical studies over the next decade should lead to more complete understanding of the neurobiology of narcolepsy and ultimately to better treatments for this chronic disabling disease.