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1.
Rev Neurol ; 76(2): 35-40, 2023 01 16.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-36631962

RESUMO

INTRODUCTION: Sodium oxybate (SXB) was administered for the first time in 1979 in 16 patients with narcolepsy with cataplexy (NT1) that improved up to 20 months. AIMS: To evaluate the effect of SXB on daytime sleepiness and sleep architecture by video-polysomnography in a sample of 23 NT1 adult patients (13 men, 10 females) treated up to three years. Additional goal was to study the presence of sleep comorbidities. PATIENTS AND METHODS: NT1 patients were diagnosed according to International Classification of Sleep Disorders, third edition. We conducted a longitudinal observational study and a video-polysomnography comparing the sleep parameters of patients treated with an initial nocturnal dose of 4.5 g of SXB after six months (FU-1), one year (FU-2) and three years (FU-3) of uninterrupted treatment. Video-polysomnography parameters were analyzed including apnea-hypopnea and periodic leg movements indexes. RESULTS: Patients were HLA-DQB1*06:02 positive except a familial case. Thirteen patients (56%) discontinued SXB treatment over the three-year of the study. The two-nightly doses has been one of the reason for discontinuing treatment as well as insufficient compliance, mild or severe side effects, comorbidities and pregnancy. We found significant differences at FU-2 in sleep structure with an increased in stage N2 (p < 0.03) and a higher periodic leg movements index (p < 0.01). At FU-3 we found significant differences in sleep structure with an increase in stage N1 (p = 0.03) and in comorbidities (periodic leg movements and apnea-hypopnea indexes). There was not significant change on daytime sleepiness during the study. CONCLUSIONS: SXB was administered in low-medium doses. Two-nightly doses and sleep fragmentation linked to sleep comorbidities at long-term lead to drug withdrawal.


TITLE: Efecto a largo plazo del oxibato de sodio en la somnolencia diurna y en la estructura del sueño en pacientes con narcolepsia de tipo 1.Introducción. El oxibato de sodio (SXB) se utilizó en 1979 en 16 enfermos con narcolepsia-cataplejía (NT1) que mejoraron tras 20 meses de tratamiento. Objetivos. Evaluar el efecto del SXB en la somnolencia diurna y en la estructura del sueño mediante videopolisomnografía en una muestra de 23 enfermos de NT1 (13 hombres y 10 mujeres) tratados durante tres años. Investigamos adicionalmente la presencia de comorbilidad. Pacientes y métodos. Diagnosticamos a los enfermos de acuerdo con la Clasificación Internacional de Trastornos del Sueño, tercera edición. Realizamos un estudio longitudinal, observacional y de videopolisomnografía, comparando los parámetros de sueño y los índices de apnea-hipopnea y de movimientos periódicos de las piernas de los enfermos, tratados con una dosis nocturna inicial de 4,5 g de SXB al cabo de seis meses (C-1), un año (C-2) y tres años (C-3) de tratamiento ininterrumpido. Resultados. Todos los enfermos eran HLA-DQB1*06:02 positivos, excepto un caso familiar. Trece enfermos (56%) interrumpieron el tratamiento debido a las dos tomas nocturnas, así como a la presencia de efectos secundarios, comorbilidad y embarazo. Encontramos diferencias significativas en C-2 en la estructura del sueño con aumento del estadio N2 (p < 0,03) y del índice de movimientos periódicos de las piernas (p < 0,01). En el control C-3 encontramos diferencias significativas en la estructura del sueño con aumento del estadio N1 (p = 0,03), y de los índices de movimientos periódicos de las piernas y de apnea-hipopnea. Conclusiones. El SXB se administró en dos dosis nocturnas, lo que, unido a la fragmentación del sueño y a la aparición de comorbilidades, condujo a la interrupción del tratamiento a largo plazo.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Oxibato de Sódio , Masculino , Adulto , Feminino , Humanos , Oxibato de Sódio/efeitos adversos , Seguimentos , Apneia/induzido quimicamente , Apneia/tratamento farmacológico , Narcolepsia/tratamento farmacológico , Sono
2.
Rev. neurol. (Ed. impr.) ; 76(2): 35-40, Ene-Jun. 2023. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-215005

RESUMO

Introducción: El oxibato de sodio (SXB) se utilizó en 1979 en 16 enfermos con narcolepsia-cataplejía (NT1) que mejoraron tras 20 meses de tratamiento. Objetivos: Evaluar el efecto del SXB en la somnolencia diurna y en la estructura del sueño mediante videopolisomnografía en una muestra de 23 enfermos de NT1 (13 hombres y 10 mujeres) tratados durante tres años. Investigamos adicionalmente la presencia de comorbilidad. Pacientes y métodos: Diagnosticamos a los enfermos de acuerdo con la Clasificación Internacional de Trastornos del Sueño, tercera edición. Realizamos un estudio longitudinal, observacional y de videopolisomnografía, comparando los parámetros de sueño y los índices de apnea-hipopnea y de movimientos periódicos de las piernas de los enfermos, tratados con una dosis nocturna inicial de 4,5 g de SXB al cabo de seis meses (C-1), un año (C-2) y tres años (C-3) de tratamiento ininterrumpido.Resultados: Todos los enfermos eran HLA-DQB1*06:02 positivos, excepto un caso familiar. Trece enfermos (56%) interrumpieron el tratamiento debido a las dos tomas nocturnas, así como a la presencia de efectos secundarios, comorbilidad y embarazo. Encontramos diferencias significativas en C-2 en la estructura del sueño con aumento del estadio N2 (p < 0,03) y del índice de movimientos periódicos de las piernas (p < 0,01). En el control C-3 encontramos diferencias significativas en la estructura del sueño con aumento del estadio N1 (p = 0,03), y de los índices de movimientos periódicos de las piernas y de apnea-hipopnea. Conclusiones: El SXB se administró en dos dosis nocturnas, lo que, unido a la fragmentación del sueño y a la aparición de comorbilidades, condujo a la interrupción del tratamiento a largo plazo.(AU)


Introduction: Sodium oxybate (SXB) was administered for the first time in 1979 in 16 patients with narcolepsy with cataplexy (NT1) that improved up to 20 months. Aims: To evaluate the effect of SXB on daytime sleepiness and sleep architecture by video-polysomnography in a sample of 23 NT1 adult patients (13 men, 10 females) treated up to three years. Additional goal was to study the presence of sleep comorbidities. Patients and methods: NT1 patients were diagnosed according to International Classification of Sleep Disorders, third edition. We conducted a longitudinal observational study and a video-polysomnography comparing the sleep parameters of patients treated with an initial nocturnal dose of 4.5 g of SXB after six months (FU-1), one year (FU-2) and three years (FU-3) of uninterrupted treatment. Video-polysomnography parameters were analyzed including apnea-hypopnea and periodic leg movements indexes. Results: Patients were HLA-DQB1*06:02 positive except a familial case. Thirteen patients (56%) discontinued SXB treatment over the three-year of the study. The two-nightly doses has been one of the reason for discontinuing treatment as well as insufficient compliance, mild or severe side effects, comorbidities and pregnancy. We found significant differences at FU-2 in sleep structure with an increased in stage N2 (p < 0.03) and a higher periodic leg movements index (p < 0.01). At FU-3 we found significant differences in sleep structure with an increase in stage N1 (p = 0.03) and in comorbidities (periodic leg movements an apnea-hypopnea indexes). There was not significant change on daytime sleepiness during the study. Conclusions: SXB was administered in low-medium doses. Two-nightly doses and sleep fragmentation linked to sleep comorbidities at long-term lead to drug withdrawal.(AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Polissonografia , Privação do Sono , Transtornos do Sono-Vigília , Narcolepsia , Cataplexia , Oxibato de Sódio , Sonolência , Neurologia , Doenças do Sistema Nervoso , Espanha , Estudos Longitudinais
3.
Sleep Med Rev ; 67: 101735, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36563570

RESUMO

Repetitive transcranial magnetic stimulation (rTMS) is a widely used non-invasive neuromodulatory technique. When applied in sleep medicine, the main hypothesis explaining its effects concerns the modulation of synaptic plasticity and the strength of connections between the brain areas involved in sleep disorders. Recently, there has been a significant increase in the publication of rTMS studies in primary sleep disorders. A multi-database-based search converges on the evidence that rTMS is safe and feasible in chronic insomnia, obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), and sleep deprivation-related cognitive deficits, whereas limited or no data are available for narcolepsy, sleep bruxism, and REM sleep behavior disorder. Regarding efficacy, the stimulation of the dorsolateral prefrontal cortex bilaterally, right parietal cortex, and dominant primary motor cortex (M1) in insomnia, as well as the stimulation of M1 leg area bilaterally, left primary somatosensory cortex, and left M1 in RLS reduced subjective symptoms and severity scale scores, with effects lasting for up to weeks; conversely, no relevant effect was observed in OSAS and narcolepsy. Nevertheless, several limitations especially regarding the stimulation protocols need to be considered. This review should be viewed as a step towards the further contribution of individually tailored neuromodulatory techniques for sleep disorders.


Assuntos
Narcolepsia , Síndrome das Pernas Inquietas , Apneia Obstrutiva do Sono , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Humanos , Estimulação Magnética Transcraniana/métodos , Encéfalo
4.
Sleep Med ; 101: 478-484, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36525847

RESUMO

OBJECTIVE: To investigate adolescents' and parents' preferences concerning information on narcolepsy. METHODS: During a one-year cross-sectional study, adolescents (12-20 years old) with narcolepsy and parents attending the Narcolepsy Center of Bologna (Italy) were invited to fill in a questionnaire including 28 pieces of information regarding narcolepsy, 14 concerning medical issues (i.e., diagnosis, prognosis, treatment, management) and 14 concerning psychosocial issues (i.e., impact on everyday life, relationships, possible support). Participants were asked to indicate: the importance of each item on a 5-point Likert scale; when each piece of information should be provided (diagnostic suspicion, confirmed diagnosis, follow-up visits, upon patient's request); and who should provide it (doctor, nurse, psychologist, parents and/or others). RESULTS: Sixty-two adolescents (37% female, mean age 16.4 years) and 96 parents (58% female, mean age 48.2 years) agreed to participate (100% response rate). Parents rated all items as important (score≥4), while, according to adolescents, 11/14 medical and psychosocial issues were important. The moment of diagnosis was considered the right time to give almost all medical information. Regarding psychosocial issues, mothers mainly indicated the time of diagnosis, while fathers also indicated follow-up visits, and some children opted for follow-up visits or information upon request. The doctor was the preferred provider but when information concerned psychosocial issues, adolescents also indicated the parents, and parents also indicated the psychologist. CONCLUSIONS: This study suggests that information on narcolepsy should be comprehensive and tailored, and that parents and psychologists may support the doctor in providing information when narcolepsy is diagnosed during adolescence.


Assuntos
Narcolepsia , Pais , Criança , Humanos , Feminino , Adolescente , Pessoa de Meia-Idade , Adulto Jovem , Adulto , Masculino , Estudos Transversais , Pais/psicologia , Mães , Inquéritos e Questionários , Narcolepsia/diagnóstico
5.
Sleep Med ; 101: 522-527, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36535226

RESUMO

INTRODUCTION: Sleep is a modulator of glymphatic activity which is altered in various sleep disorders. Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness (EDS), rapid onset of rapid eye movement (REM) sleep, cataplexy, disturbed night sleep with fragmentation. It is categorized into two types, type 1 (NT1) and type 2 (NT2) depending on the presence of cataplexy and/or absence of orexin. We sought for alterations in glymphatic activity in narcoleptic patients using diffusion tensor imaging (DTI) along perivascular space (ALPS) index on magnetic resonance imaging (MRI). MATERIAL AND METHODS: Adult patients diagnosed with NT1 or NT2 who had polysomnography (PSG) and MRI with DTI were included in the study. Sleep recording included Epworth Sleepiness Scale (ESS) score, sleep latency during multiple sleep latency test (MSLT), sleep efficiency during night PSG, wake after sleep onset (WASO), REM sleep latency during PSG, percentage of non-REM (NREM), REM sleep and wakefulness during night PSG. DTI-ALPS index was calculated for each patient and age-sex matched healthy control(HC)s. RESULTS: The study group was composed of 25 patients [F/M = 15/10, median age = 34 (29.5-44.5)], 14 with NT1 and 11 with NT2 disease. ESS, WASO and percentage of wakefulness were significantly higher in NT1 patients (p < 0.05). Mean DTI-ALPS was not significantly different neither between narcoleptic patients and HCs, nor between NT1 and NT2 patients (all, p > 0.05). However, DTI-ALPS was negatively correlated with WASO (r = -0.745, p = 0.013) and percentage of wakefulness (r = -0.837, p = 0.005) in NT1 patients. DTI-ALPS correlated negatively with percentage of N1 sleep (r = -0.781, p = 0.005) but positively with REM percentage (r = 0.618, p = 0.043) in NT2 patients. CONCLUSION: In this study, DTI-ALPS was not significantly different in narcoleptic patients than the HCs. However, the glymphatic index as assessed by DTI-ALPS correlated with PSG parameters; negatively with WASO, percentage of wakefulness in NT1, percentage of N1 sleep in NT2, and positively with REM sleep in NT2. A tendency for a reduction in DTI-ALPS in NT1 patients compared to both NT2 patients and HCs was also found. These findings might show the first evidence of an alteration of glymphatic activity, especially in NT1 patients, thus warrant further prospective studies in larger size of narcoleptic patient cohorts.


Assuntos
Cataplexia , Narcolepsia , Adulto , Humanos , Imagem de Tensor de Difusão , Estudos Prospectivos , Narcolepsia/diagnóstico , Sono
6.
BMC Neurosci ; 23(1): 82, 2022 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-36577939

RESUMO

BACKGROUND: Cataplexy is a loss of muscle tone that can lead to postural collapse, disturbing the daily life of narcolepsy patients; it is often triggered by positive emotions such as laughter in human patients. Narcolepsy model mice also show cataplexy, and its incidence increases in response to positive emotion-inducing stimuli such as chocolate and female courtship. Although such observation indicates a positive emotion-related nature of cataplexy in narcolepsy mice, they also show cataplexy without any apparent triggering stimulus ~ (spontaneous cataplexy). Therefore, we hypothesized that some spontaneous cataplexy in narcoleptic mice might indicate the remembering of happy moments. RESULTS: To test our hypothesis, we did a conditioned place preference test on orexin/hypocretin neuron-ablated (ORX-AB) mice, one of the animal models of human narcolepsy, and counted the number of cataplexy-like behaviors. ORX-AB mice successfully remembered the chocolate-associated chamber, and the number of cataplexy-like behaviors significantly increased in the chocolate-associated chamber but not in the control chamber. In addition, ORX-AB mice remembered the aversive odor-associated chamber and avoided entering without affecting the number of cataplexy-like behaviors. Finally, similar activation of the nucleus accumbens, a positive emotion-related nucleus, was observed during both spontaneous and chocolate-induced cataplexy behaviors. CONCLUSIONS: These results support our hypothesis and will promote the usefulness of a narcolepsy mice model in emotion research and serve as a basis for a better understanding of cataplexy in narcolepsy patients.


Assuntos
Cataplexia , Narcolepsia , Humanos , Camundongos , Feminino , Animais , Orexinas/metabolismo , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Modelos Animais de Doenças
7.
BMC Neurol ; 22(1): 439, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401198

RESUMO

BACKGROUND: Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1. CASE PRESENTATION: We present the case of a pair of 17-year-old male, monozygotic twins discordant for NT1. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. To describe the genetic background for the NT1 discordant manifestations in this case, we present the whole-genome analysis of this monozygotic twin pair. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). CONCLUSIONS: The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease.


Assuntos
Cataplexia , Narcolepsia , Masculino , Humanos , Orexinas , Brasil , Narcolepsia/diagnóstico , Narcolepsia/genética , Polissonografia
9.
Front Immunol ; 13: 902840, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36311717

RESUMO

In the wake of the A/California/7/2009 H1N1 influenza pandemic vaccination campaigns in 2009-2010, an increased incidence of the chronic sleep-wake disorder narcolepsy was detected in children and adolescents in several European countries. Over the last decade, in-depth epidemiological and immunological studies have been conducted to investigate this association, which have advanced our understanding of the events underpinning the observed risk. Narcolepsy with cataplexy (defined as type-1 narcolepsy, NT1) is characterized by an irreversible and chronic deficiency of hypocretin peptides in the hypothalamus. The multifactorial etiology is thought to include genetic predisposition, head trauma, environmental triggers, and/or infections (including influenza virus infections), and an increased risk was observed following administration of the A/California/7/2009 H1N1 vaccine Pandemrix (GSK). An autoimmune origin of NT1 is broadly assumed. This is based on its strong association with a predisposing allele (the human leucocyte antigen DQB1*0602) carried by the large majority of NT1 patients, and on links with other immune-related genetic markers affecting the risk of NT1. Presently, hypotheses on the underlying potential immunological mechanisms center on molecular mimicry between hypocretin and peptides within the A/California/7/2009 H1N1 virus antigen. This molecular mimicry may instigate a cross-reactive autoimmune response targeting hypocretin-producing neurons. Local CD4+ T-cell responses recognizing peptides from hypocretin are thought to play a central role in the response. In this model, cross-reactive DQB1*0602-restricted T cells from the periphery would be activated to cross the blood-brain barrier by rare, and possibly pathogen-instigated, inflammatory processes in the brain. Current hypotheses suggest that activation and expansion of cross-reactive T-cells by H1N1/09 influenza infection could have been amplified following the administration of the adjuvanted vaccine, giving rise to a "two-hit" hypothesis. The collective in silico, in vitro, and preclinical in vivo data from recent and ongoing research have progressively refined the hypothetical model of sequential immunological events, and filled multiple knowledge gaps. Though no definitive conclusions can be drawn, the mechanistical model plausibly explains the increased risk of NT1 observed following the 2009-2010 H1N1 pandemic and subsequent vaccination campaign, as outlined in this review.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Narcolepsia , Criança , Adolescente , Humanos , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Influenza Humana/complicações , Orexinas , Narcolepsia/etiologia , Narcolepsia/genética , Peptídeos
10.
Sleep Med ; 100: 442-447, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36252412

RESUMO

OBJECTIVES: Treatment for narcolepsy with sodium oxybate (SXB) has required twice-nightly dosing, at bedtime and 2.5-4 h later. This study evaluated the pharmacokinetics of FT218, an investigational, extended-release, once-nightly formulation of SXB (ON-SXB), vs twice-nightly SXB. METHODS: In this phase 1, open-label study, healthy volunteers were randomized (1:1) to ON-SXB 6 g or twice-nightly SXB (two 3-g doses administered 4 h apart); minimum 3-day washout before crossover. Doses were administered 2 h post-evening meal. Blood samples for pharmacokinetic assessments were collected predose and up to 14 h after the first dose during each treatment period. RESULTS: Twenty-eight participants were enrolled (mean age, 39.6 years; 54% women; 93% white). Mean ± SEM area under the concentration-time curve for ON-SXB was 282.7 ± 30.2  µg·h/mL vs 273.3 ± 27.8 µg·h/mL for twice-nightly SXB. Geometric mean ratio (GMR; 90% CI) was 102.9 (98.0-108.0). Maximum γ-hydroxybutyrate (GHB) plasma concentration (Cmax) was 65.8 ± 4.0 µg/mL for ON-SXB vs 77.1 ± 4.9 µg/mL for twice-nightly SXB (GMR [90% CI], 88.3 [80.5-97.0]). The GMR (90% CI) for GHB plasma concentrations 8 h post dose (C8h) for ON-SXB vs twice-nightly SXB was 61.7 (45.8-83.0). The most frequently reported adverse events were the same for ON-SXB and twice-nightly SXB (nausea, dizziness, somnolence, vomiting). CONCLUSIONS: GHB exposure and Cmax with one 6-g dose of ON-SXB were bioequivalent to those with two 3-g doses of twice-nightly SXB, whereas C8h was lower with ON-SXB. If approved, ON-SXB will provide a single bedtime oxybate option, with clinically relevant pharmacologic exposure during the entire sleep period.


Assuntos
Narcolepsia , Oxibato de Sódio , Feminino , Humanos , Adulto , Masculino , Oxibato de Sódio/efeitos adversos , Voluntários Saudáveis , Disponibilidade Biológica , Narcolepsia/tratamento farmacológico , Narcolepsia/induzido quimicamente , Sono , Estudos Cross-Over
11.
Rev. neurol. (Ed. impr.) ; 75(7): 165-171, Oct 1, 2022. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-209612

RESUMO

Introducción: La narcolepsia de tipo 1 es una enfermedad incapacitante que requiere tratamiento continuo, que no siempre es eficaz. El pitolisant es un nuevo fármaco con un mecanismo de acción diferente que ofrece una nueva opción de tratamiento. El objetivo del estudio fue analizar la efectividad y la seguridad del pitolisant en pacientes con narcolepsia de tipo 1 que no hubieran respondido o tolerado previamente los tratamientos habituales. Pacientes y métodos: Estudio observacional descriptivo multicéntrico de vida real que incluyó a pacientes diagnosticados de narcolepsia de tipo 1 no respondedores a tratamientos previos que iniciaron tratamiento con pitolisant. El estudio evaluó tres momentos: el inicio del tratamiento, la estabilización del tratamiento con pitolisant y los tres meses posteriores. Resultados: En 32 pacientes incluidos (media de edad, 44 años; 37,5% de mujeres), la media de la escala de somnolencia de Epworth se redujo de 17,1 a 13,5; un 47,8% de los pacientes mejoró subjetivamente de su cataplejía; un 65% de los pacientes mejoró su impresión clínica global a criterio médico y a criterio del paciente; y se redujo la media de medicamentos consumidos de 2,0 a 1,4. El efecto adverso más frecuente fue el insomnio, en un 43,8% de los pacientes. De los 32 pacientes, 23 mantuvieron el tratamiento durante los tres meses de seguimiento. Conclusiones: En pacientes con narcolepsia de tipo 1 que no responden a o no toleran los tratamientos disponibles, el pitolisant puede mejorar su situación clínica y reducir su consumo de medicamentos. Son necesarios estudios de mayor nivel de evidencia para confirmar estos resultados.(AU)


INTRODUCTION: Type 1 narcolepsy is a disabling disease that requires continuous treatment, which is not always effective. Pitolisant is a new drug with a different mechanism of action that offers a new treatment option. The objective of the study was to analyse the effectiveness and safety of pitolisant in patients with type 1 narcolepsy that did not respond to or tolerate previous standard treatments. PATIENTS AND METHODS: Real-life multicentre descriptive observational study that included patients diagnosed with type 1 narcolepsy who did not respond to or tolerate previous treatments and started treatment with pitolisant. The study evaluated three different moments: the start of treatment, the stabilization of treatment with pitolisant and the three months after. RESULTS: In 32 patients included (mean age, 44 years; 37.5% women) the mean of the Epworth Sleepiness Scale was reduced from 17.1 to 13.5; 47.8% of the patients improved from their cataplexy; 65% of the patients improved their clinical global impression at the physician’s and at the patient’s discretion and the mean number of medications consumed was reduced from 2.0 to 1.4. The most frequent adverse effect was insomnia in 43.8% of patients. Of the 32 patients, 23 continued with the treatment during the 3-month follow-up period. CONCLUSIONS: In patients with type I narcolepsy who do not respond to or do not tolerate the available treatments, pitolisant can improve their clinical situation and reduce their medication consumption. Studies with a higher level of evidence are needed to confirm these results.(AU)


Assuntos
Humanos , Masculino , Feminino , Narcolepsia/diagnóstico , Narcolepsia/tratamento farmacológico , Sonolência , Resultado do Tratamento , Cataplexia/diagnóstico , Cataplexia/tratamento farmacológico , Transtornos do Sono-Vigília , Pacientes , Epidemiologia Descritiva , Estudos Retrospectivos , Neurologia
12.
Sleep Med Rev ; 65: 101683, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36096986

RESUMO

Narcolepsy type 1 (NT1) is a rare neurological sleep disorder triggered by postnatal loss of the orexin/hypocretin neuropeptides. Overweight/obesity and precocious puberty are highly prevalent comorbidities of NT1, with a close temporal correlation with disease onset, suggesting a common origin. However, the underlying mechanisms remain unknown and merit further investigation. The main question we address in this review is whether the occurrence of precocious puberty in NT1 is due to the lack of orexin/hypocretin or rather to a wider hypothalamic dysfunction in the context of neuroinflammation, which is likely to accompany the disease given its autoimmune origins. Our analysis suggests that the suspected generalized neuroinflammation of the hypothalamus in NT1 would tend to delay puberty rather than hastening it. In contrast, that the brutal loss of orexin/hypocretin would favor an early reactivation of gonadotropin-releasing hormone (GnRH) secretion during the prepubertal period in vulnerable children, leading to early puberty onset. Orexin/hypocretin replacement could thus be envisaged as a potential treatment for precocious puberty in NT1. Additionally, we put forward an alternative hypothesis regarding the concomitant occurrence of sleepiness, weight gain and early puberty in NT1.


Assuntos
Narcolepsia , Neuropeptídeos , Puberdade Precoce , Criança , Hormônio Liberador de Gonadotropina , Humanos , Doenças Neuroinflamatórias , Orexinas , Puberdade Precoce/complicações
13.
Sleep Med Clin ; 17(3): 379-398, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36150801

RESUMO

Idiopathic hypersomnia (IH) includes a clinical phenotype resembling narcolepsy (with repeated, short restorative naps), and a phenotype with an excess of sleep, sleep drunkenness, drowsiness, and infrequent long, nonrestorative naps. Sleep tests reflect this heterogeneity. MSLTs are greater than 8 min in 2/3 of the cases and poorly repeatable. Sleep excess is better captured by extended monitoring identifying 11 to 16h of sleep/24 h. Patients with IH are young and more often female. Possible mechanisms of IH include deficiencies in arousal systems, inappropriate stimulation of sleep-inducing systems, and long biological night. Treatments now include robust studies of modafinil, clarithromycin, and sodium oxybate.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Hipersonia Idiopática , Narcolepsia , Oxibato de Sódio , Claritromicina , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Feminino , Humanos , Hipersonia Idiopática/diagnóstico , Hipersonia Idiopática/tratamento farmacológico , Modafinila , Medicina de Precisão , Espiperona/análogos & derivados
14.
Sleep Med Clin ; 17(3): 399-405, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36150802

RESUMO

Lifestyle adjustment, in combination with symptomatic pharmacologic treatment, allows most patients, particularly those with an inability to stay awake during the day, to live a relatively normal life. New pharmacologic substances show encouraging results in phase 2 and 3 studies to improve the current situation. More dedicated studies in IH, particularly in those who suffer from an increased need for sleep, are needed.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Humanos , Narcolepsia/tratamento farmacológico , Sono , Vigília
15.
Sleep Med Clin ; 17(3): 445-452, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36150806

RESUMO

Pregnancy is a unique physiologic state whose characteristics often predispose women to new-onset sleep disturbances or exacerbations of preexisting sleep disorders. Pregnancy-related factors that can disrupt sleep include heartburn, nocturnal oxytocin secretion, nocturia, and fetal movement. Sleep disorders in pregnancy include insomnia (primary and secondary), restless legs syndrome, and narcolepsy.


Assuntos
Narcolepsia , Síndrome das Pernas Inquietas , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Feminino , Humanos , Narcolepsia/tratamento farmacológico , Ocitocina/uso terapêutico , Gravidez , Síndrome das Pernas Inquietas/terapia , Distúrbios do Início e da Manutenção do Sono/complicações , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/tratamento farmacológico
16.
Sleep Med Clin ; 17(3): 485-503, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36150809

RESUMO

Excessive daytime sleepiness (EDS) is defined as "irresistible sleepiness in a situation when an individual would be expected to be awake, and alert." EDS has been a big concern not only from a medical but also from a public health point of view. Patients with EDS have the possibility of falling asleep even when they should wake up and concentrate, for example, when they drive, play sports, or walk outside. In this article, clinical characteristics of common hypersomnia and pharmacologic treatments of each hypersomnia are described.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Humanos , Sonolência , Vigília
17.
Pharmacol Biochem Behav ; 220: 173464, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36108771

RESUMO

Narcolepsy type 1 (NT1), caused by loss of orexin neurons, is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, hypnagogic/hypnopompic hallucinations and sleep paralysis, as well as a high risk of obesity. Danavorexton (TAK-925) is a novel brain-penetrant orexin 2 receptor (OX2R)-selective agonist currently being evaluated in clinical trials for the treatment of hypersomnia disorders including NT1. Thus, detailed characterization of danavorexton is critical for validating therapeutic potential of OX2R-selective agonists. Here, we report preclinical characteristics of danavorexton as a therapeutic drug for NT1. Danavorexton showed rapid association/dissociation kinetics to OX2R. The activation mode of endogenous OX2R by danavorexton and orexin peptide was very similar in an electrophysiological analysis. In orexin/ataxin-3 mice, a mouse model of NT1, danavorexton promoted wakefulness, and ameliorated fragmentation of wakefulness during the active phase after both acute and repeated administration, suggesting a low risk of receptor desensitization. Electroencephalogram (EEG) power spectral analysis revealed that danavorexton, but not modafinil, normalized dysregulated EEG power spectrum in orexin/ataxin-3 mice during the active phase. Finally, repeated administration of danavorexton significantly suppressed the body weight gain in orexin/ataxin-3 mice. Danavorexton may have the potential to treat multiple symptoms of NT1. These preclinical findings, together with upcoming clinical observations of danavorexton, could improve our understanding of the pathophysiology of NT1 and therapeutic potential of OX2R agonists.


Assuntos
Narcolepsia , Animais , Ataxina-3 , Modelos Animais de Doenças , Camundongos , Narcolepsia/tratamento farmacológico , Receptores de Orexina/agonistas , Orexinas , Vigília
18.
J Psychiatr Res ; 155: 202-210, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36070638

RESUMO

Given the high rate of depression associated with narcolepsy or obstructive sleep apnea (OSA), this analysis compared effects of solriamfetol treatment of excessive daytime sleepiness (EDS) in participants with/without a history of depression (DHx+/DHx-). This secondary analysis included data from two randomized, controlled trials in which participants were randomized to 12 weeks placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg/day. Efficacy/safety (combined solriamfetol doses) was summarized for DHx+/DHx-subgroups. 27.5% (65/236) with narcolepsy and 23.4% (111/474) with OSA were DHx+. In narcolepsy (DHx+ and DHx-), 40-min Maintenance of Wakefulness Test (MWT40) mean sleep latency increased (5.4 and 7.0 min), Epworth Sleepiness Scale (ESS) score decreased (3.8 and 3.5 points), and percentage of participants improved on Patient Global Impression of Change (PGI-C) was higher (31.7% and 39.4%) relative to placebo. In OSA (DHx+ and DHx-), MWT40 mean sleep latency increased (7.7 and 10.7 min), ESS decreased (3.5 and 3.7 points), and percentage of participants improved on PGI-C was higher (41.1% and 29.4%) relative to placebo. Common treatment-emergent adverse events (headache, decreased appetite, nausea, anxiety) were similar in DHx+/DHx-. This study suggests that safety and efficacy of solriamfetol for treating EDS in narcolepsy and OSA are not affected by depression history. Moreover, the findings emphasize the high prevalence of depression in people with sleep disorders and suggest that increased awareness of this association may have clinical significance.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Apneia Obstrutiva do Sono , Carbamatos , Depressão/complicações , Depressão/tratamento farmacológico , Distúrbios do Sono por Sonolência Excessiva/complicações , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Método Duplo-Cego , Humanos , Narcolepsia/complicações , Narcolepsia/tratamento farmacológico , Fenilalanina/análogos & derivados , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/tratamento farmacológico , Resultado do Tratamento
19.
Lancet ; 400(10357): 1033-1046, 2022 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-36115367

RESUMO

Excessive daytime sleepiness (EDS) is a public health issue. However, it remains largely undervalued, scarcely diagnosed, and poorly supported. Variations in the definition of EDS and limitations in clinical assessment lead to difficulties in its epidemiological study, but the relevance of this symptom from a socioeconomic perspective is inarguable. EDS might be a consequence of several behavioural issues leading to insufficient or disrupted sleep, as well as a consequence of sleep disorders including sleep apnoea syndrome, circadian disorders, central hypersomnolence disorders (narcolepsy and idiopathic hypersomnia), other medical or psychiatric conditions, or medications. Furthermore, EDS can have implications for health as it is thought to act as a risk factor for other conditions, such as cardiovascular and neurodegenerative disorders. Because of the heterogeneous causes of EDS and the complexity of its pathophysiology, management will largely depend on the cause, with the final aim of making treatment specific to the individual using precision medicine and personalised medicine.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Transtornos do Sono-Vigília , Causalidade , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/epidemiologia , Distúrbios do Sono por Sonolência Excessiva/etiologia , Humanos , Narcolepsia/diagnóstico , Narcolepsia/tratamento farmacológico , Fatores de Risco
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