Sequential Presentation of Obsessive-Compulsive Disorder and Narcolepsy in a 10-Year-Old Girl With Wolfram Syndrome 1.

ABSTRACT: Wolfram syndrome 1 (WS1) is a rare, autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, insulin-dependent diabetes mellitus, optic atrophy, and deafness resulting from loss-of-function genetic variants in the WFS1 gene. Individuals with WS1 manifest a spectrum of neuropsychiatric disorders. Here, we report a pediatric case of WS1, which stemmed from a novel biallelic WFS1 loss-of-function genetic variant. The individual initially presented with obsessive-compulsive disorder, which was successfully managed by fluvoxamine. After 2 months, the child manifested excessive daytime sleepiness. Clinical evaluation and sleep recordings revealed a diagnosis of narcolepsy type 2. Excessive daytime sleepiness was improved with methylphenidate. To the best of our knowledge, this is the first report of narcolepsy in WS1, which possibly arose during a progressive neurodegenerative process. We emphasize the need for in-depth screening for neuropsychiatric phenotypes and sleep-related disorders in WS1, for clinical management, which significantly improves the quality of life.

Child Neurology: Common Occurrence of Narcolepsy Type 1 and Myasthenia Gravis.

Narcolepsy with cataplexy and myasthenia gravis are both chronic neurologic conditions causing symptoms of muscle weakness, often affecting facial muscles, and have both been attributed to an immune-mediated etiology. We report an adolescent girl diagnosed with both conditions and discuss possible shared mechanisms and the diagnostic challenges presented by her case to inform and aid clinicians managing children and young people with these rare conditions.

[Constructing a cataplexy face prediction model for narcolepsy type 1 based on ResNet-18].

Objective: To establish a prediction model for the identifying of cataplexy facial features based on clinical shooting videos by using a deep learning image recognition network ResNet-18. Methods: A cross-sectional study. Twenty-five narcolepsy type 1 patients who were first diagnosed and never received treatment and 25 healthy controls recruited by advertisement in the Second Affiliated Hospital of Nanchang University from 2020 to 2023.After image preprocessing, a total of 1 180 images were obtained, including 583 cataplexy faces and 597 normal faces.90% were selected as the training set and validation set, and then expanded the data by 5 times.80% of the expanded data set was extracted as the training set and 20% as the validation set, that is, the number of the training set was (583+597)×0.9×0.8×5=4 248, the number of the validation set was (583+597)×0.9×0.2×5=1 062. The data sets for training and validation were used train parameters to establish the model and were trained through the five-fold cross-validation method, to establish the ResNet-18 cataplexy face recognition model via transfer learning.10% (118 images) of the original non-amplified images were extracted as the test set. The test set data did not participate in data enhancement and model training, and was only used to evaluate the final performance of the model. Finally, ResNet-18 was compared with VGG-16, ResNet-34 and Inception V3 deep learning models, and the receiver operating characteristic curve was used to evaluate the value of ResNet-18 image recognition network in cataplexy face recognition. Results: Among 25 patients with narcolepsy type 1, 15 were males and 10 were females, aged [M (Q1, Q3)] of 14.0(11.0, 20.5) years.Among 25 healthy controls, 14 were males and 11 were females, with a median age of 16.0(14.4, 23.0) years.The overall accuracy of ResNet-18 image recognition network in the test set was 90.9%, the sensitivity was 96.4% and the specificity was 85.2%. The area under the ROC curve was 0.99(95%CI:0.96-1.00). The ResNet-18 model parameter amount was 11.69 M, the floating point operation amount was 1 824.03 M, and the single image recognition time was 5.9 ms. Conclusions: The cataplexy face prediction model built based on the deep learning image recognition network ResNet-18 has a high accuracy in identifying cataplexy faces.

A systematic review on the contribution of DNA methylation to hearing loss.

BACKGROUND: DNA methylation may have a regulatory role in monogenic sensorineural hearing loss and complex, polygenic phenotypic forms of hearing loss, including age-related hearing impairment or Meniere disease. The purpose of this systematic review is to critically assess the evidence supporting a functional role of DNA methylation in phenotypes associated with hearing loss. RESULTS: The search strategy yielded a total of 661 articles. After quality assessment, 25 records were selected (12 human DNA methylation studies, 5 experimental animal studies and 8 studies reporting mutations in the DNMT1 gene). Although some methylation studies reported significant differences in CpG methylation in diverse gene promoters associated with complex hearing loss phenotypes (ARHI, otosclerosis, MD), only one study included a replication cohort that supported a regulatory role for CpG methylation in the genes TCF25 and POLE in ARHI. Conversely, several studies have independently confirmed pathogenic mutations within exon 21 of the DNMT1 gene, which encodes the DNA (cytosine-5)-methyltransferase 1 enzyme. This methylation enzyme is strongly associated with a rare disease defined by autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Of note, rare variants in DNMT1 and DNMT3A genes have also been reported in noise-induced hearing loss. CONCLUSIONS: Evidence supporting a functional role for DNA methylation in hearing loss is limited to few genes in complex disorders such as ARHI. Mutations in the DNMT1 gene are associated with ADCA-DN, suggesting the CpG methylation in hearing loss genes deserves further attention in hearing research.

From past to future: 50 years of pharmacological interventions to treat narcolepsy.

The history of narcolepsy research began with the pioneering work of Jean-Baptiste-Édouard Gélineau in the late 19th century. In the 1880s, Gélineau introduced the term "narcolepsy" to describe a condition characterized by sudden and uncontrollable episodes of sleep. His clinical descriptions laid the foundation for our understanding of this complex disorder. Over the last half-century, the pharmacological landscape for narcolepsy treatment has evolved remarkably, shifting from merely managing symptoms to increasingly targeting its underlying pathophysiology. By the 1930s, treatments such as ephedrine and amphetamine were introduced to alleviate excessive daytime sleepiness, marking significant advancements in narcolepsy management. These stimulants provided temporary relief, helping patients maintain wakefulness during the day. As research progressed, the focus shifted towards understanding the disorder's underlying mechanisms. The discovery of orexin (also known as hypocretin) in the late 1990s revolutionized the field. This breakthrough underscored the importance of orexin in regulating sleep-wake cycles and provided new targets for pharmacological intervention. Looking ahead, the future of narcolepsy pharmacotherapy is poised for further innovation. The ongoing exploration of orexin receptor agonists and the potential development of neuroprotective therapeutic targets underscore a promising horizon. Emerging research into the genetic and immunological underpinnings of narcolepsy opens new avenues for personalized medicine approaches and the identification of biomarkers for more precise treatment strategies. Additionally, the refinement of existing treatments through improved delivery systems and the investigation of combination therapies offer opportunities for enhanced efficacy and improved quality of life for patients with narcolepsy.

The value of using ELISA to detect orexin-A in cerebrospinal fluid in the diagnosis of narcolepsy.

Orexin in cerebrospinal fluid (CSF) is a neuropeptide synthesized by a cluster of neurons in the lateral hypothalamus. It mainly functions to maintain arousal, regulate feeding, and participate in reward mechanisms. Radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) can detect CSF orexin. At present, RIA is widely used but is limited by various conditions, which is not conducive to its widespread development. We aimed to determine whether ELISA can replace RIA in detecting orexin in CSF. We investigated the results of 20 patients with central disorders of hypersomnolence, including 11 with narcolepsy type 1, 2 with narcolepsy type 2, 5 with idiopathic hypersomnia, and 2 with other causes of somnolence. RIA and ELISA were used to detect CSF orexin, and P values <.05 were considered to be significant. In the narcolepsy and non-narcolepsy type 1 groups, there was no correlation between the RIA and ELISA results (P > .05). In the narcolepsy type 1 group, the ELISA and RIA results were significantly different (P < .05), but this was not observed in the non-narcolepsy type 1 group (P > .05). The accuracy of ELISA to detect CSF orexin was lower than that of RIA (P < .05). ELISA cannot replace RIA in the measurement of CSF orexin, and RIA is recommended as the first choice when narcolepsy is suspected.

Development and validation of a machine learning model for prediction of comorbid major depression disorder among narcolepsy type 1.

BACKGROUND: Major depression disorder (MDD) forms a common psychiatric comorbidity among patients with narcolepsy type 1 (NT1), yet its impact on patients with NT1 is often overlooked by neurologists. Currently, there is a lack of effective methods for accurately predicting MDD in patients with NT1. OBJECTIVE: This study utilized machine learning (ML) algorithms to identify critical variables and developed the prediction model for predicting MDD in patients with NT1. METHODS: The study included 267 NT1 patients from four sleep centers. The diagnosis of comorbid MDD was based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5). ML models, including six full models and six compact models, were developed using a training set. The performance of these models was compared in the testing set, and the optimal model was evaluated in the testing set. Various evaluation metrics, such as Area under the receiver operating curve (AUC), precision-recall (PR) curve and calibration curve were employed to assess and compare the performance of the ML models. Model interpretability was demonstrated using SHAP. RESULT: In the testing set, the logistic regression (LG) model demonstrated superior performance compared to other ML models based on evaluation metrics such as AUC, PR curve, and calibration curve. The top eight features used in the LG model, ranked by feature importance, included social impact scale (SIS) score, narcolepsy severity scale (NSS) score, total sleep time, body mass index (BMI), education years, age of onset, sleep efficiency, sleep latency. CONCLUSION: The study yielded a straightforward and practical ML model for the early identification of MDD in patients with NT1. A web-based tool for clinical applications was developed, which deserves further verification in diverse clinical settings.

Accidental calcium, magnesium, potassium and sodium oxybates (Xywave) overdose: mistiming of a single night's narcolepsy medication leading to respiratory failure requiring mechanical ventilation.

While typically thought of as an illicit substance, oxybate salts or gamma-hydroxybutyrate (GHB) has more recently been prescribed to treat narcolepsy by enhancing night-time sleep resulting in decreased daytime drowsiness. This case involves a college-aged female with prescribed GHB for narcolepsy who took her second nightly dose too early. This resulted in mental depression, respiratory failure, intubation and mechanical ventilation. The patient was successfully extubated in the intensive care unit several hours later with no residual morbidity. We were unable to identify any prior reports of mixed-salt oxybate toxicity following mistimed drug administration. This case should serve as a warning to emergency physicians to be on the lookout for GHB as part of the differential diagnosis for patients with narcolepsy presenting with altered mental status. It should also serve as a warning to patients and prescribers that this medication can have outcomes that require immediate medical intervention.

Causal relationship between narcolepsy and anxiety: A two-sample Mendelian randomization study.

BACKGROUND: The aim of this study was to assess the causal relationship between narcolepsy and anxiety using Mendelian randomization (MR) methodology. METHODS: Our research applied a bidirectional two-sample Mendelian Randomization strategy to explore the linkage between narcolepsy and anxiety. Utilizing summary data from GWAS on both conditions, we primarily employed the inverse-variance weighted technique for our analysis. To evaluate heterogeneity and horizontal pleiotropy, we utilized tools such as the MR Egger method, the weighted median method, Cochran's Q statistic, and the MR Egger intercept. RESULTS: The analysis using the inverse variance-weighted method showed a clear positive link between narcolepsy and anxiety, with an odds ratio of 1.381 (95% CI: 1.161-1.642, p < 0.001). Tests for heterogeneity and horizontal pleiotropy, including MR Egger and IVW methods, indicated no significant findings (p-values 0.616 and 0.637, respectively, for heterogeneity; p = 0.463 for pleiotropy). Furthermore, no reverse causation was observed between anxiety and narcolepsy (odds ratio 1.034, 95% CI: 0.992-1.078, p = 0.111), with consistent findings across various analytical approaches. CONCLUSION: This research suggests a possible causal link between narcolepsy and anxiety disorders. The results illuminate this connection and advocate additional studies to elucidate the mechanisms involved and to identify effective interventions.

Hits and misses with animal models of narcolepsy and the implications for drug discovery.

INTRODUCTION: Narcolepsy is a chronic and rare neurological disorder characterized by disordered sleep. Based on animal models and further research in humans, the dysfunctional orexin system was identified as a contributing factor to the pathophysiology of narcolepsy. Animal models played a larger role in the discovery of some of the pharmacological agents with established benefit/risk profiles. AREAS COVERED: In this review, the authors examine the phenotypes observed in animal models of narcolepsy and the characteristics of clinically used pharmacological agents in these animal models. Additionally, the authors compare the effects of clinically used pharmacological agents on the phenotypes in animal models with those observed in narcolepsy patients. EXPERT OPINION: Research in canine and mouse models have linked narcolepsy to the O×R2mutation and orexin deficiency, leading to new diagnostic criteria and a drug development focus. Advancements in pharmacological therapies have significantly improved narcolepsy management, with insights from both clinical experience and from animal models having led to new treatments such as low sodium oxybate and solriamfetol. However, challenges persist in addressing symptoms beyond excessive daytime sleepiness and cataplexy, highlighting the need for further research, including the development of diurnal animal models to enhance understanding and treatment options for narcolepsy.

Navigating narcolepsy: exploring coping strategies and their association with quality of life in patients with narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic neurological disorder characterized by symptoms such as excessive daytime sleepiness, sudden sleep episodes, disrupted nocturnal sleep, cataplexy, sleep paralysis, and hypnagogic hallucinations, which significantly impact the overall well-being and quality of life of individuals. While psychological factors have gained attention, there is limited research on the coping strategies employed by patients with NT1 and their association with quality of life. This study aimed to compare coping strategies in patients with NT1 and controls, as well as assess the relationship between coping strategies and quality of life in patients with NT1. A total of 122 individuals diagnosed with NT1 and 138 controls were enrolled in this cross-sectional study. Participants completed questionnaires assessing coping strategies and health-related quality of life. A Mann-Whitney U test was conducted to compare the use of different coping strategies by patients with NT1 and controls. Spearman's rho correlation was performed to examine the association between coping strategies and quality of life in the NT1 group. Results showed that patients with NT1 exhibited differences in the use of coping strategies compared to controls. They reported lower use of active coping, planning, instrumental, and emotional social support, and higher use of behavioral and mental disengagement. Denial and behavioral disengagement were significantly and negatively associated with quality of life. Identifying coping strategies and their association with quality of life may aid in the development of tailored interventions aimed at improving the adoption of effective coping strategies and reducing the use of maladaptive coping strategies.

Executive function performance in children and adolescent patients with narcolepsy type 1.

OBJECTIVE: The executive function profile in patients with narcolepsy type 1 (NT1) has been mentioned; however, limited research exists on children and adolescent patients with NT1.This study aims to assess executive function in children and adolescent patients with NT1 in China, examine potential influencing factors and evaluate the short-term treatment effect on executive function. METHODS: 53 NT1 patients (36 males, age 12.2 ± 3.4 years) and 37 healthy controls (23 males, age 12.2 ± 2.5 years) underwent self-reported measures assessing subjective sleepiness, depression, anxiety and sleep quality. A comprehensive neuropsychological test was administered to assess executive function domains, including processing speed, inhibitory control, cognitive flexibility and working memory. These assessments were repeated in NT1 patients after three-day regular drug treatment. RESULTS: NT1 patients exhibited higher levels of excessive daytime sleepiness, depression, anxiety, and poor sleep quality compared to healthy controls. Patients showed impaired processing speed, inhibitory control and cognitive flexibility (p < 0.05), whereas working memory was unaffected (p > 0.05). Regression analysis revealed that parameters from sleep monitoring, such as sleep efficiency and sleep latency, were correlated with executive function performance after controlling for age, gender, and education years. The short-term treatment led to improvements in inhibitory control, cognitive flexibility, and working memory. CONCLUSION: The findings showed that executive function was impaired among children and adolescent patients with NT1, which was associated with objective sleep parameters. Furthermore, this study emphasizes the necessity of neuropsychological assessments and early interventions among children and adolescent NT1 patients.

Encefalitis autoinmune tras vacunación e infección por el SARS-CoV-2 en un paciente con narcolepsia de tipo 1 / Autoimmune encephalitis mediated by postvaccination and infection of SARS-CoV-2 in a patient with a narcolepsy type 1

Introducción Presentamos un paciente diagnosticado de narcolepsia de tipo 1 que desarrolló una encefalitis autoinmune posvacunal y/o tras una infección por el SARS-CoV-2. Caso clínico Paciente de 23 años que es remitido a urgencias por trastorno del lenguaje y temblor, acompañados de cefalea, trastorno del comportamiento, disfunción autonómica, crisis focal motora derecha y letargo. El paciente había sido vacunado siete semanas antes con la primera dosis de la vacuna Moderna (ARN mensajero) y, cuatro semanas después de la vacunación, presentó una infección por el SARS-CoV-2 con test de antígenos positivo. Resultados La exploración neurológica mostró un nivel de conciencia normal y una afasia mixta de predominio motor (campimetría, pares craneales, reflejos y sensibilidad normales). El test de reacción en cadena de la polimerasa para la COVID-19 fue negativo. En el líquido cefalorraquídeo se apreció una linfocitosis y proteínas elevadas. Los cultivos para hongos y bacterias fueron negativos. Los anticuerpos onconeuronales fueron normales. La resonancia magnética cerebral mostró en la secuencia de difusión una restricción con afectación cortical y morfología giral en el hemisferio cerebral izquierdo, y distribución parcheada con afectación de lóbulo frontal y temporal izquierdos. Una tomografía axial computarizada de tórax-abdomen-pelvis fue normal, al igual que las ecografías pélvica y escrotal. Al paciente se le trató con plasmaféresis y corticoides, con buena evolución clínica y resolución casi completa de las anomalías en la neuroimagen. Conclusión Se trata de un paciente con narcolepsia de tipo 1 con criterios de encefalitis autoinmune de comienzo subagudo. La infección por el SARS-CoV-2 o la vacunación, o ambas, constituyen un riesgo para desarrollar una o más enfermedades autoinmunes con la edad –como sucede en este caso–, lo que permite comprender la implicación de procesos inmunomediados en la fisiopatología de estas enfermedades. (AU)

INTRODUCTION We present a narcolepsy type 1 patient that develop an autoimmune encephalitis post vaccine and/or a SARS-CoV-2 infection.CASE REPORTAt 23 years old, the patient was referred to the emergency room with difficult speaking, headache and tremor followed by changes in behavior, autonomic dysfunction, right focal motor seizure and lethargy. He has received seven weeks before mRNA-1273 (Moderna) vaccine followed by a SARS-CoV-2 infection four weeks after vaccination (positive antigen test).RESULTSThe neurological examination was normal (visual fields, cranial nerves, motor, sensory and reflexes). Nasopharyngeal swab polymerase chain reaction (PCR) testing for COVID-19 was negative. Cerebrospinalfluid (CSF) had highly elevated protein and lymphocytic pleocytosis. CSF bacterial and fungal cultures for viral infections were negative. Brain magnetic resonance imaging (MRI) showed no abnormality on the non-enhanced sequences but the diffusion weighted imaging showed restricted diffusion with high signal on the left hemisphere mainly in the cerebral cortex with a gyro morphology, patched distribution with involvement of the temporal and frontal lobes. Chest, abdomen and pelvis computed tomography; pelvic and scrotum ultrasound, showed no malignancy. Onconeural antibodies were negative. The patient was treated with plasmapheresis and corticosteroids with a good clinical outcome and near complete resolution of the MRI abnormalities. CONCLUSION. The patient fulfilled the diagnostic criteria for autoimmune encephalitis with subacute onset. COVID-19 infection and vaccination could constitute a risk in a patient with narcolepsy as in this case and, could help to provide better understanding of the implication of immune-mediated processes in the pathophysiology of the diseases. (AU)

Effects of modafinil on nocturnal sleep patterns in patients with narcolepsy: A cohort study.

BACKGROUND: Patients with narcolepsy often experience disturbed nighttime sleep. Modafinil is commonly prescribed for hypersomnolence, but its impacts on nocturnal sleep remain unclear. This study uses actigraphy to examine the effect of modafinil on both hypersomnolence and nocturnal sleep patterns in patients with narcolepsy. METHODS: Prior to treatment, 87 patients with narcolepsy wore an actigraphy for 7-14 days to assess their nighttime sleep. After evaluation, they received a daily dose of 200-400 mg of modafinil in the morning and wore an actigraphy again six months after initiating treatment. Questionnaires, including the Epworth-Sleepiness-Scale (ESS), the Visual-Analogue-for-Hypersomnolence (VAS), and the Short-Form-36-Health-Survey (SF-36), were used to evaluate hypersomnolence and quality of life both before and after treatment. Paired t-tests and independent samples t-tests were used for pre- and post-treatment comparisons and subgroup analysis. We used the Pearson's correlation test to measure the correlations between the sleep parameters of the actigraphy and data of the questionnaires. RESULTS: Improvements in hypersomnolence were noted following modafinil treatment, and we observed no significant deterioration in nocturnal sleep parameters by the actigraphy. The total number of awakenings by actigraphy significantly decreased (p = 0.005), especially in females (p = 0.008), while sleep onset latency significantly increased in children/adolescents (p = 0.014). Correlations were found between the sleep parameters of the actigraphy and ESS, VAS, and SF-36 scores. CONCLUSION: Modafinil treatment may not worsen nighttime sleep in patients with narcolepsy. However, it should be administered with care in children and adolescents.

MRS study on the correlation between frontal GABA+/Glx ratio and abnormal cognitive function in medication-naive patients with narcolepsy.

OBJECTIVE: To compare the GABA+/Glx (glutamate-glutamine) ratio in the prefrontal lobe under non-rapid eye movement sleep between patients with narcolepsy type 1 (NT1) and normal controls and explore the correlation between this difference and abnormal cognitive function, using synchronous electroencephalography-functional magnetic resonance spectroscopy (EEG-fMRS). METHODS: MRS measurements of GABA+ and Glx concentrations as well as synchronous EEG data were obtained from 26 medication-naive patients with NT1 and 29 sex- and age-matched healthy community volunteers. Cognition was appraised with the Beijing version of the Montreal Cognitive Assessment, and daytime sleepiness was measured using the Epworth Sleepiness Scale. All subjects recorded a 2-week sleep log as well as an overnight polysomnography within 1 week before MR scanning to understand their sleep habits and determine sleep stages. After PSG, they also underwent multiple sleep latency trials. Patient/control group differences in the individual measurements of GABA+ and Glx and the GABA+/Glx ratio and their relationship with cognition were assessed. RESULTS: The GABA+/Glx ratio and GABA + levels of patients with narcolepsy were higher than those of the control group (P＜0.0001 and P = 0.0008, respectively). However, there was no significant difference in Glx levels (P = 0.6360). The GABA+/Glx ratio negatively correlated with abnormal cognitive function (r = -0.6710, P = 0.0002). Moreover, GABA + levels were inversely proportional to rapid eye movement sleep latency (REML) in patients with narcolepsy (r = -0.5019, P = 0.0106). CONCLUSION: The GABA+/Glx ratio in the prefrontal lobe was higher in NT1 patients during N2 sleep than in normal controls, mainly caused by GABA + levels; this ratio was negatively related to abnormal cognitive function. In addition, GABA + levels were inversely proportional to REML.

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.

Autoimmune encephalitis mediated by postvaccination and infection of SARS-CoV-2 in a patient with a narcolepsy type 1. / Encefalitis autoinmune tras vacunación e infección por el SARS-CoV-2 en un paciente con narcolepsia de tipo 1.

INTRODUCTION: We present a narcolepsy type 1 patient that develop an autoimmune encephalitis post vaccine and/or a SARS-CoV-2 infection. CASE REPORT: At 23 years old, the patient was referred to the emergency room with difficult speaking, headache and tremor followed by changes in behavior, autonomic dysfunction, right focal motor seizure and lethargy. He has received seven weeks before mRNA-1273 (Moderna) vaccine followed by a SARS-CoV-2 infection four weeks after vaccination (positive antigen test). RESULTS: The neurological examination was normal (visual fields, cranial nerves, motor, sensory and reflexes). Nasopharyngeal swab polymerase chain reaction (PCR) testing for COVID-19 was negative. Cerebrospinalfluid (CSF) had highly elevated protein and lymphocytic pleocytosis. CSF bacterial and fungal cultures for viral infections were negative. Brain magnetic resonance imaging (MRI) showed no abnormality on the non-enhanced sequences but the diffusion weighted imaging showed restricted diffusion with high signal on the left hemisphere mainly in the cerebral cortex with a gyro morphology, patched distribution with involvement of the temporal and frontal lobes. Chest, abdomen and pelvis computed tomography; pelvic and scrotum ultrasound, showed no malignancy. Onconeural antibodies were negative. The patient was treated with plasmapheresis and corticosteroids with a good clinical outcome and near complete resolution of the MRI abnormalities. CONCLUSION: The patient fulfilled the diagnostic criteria for autoimmune encephalitis with subacute onset. COVID-19 infection and vaccination could constitute a risk in a patient with narcolepsy as in this case and, could help to provide better understanding of the implication of immune-mediated processes in the pathophysiology of the diseases.

TITLE: Encefalitis autoinmune tras vacunación e infección por el SARS-CoV-2 en un paciente con narcolepsia de tipo 1.Introducción. Presentamos un paciente diagnosticado de narcolepsia de tipo 1 que desarrolló una encefalitis autoinmune posvacunal y/o tras una infección por el SARS-CoV-2. Caso clínico. Paciente de 23 años que es remitido a urgencias por trastorno del lenguaje y temblor, acompañados de cefalea, trastorno del comportamiento, disfunción autonómica, crisis focal motora derecha y letargo. El paciente había sido vacunado siete semanas antes con la primera dosis de la vacuna Moderna (ARN mensajero) y, cuatro semanas después de la vacunación, presentó una infección por el SARS-CoV-2 con test de antígenos positivo. Resultados. La exploración neurológica mostró un nivel de conciencia normal y una afasia mixta de predominio motor (campimetría, pares craneales, reflejos y sensibilidad normales). El test de reacción en cadena de la polimerasa para la COVID-19 fue negativo. En el líquido cefalorraquídeo se apreció una linfocitosis y proteínas elevadas. Los cultivos para hongos y bacterias fueron negativos. Los anticuerpos onconeuronales fueron normales. La resonancia magnética cerebral mostró en la secuencia de difusión una restricción con afectación cortical y morfología giral en el hemisferio cerebral izquierdo, y distribución parcheada con afectación de lóbulo frontal y temporal izquierdos. Una tomografía axial computarizada de tórax-abdomen-pelvis fue normal, al igual que las ecografías pélvica y escrotal. Al paciente se le trató con plasmaféresis y corticoides, con buena evolución clínica y resolución casi completa de las anomalías en la neuroimagen. Conclusión. Se trata de un paciente con narcolepsia de tipo 1 con criterios de encefalitis autoinmune de comienzo subagudo. La infección por el SARS-CoV-2 o la vacunación, o ambas, constituyen un riesgo para desarrollar una o más enfermedades autoinmunes con la edad ­como sucede en este caso­, lo que permite comprender la implicación de procesos inmunomediados en la fisiopatología de estas enfermedades.

Single cell transcriptomics of cerebrospinal fluid cells from patients with recent-onset narcolepsy.

Narcolepsy is a rare cause of hypersomnolence and may be associated or not with cataplexy, i.e. sudden muscle weakness. These forms are designated narcolepsy-type 1 (NT1) and -type 2 (NT2), respectively. Notable characteristics of narcolepsy are that most patients carry the HLA-DQB1*06:02 allele and NT1-patients have strongly decreased levels of hypocretin-1 (synonym orexin-A) in the cerebrospinal fluid (CSF). The pathogenesis of narcolepsy is still not completely understood but the strong HLA-bias and increased frequencies of CD4+ T cells reactive to hypocretin in the peripheral blood suggest autoimmune processes in the hypothalamus. Here we analyzed the transcriptomes of CSF-cells from twelve NT1 and two NT2 patients by single cell RNAseq (scRNAseq). As controls, we used CSF cells from patients with multiple sclerosis, radiologically isolated syndrome, and idiopathic intracranial hypertension. From 27,255 CSF cells, we identified 20 clusters of different cell types and found significant differences in three CD4+ T cell and one monocyte clusters between narcolepsy and multiple sclerosis patients. Over 1000 genes were differentially regulated between patients with NT1 and other diseases. Surprisingly, the most strongly upregulated genes in narcolepsy patients as compared to controls were coding for the genome-encoded MTRNR2L12 and MTRNR2L8 peptides, which are homologous to the mitochondria-encoded HUMANIN peptide that is known playing a role in other neurological diseases including Alzheimer's disease.

[Research Progress in the Correlation Between Dopamine and Clinical Characterization of Narcolepsy].

Dopamine,a neurotransmitter ubiquitous in the body fluids,blood,and urine of mammals and humans,is responsible for regulating their functions and metabolism.The dopamine system is involved in the neurobiological mechanisms of narcolepsy in animals and humans.However,researchers have drawn different or even opposite conclusions when measuring the dopamine level in the cerebrospinal fluid of narcolepsy patients.Studies have confirmed that the occurrence of narcolepsy is related to the irreversible loss of orexins.The autoimmune reaction caused by the interactions of environmental factors with genetic factors destroys the hypothalamic orexin neurons and reduces orexin secretion,thereby lowering the level of arousal.We introduce the research progress and current status of dopamine and clinical characterization of narcolepsy by reviewing more than 40 articles published from 1982 to 2023,aiming to provide a reference for studying the relationship between the dopamine level and clinical characterization of narcolepsy and searching for the biomarkers of type 2 narcolepsy.

Microglia Density and Its Association With Disease Duration, Severity, and Orexin Levels in Patients With Narcolepsy Type 1.

BACKGROUND AND OBJECTIVES: Narcolepsy type 1 (NT1) is due to the loss of hypothalamic neurons that produce orexin (ORX), by a suspected immune-mediated process. Rare postmortem studies are available and failed to detect any inflammation in the hypothalamic region, but these brains were collected years after the first symptoms. In vivo studies close to disease onset are lacking. We aimed to explore microglia density in the hypothalamus and thalamus in NT1 compared with controls using [18F]DPA-714 PET and to study in NT1 the relationships between microglia density in the hypothalamus and in other regions of interest (ROIs) with disease duration, severity, and ORX levels. METHODS: Patients with NT1 and controls underwent a standardized clinical evaluation and [18F]DPA-714 PET imaging using a radiolabeled ligand specific to the 18 kDa translocator protein (TSPO). TSPO genotyping determined receptor affinity. Images were processed on peripheral module interface using standard uptake value (SUV) on ROIs: hypothalamus, thalamus, frontal area, cerebellum, and the whole brain. SUV ratios (SUVr) were calculated by normalizing SUV with cerebellum uptake. RESULTS: A total of 41 patients with NT1 (21 adults, 20 children, 10 with recent disease onset <1 year) and 35 controls were included, with no significant difference between groups for [18F]DPA-714 binding (SUV/SUVr) in the hypothalamus and thalamus. Unexpectedly, significantly lower SUVr in the whole brain was found in NT1 compared with controls (0.97 ± 0.06 vs 1.08 ± 0.22, p = 0.04). The same finding between NT1 and controls in the whole brain was observed in those with high or mixed TSPO affinity (p = 0.03 and p = 0.04). Similar trend was observed in the frontal area in NT1 (0.96 ± 0.09 vs 1.09 ± 0.25, p = 0.05). In NT1, no association was found between SUVr in different ROIs and age, disease duration, severity, or ORX levels. DISCUSSION: We found no evidence of in vivo increased microglia density in NT1 compared with controls, even close to disease onset, and even unexpectedly a decrease in the whole brain of these patients. These findings do not support the presence of neuroinflammation in the destruction process of ORX neurons. TRIAL REGISTRATION INFORMATION: ClinicalTrials.org NCT03754348.