¿Qué es el test de latencia múltiple de sueño y cuál es su uso en pediatría? / What is the multiple sleep latency test and what is its use in pediatrics?

La prueba de latencia múltiple del sueño nos permite evaluar objetivamente las variaciones normales y patológicas en la somnolencia y el estado de alerta. Es una prueba que evalúa qué tan rápido una persona se duerme en condiciones estandarizadas que facilitan el sueño, y se repite a intervalos de 2 horas durante todo el día. Es el estándar para documentar el inicio del sueño REM (SOREMP), que es un síntoma de narcolepsia y en la somnolencia idiopática podría ser útil. Su uso está ampliamente descrito en adultos, pero la prueba no es tan común en niños. En esta revisión, se analizan los valores en adultos y niños, y su utilidad, a partir de la historia de la prueba.

The multiple sleep latency test allows us to objectively assess normal and pathological variations in sleepiness and alertness. It is a test that assesses how quickly a person falls asleep under standardized conditions that facilitate sleep and is repeated at 2-h intervals throughout the day. is the standard for documenting sleep onset REM (SOREMP), which is a symptom of Narcolepsy and idiopathic sleepiness could be useful. Its use is widely described in adults, but the test is not so common in children. In this review, we analyze the values in adults and children, and their usefulness, based on from the history of the test.

Perioperative Management of Insomnia, Restless Legs, Narcolepsy, and Parasomnias.

Obstructive sleep apnea (OSA) has been shown to increase risk of adverse perioperative events. More recently, investigators have begun to examine other common sleep disorders to assess how they may be impacted by the perioperative environment, as well as influence postoperative outcomes. There are a number of mechanisms by which such common sleep disorders (eg, insomnia, restless legs syndrome, narcolepsy, and parasomnias) may have consequences in the perioperative setting, both related to the underlying pathophysiology of the diseases as well as their treatments. This review will highlight the current state of the literature and offer recommendations for management of these conditions during the perioperative journey.

Secondary Narcolepsy in Children.

Secondary narcolepsy occurs as a consequence of lesions involving the hypothalamic region that subserve wakefulness. Although observations on the characteristics of secondary narcolepsy have been published in adults, information on this topic in children is sparse. This is a retrospective study of characteristics and outcome of secondary narcolepsy in children. The medical records of 10 children with this condition at Mayo Clinic, Rochester, were reviewed. Characteristics of the underlying neurologic disorder, narcolepsy subtype, multiple sleep latency tests, medications used and outcome were extracted. Age at diagnosis of narcolepsy was between 6 and 17 years. Five of 10 patients had onset of excessive sleepiness within 1 year of diagnosis of the primary neurologic disorder. Six of 10 patients had type 1 narcolepsy (with cataplexy) whereas 4/10 had type 2 (without cataplexy). The clinical course was variable, with 8/10 continuing to require treatment for sleepiness at a mean period 6.6±6.2 years after diagnosis. One patient with narcolepsy type 1 due to Niemann Pick type C disease had died. One patient with narcolepsy type 2 due to craniopharyngioma had spontaneous remission of sleepiness. The 5/10 patients surviving with narcolepsy type 1 have continued to require pharmacotherapy for both sleepiness and cataplexy. This study draws attention to an important chronic sequel of childhood brain lesions that has variable, etiology-specific outcome. The rare occurrence of spontaneous resolution of childhood narcolepsy symptoms, not previously described, is also discussed.

The olfactory bulb: A link between environmental agents and narcolepsy, from the standpoint of autoimmune etiology.

Narcolepsy type 1 is a lifelong sleep disorder characterized by the loss of hypocretin-producing neurons in the brain. Environmental agents, including influenza, neurotoxic metals, and combustion smoke, have been implicated in the pathogenesis, especially in carriers of the human leukocyte antigen class II DQB1*06:02 allele. Sensitive experimental approaches have recently revealed hypocretin-autoreactive CD4+ and CD8+ T cells in the blood of narcoleptic patients. However, such potentially harmful cells are also detectable, to a lesser degree, in control DQB1*06:02 carriers, suggesting that the integrity of the blood-brain barrier (BBB) provides a neuroprotective effect. Here, we present the hypothesis that external toxic agents induce neuroinflammation in the olfactory bulb and concomitant overproduction of proinflammatory cytokines (e.g., tumor necrosis factor-α and interferon-γ); this, in turn, compromises the BBB, allowing autoimmune cells to access and kill hypocretinergic neurons. Such sequential pathological alterations could occur insidiously, passing unnoticed and consequently being underestimated. The elevated number of autoreactive T cells in narcoleptics relative to controls might reflect externally induced immunomodulation rather than a direct disease trigger.

An overview of hypocretin based therapy in narcolepsy.

INTRODUCTION: Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since hypocretin deficiency is assumed to be the main cause of narcoleptic symptoms, hypocretin replacement will be the most essential treatment for narcolepsy. Unfortunately, this option is still not available clinically. There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy. Together with these options, immunotherapy treatments to prevent hypocretin neuronal death should also be developed. AREAS COVERED: In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments. EXPERT OPINION: Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models. If this option is effective in humans, hypocretin cell transplants or gene therapy technology may become realistic in the future.

Polysomnographic findings in craniopharyngioma patients.

PURPOSE: The purpose of this study is to evaluate whether damage to the hypothalamus due to craniopharyngioma or consequent surgery may involve the sleep-wake regulatory system, resulting in sleep disturbances and sleepiness. METHODS: Seven craniopharyngioma patients and 10 healthy controls were evaluated with sleep questionnaires including the Epworth Sleepiness Scale, polysomnography, and a multiple sleep latency test (MSLT). Five patients and eight controls had lumbar puncture performed to determine hypocretin-1 levels. RESULTS: Patients tended to feel sleepier than control individuals of the same age (p = 0.09). No subjects had symptoms of hypnagogic hallucinations, sleep paralyses, or cataplexies. Four patients and one control had periodic leg movements (PLMs). One patient had fragmented sleep pattern, rapid eye movement (REM) sleep without atonia, and PLMs. One patient had short sleep periods during the daytime. Four patients had fragmented sleep pattern. With the MSLT, four patients and two controls had mean sleep latency of < 8 min. One patient and three controls had sudden onset of REM sleep in 2/5 and 3/5 sleep periods, respectively. All subjects showed normal hypocretin-1 levels. Four patients had electrophysiological findings indicative of central hypersomnia including one patient meeting the criteria of narcolepsy. CONCLUSION: The sleep-wake regulatory system may be involved in craniopharyngioma patients.

Investigational therapies for the treatment of narcolepsy.

INTRODUCTION: Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.

Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes.

OBJECTIVE: Cardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness. PATIENTS AND METHODS: The cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed. A linear regression analysis with multivariate models was used with stepwise variable selection. RESULTS: In narcolepsy patients, maximal oxygen uptake (VO2peak) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p = 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO2peak%) and to a standard deviation (VO2peakSD) of -1.08 ± 1.63 mL/kg/min of the population norm. VO2peak depended primarily on gender (p = 0.007) and on sleepiness (p = 0.046). VO2peak% depended on sleepiness (p = 0.028) and on age (p = 0.039). VO2peakSD depended on the number of cataplexy episodes per month (p = 0.015) and on age (p = 0.030). CONCLUSIONS: Cardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency.

Orexin neurons suppress narcolepsy via 2 distinct efferent pathways.

The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

ImmunoChip study implicates antigen presentation to T cells in narcolepsy.

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Executive attention and working memory in narcoleptic outpatients / Atenção executiva e memória de trabalho em pacientes com narcolepsia

OBJECTIVE: This pioneering study aimed to evaluate executive attention and working memory in Brazilian narcoleptic outpatients. METHODS: Narcoleptic group: 19 treated narcoleptic outpatients (13 F; 6 M) (mean age=37.58; SD = 8.93); control group: 19 subjects (15 F; 4 M) (mean age=34.42; SD=12.31). INSTRUMENTS: Epworth Sleepiness Scale - Brazilian Portuguese Version (ESS-BR), Victoria Stroop Test (VST), Trail Making Test (TMT) and Letter-Number Sequencing (LNS) of WAIS-III. RESULTS: Significant difference at Excessive Daytime Sleepiness (EDS) (p<0.001) and at working memory (p=0.009) with worse results for narcoleptic patients. Patients were slower at VST-1 (p=0.002), VST-2 (p=0.045) and at TMT-A (p=0.016), TMT-B (p=0.006) and B-A (p=0.024). CONCLUSION: Narcoleptic patients showed higher degrees of EDS, an impaired executive attention at a temporal level and lower performance in working memory when compared to normal controls.

OBJETIVO: Este estudo pioneiro teve como objetivo avaliar a atenção executiva e a memória de trabalho em pacientes brasileiros com narcolepsia. MÉTODOS: Grupo-estudo: 19 narcolépticos tratados (13 M; 6 H), com média de idade de 37,58 anos, DP=8,93; grupo-controle: 19 sujeitos (15 M; 4 H), com média de idade de 34,42 anos, DP=12,31. UTILIZARAM-SE: a Escala de Sonolência de Epworth-BR, Victoria Stroop Test (VST), Trail Making Test (TMT) e Sequência de Números e Letras (SNL) da WAIS-III. RESULTADOS: Houve diferença significativa nos graus de Sonolência Diurna Excessiva (SDE) (p<0,001) e na memória de trabalho (p=0,009), com piores resultados para o grupo-estudo. Do mesmo modo, verificaram-se tempos aumentados no grupo-estudo para execução do VST-1 (p=0,002), VST-2 (p=0,045) e TMT-A (p=0,016), e TMT-B (p=0,006) e B-A (p=0,024). CONCLUSÃO: Os pacientes com narcolepsia apresentaram graus mais elevados de SDE, prejuízo na atenção executiva em nível temporal e desempenho inferior da memória de trabalho em relação aos sujeitos-controles.

Fisiopatologia da narcolepsia / Pathophysiology of narcolepsy

Introdução: A narcolepsia é um distúrbio primário do sistema nervoso central com uma prevalência ao redor de 0.02%. A narcolepsia é caracterizada por sonolência diurna excessiva, cataplexia, alucinações hipnagógicas, paralisia do sono e fragmentação do sono. Diagnóstico: O diagnóstico da narcolepsia é estabelecido pela clínica e análise de cinco cochilos diurnos durante o teste de múltiplas latências do sono. Fisiopatologia: A fisiopatologia da narcolepsia não é totalmente esclarecida. Existem várias teorias que são discutidas. Há uma maior prevalência do alelo HLA DQB1*0602 e uma diminuição da concentração da hipocretina-1 na forma de narcolepsia associada à cataplexia. Recentemente foram descritos diferentes padrões no loco do receptor de linfócito T alfa e a presença de anticorpos específicos tribbles homolog 2 em pacientes com narcolepsia. Estes achados fortalecem a teoria imunológica. Tratamento: O tratamento da narcolepsia deve garantir a integração social e familiar podendo ser dividido em comportamental e medicamentoso. Conclusão: A narcolepsia é uma fascinante doença que integra a neurologia, a imunologia, a medicina do sono, a psiquiatria e a genética. Pacientes com narcolepsia possuem prejuízo no campo pessoal, profissional e familiar. Embora muitos avanços tenham sido feitos, a melhor ferramenta ainda é a informação para os colegas médicos e para a população em geral.

Narcolepsy with cataplexy masked by the use of nicotine.

This report describes a case of narcolepsy with cataplexy masked by the chronic use of cigarettes and nicotine patches. It has been described that narcoleptic smokers report relief of symptoms by smoking tobacco cigarettes. In addition, a case describing partial treatment of sleepiness using a nicotine patch in an adolescent with narcolepsy was recently reported in this journal. Our case adds to the growing literature that nicotine may be used to manage symptoms associated with narcolepsy.

Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice.

Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wake-promoting effects of orexins, but orexins must stabilize sleep through other targets.

The pathophysiologic basis of secondary narcolepsy and hypersomnia.

The symptoms of narcolepsy can occur during the course of other neurologic conditions (ie, symptomatic narcolepsy). Inherited disorders, tumors, and head trauma were the three most frequent causes for symptomatic narcolepsy. Other causes include multiple sclerosis (MS), vascular disorders, and encephalitis. Cerebrospinal fluid hypocretin-1 measures were carried out in some recent cases with symptomatic narcolepsy, and moderate decreases in hypocretin levels were seen in a large majority of these cases. Excessive daytime sleepiness (EDS) in these symptomatic cases was sometimes reversible with an improvement of the causative neurologic disorder and with an improvement of the hypocretin (orexin) status. Recently, we found that several symptomatic narcoleptic cases with MS show unique bilateral symmetric hypothalamic lesions associated with significant hypocretin ligand deficiency. In addition, these patients often share the clinical characteristics of neuromyelitis optica (NMO) and the detection of NMO-IgG (or anti-aquaporin-4 [AQP4] antibodies), suggesting a new clinical entity. Further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiologic mechanisms for occurrence of EDS and cataplexy.

Olfactory dysfunction in narcolepsy with cataplexy.

BACKGROUND: Narcolepsy-cataplexy (NC) is caused by the loss of hypocretin neurons. Several lines of evidence suggest a role for hypocretin in olfactory function. Recent data have documented that NC is associated with olfactory dysfunction but smell testing has been performed only in small studies. METHODS: One hundred thirty NC patients were recruited from two sleep disorders centers in France and Italy. They were compared to 129 age- and gender-matched healthy controls on two well standardized olfactory tests: the Sniffin' Sticks (France) and Brief Smell Identification (Italy) tests. Olfactory dysfunction was defined as a score below the tenth centile on each smell test. RESULTS: Altogether, olfactory deficit was higher in NC compared to controls (23.8% vs. 13.9%, p=0.042, OR: 1.93 CI 95%, 1.01-3.66); olfactory identification deficit was found in 35.8% of NC compared to 13.9% of controls in Italy (p=0.03), and in 11.2% vs. 8.2% in France (NS). Using the Sniffin' Sticks (France) we noted significant lower discrimination and global olfactory performance in NC compared to controls. Based on standardized criteria for Sniffin' Sticks, none of the NC patients or controls presented anosmia or severe hyposmia, but 6.4% of the NC patients had moderate hyposmia and 22.2% mild, in contrast to 6.4% of controls with only mild hyposmia. Finally except tobacco smoking, clinical potential factors including age at onset and severity of the condition did not modify olfactory performances in the whole population. CONCLUSION: Our study is the largest investigation of olfactory performance in NC showing that the disease perse is associated with mild/moderate dysfunction in a quarter of patients.

Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss?

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of narcolepsy being an immune-mediated disease. Narcolepsy is associated with polymorphisms of the genes encoding T cell receptor alpha chain, tumour necrosis factor alpha and tumour necrosis factor receptor II. Moreover the rate of streptococcal infection is increased at onset of narcolepsy. The hallmarks of anti-self reactions in the tissue--namely upregulation of major histocompatibility antigens and lymphocyte infiltrates--are missing in the hypothalamus. These findings are questionable because they were obtained by analyses performed many years after onset of disease. In some patients with narcolepsy autoantibodies to Tribbles homolog 2, which is expressed by hypocretin neurons, have been detected recently. Immune-mediated destruction of hypocretin producing neurons may be mediated by microglia/macrophages that become activated either by autoantigen specific CD4(+) T cells or superantigen stimulated CD8(+) T cells, or independent of T cells by activation of DQB1*0602 signalling. Activation of microglia and macrophages may lead to the release of neurotoxic molecules such as quinolinic acid, which has been shown to cause selective destruction of hypocretin neurons in the hypothalamus.

TNF-alpha and ghrelin: opposite effects on immune system, metabolism and mental health.

Tumor necrosis factor-alpha (TNF-alpha) is a glycoprotein hormone with important functions in inflammation and apoptosis. It plays a significant role as a pro-inflammatory cytokine in the defense against viral, bacterial and parasitic infections and autoimmune disorders. Furthermore, it influences energy homeostasis and has an anorexigenic effect on the hypothalamus. TNF-alpha has also been shown to be involved in the pathogenesis of psychiatric disorders such as depression or narcolepsy. Ghrelin is a peptide hormone which primarily regulates eating behavior through modulation of expression of orexigenic peptides in the hypothalamus. Ghrelin administration increases food intake and body weight, while weight loss in turn increases ghrelin levels. Secondly, it posesses anti-inflammatory properties. It also seems to have an impact on mental health as it is has been suggested to have antidepressant and anxiolytic properties. Therefore, TNF-alpha and ghrelin seem to have opposite effects regarding the hypothalamic regulation of eating behavior, modulation of the immune response and the state of mental health.