Progresses in clinical manifestations and treatments of narcolepsy / 中国临床药理学与治疗学

Narcolepsy is a rare disease that presents with sleep-wake disorder, which divided into narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). NT1 accounts for more than 75%, which is characterized by excessive daytime sleepiness (EDS), cataplexy attacks and nocturnal sleep symptoms (e.g. sleep paralysis, hallucinations, sleep disruptions, sleep movement disorders, etc.), accompanied by metabolic, psychiatric and emotional disturbances. The main clinical manifestation of NT2 is EDS, without cataplexy and nonspecific other symptoms of NT1. The treatments of narcolepsy mainly include the treatments of EDS and cataplexy, as well as the improvement of nocturnal sleep. This article will elaborate the advances in clinical manifestations and treatments of narcolepsy.

Recent Updates on Narcolepsy and Hypersomnia / 신경정신의학

Narcolepsy is a chronic neurological sleep disorder caused by hypocretin neuron loss, resulting in excessive daytime sleepiness, disturbed nocturnal sleep, and intrusions of aspects of rapid eye movement sleep in wakefulness, such as cataplexy, sleep paralysis, and hypnopompic/hypnagogic hallucinations. Narcolepsy disrupts the maintenance and orderly occurrence of the wake and sleep stages. Cataplexy is a highly specific symptom of narcolepsy, but many other symptoms can be observed in a variety of sleep disorders. The diagnosis of narcolepsy type 1 requires a history of excessive daytime sleepiness and one of the following : 1) a low cerebrospinal fluid hypocretin-1 level or 2) cataplexy and a positive multiple sleep latency test result. The diagnosis of narcolepsy type 2 requires a history of excessive daytime sleepiness and a positive mean sleep-latency test result. The mean sleep-latency test must be preceded by nighttime polysomnography to exclude other sleep disorders and to document adequate sleep. The mean sleep-latency test result can be falsely positive in other sleep disorders, such as shift work, sleep apnea, or sleep deprivation, and it is influenced by age, sex, and puberty. Modafinil and armodafinil can reduce the excessive daytime sleepiness without many of the side effects associated with older stimulants. Although there is no cure for narcolepsy, the treatments are often effective and include both behavioral and pharmacologic approaches.

Episodios Ictales: Descripción de un Caso Clínico / Ictal events: a case report

Caso clínico de una paciente de once años que debuta con episodios de pérdida de tono y luego hipersomnolencia. Consulta en reiteradas ocasiones con el diagnóstico de epilepsia, con estudios electroencefalográficos y resonancia magnética cerebral, normales. Tratada durante un año con ac. valproico. Posteriormente se indica realización de Polisomnograma y Test de latencias múltiples de Sueño, confirmándose diagnóstico de narcolepsia y un trastorno del ánimo. Se inicia tratamiento con psicoestimulantes y antidepresivos. Evoluciona, con una mejoría de su cataplejía, hipersomnia y aspecto anímico. Se analiza caso, como diagnóstico diferencial de niños con episodios de pérdida de tono muscular e hipersomnolencia diurna, con conservación de conciencia y además se discute el manejo y las comorbilidades asociadas.Palabras claves: Episodios ictales, hipersomnolencia, narcolepsia, cataplejía, síncope

Summary: Case report of an eleven year old patient who debuts with hypersomnolence and episodes of muscle tone loss. She repeatedly receives a diagnosis of epilepsy, with normal EEG studies and brain MRI. She received a 12 month course of valproic acid treatment. A polysomnogram and multiple sleep latency test were subsequently performed, confirming a diagnosis of narcolepsy and a mood disorder. She begins treatment with antidepressants and psychostimulants. At follow up, she shows an improvement of her cataplexy, hypersomnia and mood disorder.We analyze this case to consider this pathology in the differential diagnosis of children with daytime hypersomnolence and episodes of muscle tone loss, with conserved awareness, as well as to discuss management and associated comorbidities. Key words: Ictal hypersomnolence, narcolepsy, cataplexy, syncopal episodes.

A rare presentation of hypothyroidism.

In this case report, we have brought out a very rare presentation of hypothyroidism in the form of cataplexy and this case is of significance because there have been no similar case reports of hypothyroidism presenting as cataplexy so far. The other highlight of the case is that treatment of hypothyroidism alone resulted in complete freedom from cataplexy without the need for agrypnotic drugs.

Narcolepsy with Obstructive Sleep Apnea in a 4-Year-Old Korean Girl: A Case Report

A 4-yr-old girl has exhibited severe snoring, restless sleep and increasing daytime sleepiness over the last 3 months. The physical examination showed that she was not obese but had kissing tonsils. Polysomnography demonstrated increased apnea-hypopnea index (AHI) of 5.2, and multiple sleep latency tests (MSLT) showed shortened mean sleep latency and one sleep-onset REM period (SOREMP). She was diagnosed with obstructive sleep apnea (OSA) and underwent tonsillectomy and adenoidectomy. After the surgery, her sleep became much calmer, but she was still sleepy. Another sleep test showed normal AHI of 0.2, the mean sleep latency of 8 min, and two SOREMPs. Diagnosis of OSA to be effectively treated by surgery and narcolepsy without cataplexy was confirmed. Since young children exhibiting both OSA and narcolepsy can fail to be diagnosed with the latter, it's desirable to conduct MSLT when they have severe daytime sleepiness or fail to get better even with good treatment.

Effect of clomipramine in a dog with cataplexy / 대한수의학회지

A 5-year-old, castrated male, Maltese was presented with history of acute flaccid paralysis. The dog was presented with sudden loss of muscle tone and involuntary movements of hind limbs. Neurologic examination revealed reduced postural reaction in the bilateral hind limbs. MRI of brain showed moderate hydrocephalus, but other examination results were normal. Based on the characteristic episodes and examination results, canine cataplexy was suspected. Treatment was initiated with clomipramine as cataplexy control. Clinical signs resolved with 3-month medication. This case demonstrates therapeutic diagnosis of cataplexy. To the author's knowledge, this is the first report of cataplexy treating with clomipramine.

Late-Onset Narcolepsy with Cataplexy Unresponsive to Intravenous High-Dose Immunoglobulin Treatment

Narcolepsy with cataplexy (NC) is associated with hypocretin deficiency, and is thought to be an autoimmunity condition. The mean age at onset is estimated to be in the early 20s. Recent papers have addressed the response to immunotherapies in NC, with challenging results. We report a case of late-onset NC in a patient who did not benefit from early intravenous high-dose immunoglobulin (IVIg) therapy. This is the first reported attempt at using IVIg to treat an NC patient in Korea.

Use of PCR with Sequence-specific Primers for High-Resolution Human Leukocyte Antigen Typing of Patients with Narcolepsy

BACKGROUND: Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness, symptoms of abnormal rapid eye movement (REM) sleep, and a strong association with HLA-DRB1*1501, -DQA1*0102, and -DQB1*0602. Here, we investigated the clinico-physical characteristics of Korean patients with narcolepsy, their HLA types, and the clinical utility of high-resolution PCR with sequence-specific primers (PCR-SSP) as a simple typing method for identifying DRB1*15/16, DQA1, and DQB1 alleles. METHODS: The study population consisted of 67 consecutively enrolled patients having unexplained daytime sleepiness and diagnosed narcolepsy based on clinical and neurological findings. Clinical data and the results of the multiple sleep latency test and polysomnography were reviewed, and HLA typing was performed using both high-resolution PCR-SSP and sequence-based typing (SBT). RESULTS: The 44 narcolepsy patients with cataplexy displayed significantly higher frequencies of DRB1*1501 (Pc= 0.003), DQA1*0102 (Pc=0.001), and DQB1*0602 (Pc=0.014) than the patients without cataplexy. Among patients carrying DRB1*1501-DQB1*0602 or DQA1*0102, the frequencies of a mean REM sleep latency of less than 20 min in nocturnal polysomnography and clinical findings, including sleep paralysis and hypnagogic hallucination were significantly higher. SBT and PCR-SSP showed 100% concordance for high-resolution typing of DRB1*15/16 alleles and DQA1 and DQB1 loci. CONCLUSIONS: The clinical characteristics and somnographic findings of narcolepsy patients were associated with specific HLA alleles, including DRB1*1501, DQA1*0102, and DQB1*0602. Application of high-resolution PCR-SSP, a reliable and simple method, for both allele- and locus-specific HLA typing of DRB1*15/16, DQA1, and DQB1 would be useful for characterizing clinical status among subjects with narcolepsy.

Narcolepsy in Children / 수면정신생리

Childhood narcolepsy is one of the underdiagnosed diseases even the first symptoms often appear in childhood. Making diagnosis through history taking is not always easy because the symptoms of childhood narcolepsy are different from those of adulthood. Diagnostic laboratory tests such as sleep studies, tests for human leukocyte antigens, cerebrospinal fluid hypocretin measurement should be considered when the child has excessive daytime sleepiness without cataplexy. Treatment approach should be start as early as possible to avoid secondary academic, emotional difficulties. Both pharmacological and non-pharmacological management, and close cooperation between parents and school teachers should be maintained. In the near future, childhood narcolepsy can be a key to understand the pathogenesis of narcolepsy.

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

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

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

Diretrizes brasileiras para o diagnóstico de narcolepsia / Brazilian guidelines for the diagnosis of narcolepsy

Este artigo relata as conclusões da reunião de consenso com médicos especialistas sobre diagnóstico de narcolepsia baseada na revisão dos artigos sobre narcolepsia listados no Medline entre 1980 e 2010. A narcolepsia é uma doença crônica de início entre a primeira e segunda décadas de vida do indivíduo. Os sintomas essenciais são cataplexia e sonolência excessiva. A cataplexia é definida como episódios súbitos, recorrentes e reversíveis de fraqueza da musculatura esquelética desencadeados por situações de conteúdo emocional. Os sintomas acessórios são alucinações hipnagógicas, paralisia do sono e sono fragmentado. Critérios de diagnóstico clínico de acordo com a Classificação Internacional dos Transtornos do Sono são de sonolência excessiva e cataplexia. Recomenda-se a realização de polissonografia seguida do teste de latência múltipla do sono em um laboratório de sono para confirmação e diagnóstico de comorbidades. Quando não houver cataplexia, deve haver duas ou mais sonecas com sono REM no teste de latência múltipla do sono. Tipagem HLA-DQB1*0602 positiva com níveis de hipocretina-1 abaixo de 110pg/mL devem estar presentes para o diagnóstico de narcolepsia sem cataplexia e sem sonecas com sono REM.

This manuscript contains the conclusion of the consensus meeting on the diagnosis of narcolepsy based on the review of Medline publications between 1980-2010. Narcolepsy is a chronic disorder with age at onset between the first and second decade of life. Essential narcolepsy symptoms are cataplexy and excessive sleepiness. Cataplexy is defined as sudden, recurrent and reversible attacks of muscle weakness triggered by emotions. Accessory narcolepsy symptoms are hypnagogic hallucinations, sleep paralysis and nocturnal fragmented sleep. The clinical diagnosis according to the International Classification of Sleep Disorders is the presence of excessive sleepiness and cataplexy. A full in-lab polysomnography followed by a multiple sleep latency test is recommended for the confirmation of the diagnosis and co-morbidities. The presence of two sleep-onset REM period naps in the multiple sleep latency test is diagnostic for cataplexy-free narcolepsy. A positive HLA-DQB1*0602 with lower than 110pg/mL level of hypocretin-1 in the cerebrospinal fluid is required for the final diagnosis of cataplexy- and sleep-onset REM period -free narcolepsy.

Diretrizes brasileiras para o tratamento da narcolepsia / Brazilian guidelines for the treatment of narcolepsy

Este artigo relata as conclusões da reunião de consenso da Associação Brasileira de Sono com médicos especialistas brasileiros sobre o tratamento da narcolepsia, baseado na revisão dos artigos sobre narcolepsia publicados entre 1980 e 2010. Os objetivos do consenso são valorizar o uso de agentes avaliados em estudos randomizados placebo-controlados, emitir recomendações de consenso para o uso de outras medicações e informar pontos importantes a respeito da segurança e efeitos adversos das medicações. O tratamento da narcolepsia é baseado em diversas classes de agentes, estimulantes para sonolência excessiva, agentes antidepressivos para cataplexia e hipnóticos para sono noturno fragmentado. Medidas comportamentais são igualmente importantes e recomendadas universalmente. Todos os ensaios clínicos terapêuticos foram classificados de acordo com o nível de qualidade da evidência. Recomendações terapêuticas individualizadas para cada tipo de sintoma e recomendações gerais foram formuladas pelos autores. Modafinila é indicada como a primeira escolha para o tratamento da sonolência diurna. Agentes de segunda escolha para o tratamento da sonolência excessiva são metilfenidato de liberação lenta seguido pelo mazindol. Reboxetina, clomipramina, venlafaxina, desvenlafaxina e os inibidores seletivos de recaptação de serotonina em doses altas são a primeira escolha para o tratamento da cataplexia. Hipnóticos são utilizados para o tratamento do sono noturno fragmentado. Antidepressivos e hipnóticos são igualmente utilizados para o tratamento das alucinações hipnagógicas e paralisia do sono.

This manuscript contains the conclusion of the consensus meeting of the Brazilian Sleep Association with Brazilian sleep specialists on the treatment of narcolepsy based on the review of medical literature from 1980 to 2010. The manuscript objectives were to reinforce the use of agents evaluated in randomized placebo-controlled trials and to issue consensus opinions on the use of other available medications as well as to inform about safety and adverse effects of these medications. Management of narcolepsy relies on several classes of drugs, namely, stimulants for excessive sleepiness, antidepressants for cataplexy and hypnotics for disturbed nocturnal sleep. Behavioral measures are likewise valuable and universally recommended. All therapeutic trials were analyzed according to their class of evidence. Recommendations concerning the treatment of each single symptom of narcolepsy as well as general recommendations were made. Modafinil is the first-line pharmacological treatment of excessive sleepiness. Second-line choices for the treatment of excessive sleepiness are slow-release metylphenidate followed by mazindol. The first-line treatments of cataplexy are the antidepressants, reboxetine, clomipramine, venlafaxine, desvenlafaxine or high doses of selective serotonin reuptake inibitors antidepressants. As for disturbed nocturnal sleep the best option is still hypnotics. Antidepressants and hypnotics are used to treat hypnagogic hallucinations and sleep paralysis.

Narcolepsy: Clinical features, co-morbidities & treatment.

Narcolepsy is a neurologic illness that typically begins in the second and third decades of life. It is chronic in nature and negatively impacts the quality of life of affected patients. The classic presentation is a tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. The exact cause remains unknown, but there is significant evidence that hypocretin deficiency plays an integral role. Some primary conditions that result in secondary narcolepsy include traumatic brain injury, congenital disorders, tumours, and strokes. Some medical and psychiatric disorders share characteristics of narcolepsy, at times leading to diagnostic inaccuracy. Other sleep disorders are commonly co-morbid. Diagnosis relies on patient history and objective data gathered from polysomnography and multiple sleep latency testing. Treatment focuses on symptom relief through medication, education, and behavioural modification. Both classic pharmacological treatments as well as newer options have significant problems, especially because of side effects and abuse potential. Novel modalities are being examined to expand options for treatment.

Narcolepsy: Clinical Feature, Diagnosis and Treatment / 수면정신생리

Narcolepsy is a central neurologic system disease. It begins early in life with disabling symptoms including excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucination and nocturnal sleep fragmentation. Patient with typical symptoms of narcolepsy is diagnosed by objective data from nocturnal polysomnography and multiple sleep latency tests. Narcolepsy is controlled with various medications. Nowadays, modafinil with favorable side effects profiles compared with traditional stimulant is mainly used. Gamma hydroxyl butyrate is effective in cataplexy. Cataplexy is also controlled with antidepressant such as Venlafaxine, SSRI, and TCA. As the knowledge of pathophysiology of narcolepsy expands, new treatment including immunological method, application of hypocretin and histamine systems have been tried.

HLA-DQB1 Allele and Hypocretin in Korean Narcoleptics with Cataplexy

Cataplexy is one of the most pathognomonic symptoms in narcolepsy. This study was designed to investigate the frequency of the HLA-DQB1 allele and cerebrospinal fluid (CSF) hypocretin levels in Korean narcoleptics with cataplexy as compared with those who do not have cataplexy. Seventy-two narcoleptics were selected based on polysomnography and multiple sleep latency test as well as their history and clinical symptoms at Sleep Disorders Clinic. The patients were divided into a narcolepsy with cataplexy group (n=56) and a narcolepsy without cataplexy group (n=16). All patients were subjected to HLA typing to determine the frequency of DQB1 allele and to spinal tapping to measure the level of CSF hypocretin. In cataplexy-positive patients, as compared with cataplexy-negative patients, the frequency of HLA-DQB1*0602 was found to be significantly high (89.3% vs. 50.0%) (p=0.003). On the other hand, the frequency of HLA-DQB1*0601 was found to be significantly low (0% vs. 43.8%) (p<0.001). In 48 of 56 cataplexy-positive patients (85.7 %), hypocretin levels were decreased (< or =110 pg/mL). However, only 6 of 16 cataplexy-negative patients (37.5%) exhibited a decreased hyopcretin level (p<0.001). The high frequency of HLA-DQB1*0602, low frequency of HLA-DQB1*0601 and low hypocretin levels in cataplexy-positive groups suggest that cataplexy-positive narcolepsy might be an etiologically different disease entity from the cataplexy-negative.

Comparison of Narcolepsy with Cataplexy and without Cataplexy: Clinical Variables, HLA-DQB1*0602, and Hypocretin / 신경정신의학

OBJECTIVES: Narcolepsy is a sleep disorder, characterized by excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucination. Among these symptoms, cataplexy is one of the most pathognomonic symptoms in narcolepsy. This study was designed to investigate the clinical features, frequency of DQB1*0602 and CSF hypocretin levels in Korean narcoleptics with cataplexy to compare with those who have not cataplexy. METHODS: From August 2003 to July 2005, we selected 72 patients who have narcolepsy confirmed by nocturnal polysomnography and multiple sleep latency test (MSLT) as well as their history and clinical symptoms at Sleep Disorders Clinic of St. Vincent's Hospital, Catholic University of Korea. Patients were divided into 56 cataplexy-positive group (narcolepsy with cataplexy group) and 12 cataplexy-negative group (narcolepsy without cataplexy group). HLA typing was done in all patients for the presence of DQB1*0602, and patients received spinal tapping to measure the level of CSF hypocretin. Clinical variables were examined by semi-structured interview for narcolepsy patients. RESULTS: 1) In cataplexy-positive group, compared with cataplexy-negative group, the frequency of HLA-DQB1*0602 was found to be significantly increased (50 subjects, 89.3% vs. 8 subjects, 50.0%)(p=0.000). 2) In 48 out of 56 cataplexy-positive patients (85.7%), hypocretin levels were decreased (< or =110 pg/ml) or were below the detection limit of assay (<40 pg/ml). However, only 6 out of 16 cataplexy-negative patients (37.5%) exhibited decreased hyopcretin level. The difference between two groups were statistically significant (p=0.000). 3) Cataplexy-positive group, compared to cataplexy-negative group, reported more frequent hypnagogic hallucinations (36 subjects, 64.3% vs. 4 subjects, 25.0%)(p=0.005). However, there were no significant differences in frequency or severity of daytime sleepiness, sleep paralysis and demographic data. 4. In nocturnal polysomnography and MSLT findings, there were no significant differences in all sleep parameters between two groups. CONCLUSION: Higher frequency of HLA-DQB1*0602, and lower hypocretin levels in cataplexy-positive groups than catapelxy-negatives suggest that narcoleptics with cataplexy might be a etiologically different disease entity from narcoleptics without cataplexy. Additionally, Current criteria prevail for the diagnosis of narcolepsy need to be reclassified according to the presence of cataplexy or not.

A Case of Narcolepsy after Traumatic Brain Injury / 신경정신의학

The authors reported a case and its diagnostic process of post-traumatic narcolepsy which had developed after a head trauma. The 51-years-old patient showed frequent generalized paralytic attack, which was aggravated during stressful situation, diet time, and in front of hospital staffs. During the paralytic attack, consciousness was alert, and he never collapsed to hurt. All laboratory findings including serum potassium level were within normal limit, and also brain imaging studies and electroencephalography revealed no specific abnormal findings. Our clinical impression was a conversion disorder or a malingering at first, but after the detailed history taking and the careful observation, daytime sleep attack and some sleep problems were revealed. Thus nocturnal polysomnography and multiple sleep latency test(MSLT) were performed, and then the authors could diagnose as "narcolepsy". HLA-DR2 typing was negative. After imipramine trial, the frequency and the intensity of attack was dramatically reduced. The authors concluded that narcolepsy should be considered in the differential diagnosis of sleepiness or transient loss of muscle tone after traumatic brain injury.