Symptomatic Narcolepsy/Cataplexy in a Dog with Brainstem Meningoencephalitis of Unknown Origin.

A 4 yr old, intact female cocker spaniel was presented for investigation of acute, progressive lethargy/hypersomnia; vestibular signs; and cataplexy. A narcolepsy-cataplexy episode with associated hypertension and bradycardia was triggered during examination. There was no evidence of arrhythmia on electrocardiography during the episode. Hematology, serum biochemistry, and thoracic and abdominal imaging were unremarkable. MRI of the brain and cerebrospinal fluid analysis were compatible with meningoencephalitis of unknown origin affecting the mesencephalon, pons and rostral medulla oblongata. The dog was started on immunosuppressive treatment with prednisolone and cytosine arabinoside, which was subsequently switched to cyclosporine. Narcolepsy-cataplexy episodes could initially still be triggered by offering food; however, they gradually became shorter and less frequent until they completely subsided along with all other clinical signs after 3 wk. No relapse occurred over a 32 mo follow-up period from the diagnosis. Repeated MRI revealed marked reduction in the lesion size; cerebrospinal fluid analysis revealed no abnormalities. Although very rare, symptomatic narcolepsy/cataplexy can occur in dogs and can be secondary to brainstem encephalitis. Cardiovascular changes can occur in association with narcolepsy/cataplexy and should be considered when dealing with patients presenting with these specific clinical signs.

Narcolepsy and psychosis; case report.

Narcolepsy is an infrequent neurological disorder, included in the catalog of rare diseases. Despite the existenceof precise diagnostic criteria, this entity remains underdiagnosed. It is characterized by excessive daytime sleepiness associated with cataplexy; in some cases, hypnagogic or hypnopompic hallucinations, auditory hallucinations, and/or delusional ideation may appear. The occurrence of psychotic symptoms makes differential diagnosis extremely difficult (narcolepsy, schizophrenia, or both). Furthermore, therapeutic management may be complex, since the treatment of one of the disorders may worsen the other. Here we describe the case of a patient with this rare comorbidity, which illustrates the major difficulties associated to both differential diagnosis and therapeutic management once a definitive diagnosis has been reached.

Late Diagnosis of Narcolepsy With Cataplexy: A Novel Case of Cataplectic Facies Presenting in an Elderly Woman.

None: Cataplectic facies is an unusual feature described in children with narcolepsy and cataplexy. The typical manifestations of cataplectic facies consist of repetitive mouth opening, tongue protrusion, and ptosis. An interesting observation is that the usual emotional triggers associated with cataplexy such as laughter and joking are not always present, thus hampering diagnosis of the underlying syndrome. Cataplectic facies is thought to be a phenomenon observed in the early stages of narcolepsy type 1 and is thought to disappear by the time the patient reaches puberty. We present a unique case of an elderly woman with narcolepsy type 1 demonstrating cataplectic facies. The novel circumstances of this case highlight that facial cataplexy can present later in life, in contrast with previous descriptions that report resolution of cataplectic facies before puberty. Wider recognition of these features throughout the life course may aid in accurate diagnosis and thereby ensure swift access to appropriate treatment.

Status Cataplecticus Following Abrupt Withdrawal of Clomipramine

Presentation This is a case of a 31 year old gentleman who suffered an attack of status cataplecticus following abrupt withdrawal of clomipramine. Diagnosis Clomipramine was temporarily discontinued in order to confirm a suspected diagnosis of narcolepsy using Multiple Sleep Latency Testing. This precipitated an episode of status cataplecticus which resolved with re-introduction of therapy. A diagnosis of narcolepsy was later confirmed with undetectable levels of hypocretin/orexin in the CSF. Treatment Re-introduction of clomipramine led to resolution of status cataplecticus. The patient now remains stable with regards to his cataplexy on clomipramine 30mg. Discussion There have been a total of 4 case reports of status cataplecticus following withdrawal of antidepressant therapy. In all cases, reintroduction of anti-cataplectic therapy led to resolution of attacks. The abrupt discontinuation of an SSRI is believed to precipitate cataplexy attacks due to reduction in noradrenergic tone.

Thinking outside the box: cataplexy without narcolepsy.

Cataplexy is a transient loss of muscle tone that can be triggered by emotions such as laughter, excitement or fear. Other causes of cataplexy include Niemann-Pick type C Disease, Angelman Syndrome, Norrie Disease, Prader-Willi Syndrome. In addition, cataplexy can be a side effect of several drugs (eg, lamotrigine, clozapine, and gamma-hydroxybutyrate). Yet, the most prevalent causes of cataplexy without narcolepsy are rare genetic diseases; which explains why cataplexy is classically linked to narcolepsy. Therefore, it is essential disconnecting cataplexy from narcolepsy especially in pediatric population and after use of a few medications. In this review, we described few conditions of cataplexy not related to narcolepsy. We performed a review of literature (MEDLINE and EMBASE database), without limited date or publication restrictions.

The spectrum of REM sleep-related episodes in children with type 1 narcolepsy.

Type 1 narcolepsy is a central hypersomnia due to the loss of hypocretin-producing neurons and characterized by cataplexy, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. In children, close to the disease onset, type 1 narcolepsy has peculiar clinical features with severe cataplexy and a complex admixture of movement disorders occurring while awake. Motor dyscontrol during sleep has never been systematically investigated. Suspecting that abnormal motor control might affect also sleep, we systematically analysed motor events recorded by means of video polysomnography in 40 children with type 1 narcolepsy (20 females; mean age 11.8 ± 2.6 years) and compared these data with those recorded in 22 age- and sex-matched healthy controls. Motor events were classified as elementary movements, if brief and non-purposeful and complex behaviours, if simulating purposeful behaviours. Complex behaviours occurring during REM sleep were further classified as 'classically-defined' and 'pantomime-like' REM sleep behaviour disorder episodes, based on their duration and on their pattern (i.e. brief and vivid-energetic in the first case, longer and with subcontinuous gesturing mimicking daily life activity in the second case). Elementary movements emerging either from non-REM or REM sleep were present in both groups, even if those emerging from REM sleep were more numerous in the group of patients. Conversely, complex behaviours could be detected only in children with type 1 narcolepsy and were observed in 13 patients, with six having 'classically-defined' REM sleep behaviour disorder episodes and seven having 'pantomime-like' REM sleep behaviour disorder episodes. Complex behaviours during REM sleep tended to recur in a stereotyped fashion for several times during the night, up to be almost continuous. Patients displaying a more severe motor dyscontrol during REM sleep had also more severe motor disorder during daytime (i.e. status cataplecticus) and more complaints of disrupted nocturnal sleep and of excessive daytime sleepiness. The neurophysiological hallmark of this severe motor dyscontrol during REM sleep was a decreased atonia index. The present study reports for the first time the occurrence of a severe and peculiar motor disorder during REM sleep in paediatric type 1 narcolepsy and confirms the presence of a severe motor dyscontrol in these patients, emerging not only from wakefulness (i.e. status cataplecticus), but also from sleep (i.e. complex behaviours during REM sleep). This is probably related to the acute imbalance of the hypocretinergic system, which physiologically acts by promoting movements during wakefulness and suppressing them during sleep.

Assessing sleepiness and cataplexy in children and adolescents with narcolepsy: a review of current patient-reported measures.

OBJECTIVE: The objective of this study was to review patient-reported outcome measures assessing excessive daytime sleepiness (EDS) or cataplexy in children or adolescents to determine their usefulness and limitations in pediatric narcolepsy assessment. METHODS: Searches were performed in Embase and Medline for pediatric measures of EDS and cataplexy that are either patient- or proxy-reported, and searches of http://www.clinicaltrials.gov/ were conducted for studies in narcolepsy that included at least one patient-reported measure. Further review was performed if sleepiness questionnaires (child or proxy-reported), sleep questionnaires that may contain sleepiness questions, proxy-reported child behavior questionnaires, or information on cataplexy measures were mentioned. RESULTS: All self-reported cataplexy questionnaires from among 27 citations were study-specific diaries and were not identifiable as a recognized validated questionnaire. For EDS, 118 of 401 abstracts were further reviewed and the names of 21 questionnaires identified, of which eight questionnaires did not return additional citations of their validation. The Epworth Sleepiness Scale (ESS) or a modified version was the most frequently used measure of EDS. Although all measures were associated with limitations for use in the pediatric population, the ESS has been successfully used in adolescents and was deemed readily amenable to further modification for children. CONCLUSIONS: There remains a dearth of validated measures for assessing EDS and cataplexy in children and adolescents with narcolepsy. The need for these measures may be filled by modification or adaptation of existing adult measures; a daily cataplexy diary and the ESS may be readily modified to make them child-friendly with regard to wording and settings, but should still undergo psychometric validation.

Narcolepsy.

Narcolepsy is a chronic sleep disorder that has a typical onset in adolescence and is characterized by excessive daytime sleepiness, which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2), both of which have similar clinical profiles, except for the presence of cataplexy, which occurs only in patients with narcolepsy type 1. The pathogenesis of narcolepsy type 1 is hypothesized to be the autoimmune destruction of the hypocretin-producing neurons in the hypothalamus; this hypothesis is supported by immune-related genetic and environmental factors associated with the disease. However, direct evidence in support of the autoimmune hypothesis is currently unavailable. Diagnosis of narcolepsy encompasses clinical, electrophysiological and biological evaluations, but simpler and faster procedures are needed. Several medications are available for the symptomatic treatment of narcolepsy, all of which have quite good efficacy and safety profiles. However, to date, no treatment hinders or slows disease development. Improved diagnostic tools and increased understanding of the pathogenesis of narcolepsy type 1 are needed and might lead to therapeutic or even preventative interventions.

Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy. METHODS: For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045. FINDINGS: The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001). Treatment-related adverse events were significantly more common in the pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; p=0·048). There were no serious adverse events, but one case of severe nausea in the pitolisant group. The most frequent adverse events in the pitolisant group (headache, irritability, anxiety, and nausea) were mild or moderate except one case of severe nausea. No withdrawal syndrome was detected following pitolisant treatment; one case was detected in the placebo group. INTERPRETATION: Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options. FUNDING: Bioprojet, France.

Pituitary Macrotumor Causing Narcolepsy-Cataplexy in a Dachshund.

Familial narcolepsy secondary to breed-specific mutations in the hypocretin receptor 2 gene and sporadic narcolepsy associated with hypocretin ligand deficiencies occur in dogs. In this report, a pituitary mass is described as a unique cause of narcolepsy-cataplexy in a dog. A 6-year-old male neutered Dachshund had presented for acute onset of feeding-induced cataplexy and was found to have a pituitary macrotumor on magnetic resonance imaging (MRI). Cerebral spinal fluid hypocretin-1 levels were normal, indicating that tumor effect on the ventral lateral nucleus of the hypothalamus was not the cause of the dog's narcolepsy-cataplexy. The dog was also negative for the hypocretin receptor 2 gene mutation associated with narcolepsy in Dachshunds, ruling out familial narcolepsy. The Dachshund underwent stereotactic radiotherapy (SRT), which resulted in reduction in the mass and coincident resolution of the cataplectic attacks. Nine months after SRT, the dog developed clinical hyperadrenocorticism, which was successfully managed with trilostane. These findings suggest that disruptions in downstream signaling of hypocretin secondary to an intracranial mass effect might result in narcolepsy-cataplexy in dogs and that brain MRI should be strongly considered in sporadic cases of narcolepsy-cataplexy.

Post Tick-Borne Encephalitis Virus Vaccination Narcolepsy with Cataplexy.

STUDY OBJECTIVES: Narcolepsy with cataplexy (NC) is a chronic neurological disorder thought to result from an altered immune response based on a genetic predisposition coupled with environmental factors. Pandemrix vaccination has been reported to increase the risk of narcolepsy. We aimed at identifying other vaccines associated with the onset of narcolepsy. METHODS: Case series and retrospective database study. RESULTS: We identified four cases of NC following a tick-borne encephalitis (TBE) vaccination with FSME Immun. Additional four cases could be detected in the database of the Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines in Germany. CONCLUSIONS: Our findings implicate TBE vaccination as a potential additional environmental factor for the development of NC and add additional evidence for an immunological mechanism in the pathogenesis of the disease.

Post-H1N1 Flu Vaccination Narcolepsy in Switzerland: A Retrospective Survey in the 30 Sleep-Certified Swiss Centers.

Narcolepsy-cataplexy is a sleep-wake disorder and suggested to be immune-mediated, involving genetic and environmental factors. The autoimmune process eventually leads to a loss of hypocretin neurons in the lateral hypothalamus. Epidemiological studies in several countries proved an increased incidence of narcolepsy after H1N1 flu vaccination and infection. This survey in 30 sleep centers in Switzerland led to the identification of 9 H1N1-vaccinated children and adults as newly diagnosed narcolepsy. Clinical features included the abrupt and severe onset of sleepiness, cataplexy and sleep fragmentation.

Sleep assessments for a mild traumatic brain injury trial in a military population.

Baseline sleep characteristics were explored for 71 U.S. military service members with mild traumatic brain injury (mTBI) enrolled in a post-concussive syndrome clinical trial. The Pittsburgh Sleep Quality Index (PSQI), sleep diary, several disorder-specific questionnaires, actigraphy and polysomnographic nap were collected. Almost all (97%) reported ongoing sleep problems. The mean global PSQI score was 13.5 (SD=3.8) and 87% met insomnia criteria. Sleep maintenance efficiency was 79.1% for PSQI, 82.7% for sleep diary and 90.5% for actigraphy; total sleep time was 288, 302 and 400 minutes, respectively. There was no correlation between actigraphy and subjective questionnaires. Overall, 70% met hypersomnia conditions, 70% were at high risk for obstructive sleep apnea (OSA), 32% were symptomatic for restless legs syndrome, and 6% reported cataplexy. Nearly half (44%) reported coexisting insomnia, hypersomnia and high OSA risk. Participants with post-traumatic stress disorder (PTSD) had higher PSQI scores and increased OSA risk. Older participants and those with higher aggression, anxiety or depression also had increased OSA risk. The results confirm poor sleep quality in mTBI with insomnia, hypersomnia, and OSA risk higher than previously reported, and imply sleep disorders in mTBI may be underdiagnosed or exacerbated by comorbid PTSD.

Environmental factors in the development of narcolepsy with cataplexy. A case-control study.

INTRODUCTION: Epidemiological studies suggest the importance of environmental factors in the etiology of narcolepsy-cataplexy in genetically predisposed subjects. AIM: To assess the role of environmental factors in the development of narcolepsy-cataplexy, using a case-control design with control subjects being matched for ethnicity and age. PATIENTS AND METHODS: All patients were recruited through two outpatient clinics at the community of Madrid, ant the diagnosis of narcolepsy fulfilled the criteria of the International Classification on Sleep Disorders-2005. A questionnaire, including 54 environmental psychological stressor life events and 42 infectious diseases items, was administered to 54 patients. We specifically assessed the stressful factors and infectious diseases that occurred in the year preceding the onset of the first symptom of narcolepsy (excessive daytime sleepiness and/or cataplexy). The same questionnaire was administered to 84 control subjects recruited from non-related family members of the same community. RESULTS: Fifty four patients (55.6% males) answered the questionnaire, The mean age at onset of the first symptom was 21.6 ± 9.3 years, and the mean age at diagnosis was 36.5 ± 12.4 years. The main finding in narcoleptic patients as compared to control subjects was major changes in the 'number of arguments with partner, family, or friends' (odds ratio: 5.2; 95% confidence interval: 1.8-14.5). This can be interpreted as having a protective function and it suggests that psychological mechanisms are present since the beginning of the disease. As for the infectious factors, chickenpox was the most frequently reported. No significant differences were found in terms of total numbers of stress-related and infectious factors between cases and controls. CONCLUSION: Prospective studies regarding the interaction between environmental and genetic factors are warranted.

TITLE: Factores ambientales en la etiologia de la narcolepsia-cataplejia. Estudio de casos y controles de una serie.Introduccion. Los estudios epidemiologicos subrayan la importancia de los factores ambientales en la etiologia de la narcolepsia con cataplejia en pacientes geneticamente predispuestos. Objetivo. Evaluar el papel de los factores ambientales en la etiologia de la narcolepsia-cataplejia utilizando un diseño de casos y controles comparados por edad y etnia. Pacientes y metodos. Todos los pacientes fueron diagnosticados en nuestras unidades de sueño, segun los criterios de la Clasificacion Internacional de los Trastornos del Sueño de 2005. Utilizamos un cuestionario consistente en 54 preguntas relacionadas con acontecimientos psicologicos estresantes y 42 enfermedades infecciosas en 54 pacientes. Evaluamos especificamente la presencia de factores estresantes y/o infecciosos en el año previo al comienzo del primer sintoma de narcolepsia-cataplejia (somnolencia excesiva diurna y/o cataplejia). El mismo cuestionario se administro a 84 controles, miembros de la misma comunidad, sin relacion de parentesco. Resultados. Respondieron el cuestionario 54 pacientes (55,6%, hombres) (edad media del primer sintoma: 21,6 ± 9,3 años; edad media del diagnostico: 36,5 ± 12,4 años) y 84 controles. El principal hallazgo fue un cambio importante en el 'numero de discusiones con la pareja, la familia o los amigos' (odds ratio: 5,2; intervalo de confianza al 95%: 1,8-14,5) en los narcolepticos, lo que sugiere que los mecanismos psicologicos estan presentes desde el comienzo de la enfermedad con una funcion protectora. La varicela fue el factor infeccioso mas frecuente. No se obtuvieron diferencias significativas en el numero de factores psicologicos estresantes e infecciosos entre los pacientes narcolepticos y los controles. Conclusion. Estudios prospectivos epidemiologicos en series de individuos susceptibles geneticamente estan justificados para aclarar la implicacion de los factores ambientales en la etiopatogenia de la narcolepsia-cataplejia.

Dramatic Cataplexy Improvement Following Right Parietal Surgery.

This is the case of a 34-year-old woman with severe narcolepsy with cataplexy who experienced a dramatic reduction in cataplexy symptoms after resection of a right parietal astrocytoma. The patient underwent detailed neurological exam, neuropsychological testing, polysomnography and multiple sleep latency testing following surgery.

Successful treatment of cataplexy in patients with early-infantile Niemann-Pick disease type C: use of tricyclic antidepressants.

Cataplexy is a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions such as anger, laugh, humor or surprise and it is considered to represent the physiologic atonia of rapid eye movement sleep. On the other hand, Niemann-Pick type C is a neurodegenerative lysosomal storage disease, characterized by the accumulation of cholesterol and glycosphingolipids. Cataplexy is a relatively specific and common neurologic sign seen in almost 50% of all patients with Niemann-Pick type C. The aim of this report is to demonstrate the successful treatment of cataplexy with the use of a tricyclic antidepressant imipiramine, in two patients between the ages 6-9, with mild to moderate mental retardation, molecularly diagnosed as Niemann-Pick type C 1 and currently under miglustat treatment and to discuss the possible mechanisms of drug action in the light of cataplexy and Niemann-Pick type C pathophysiology.

Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset.

Sleep and behavioral monitoring of young mice is necessary for understating the progress of symptoms in congenital and acquired diseases associated with sleep and movement disorders. In the current study, we have developed a non-invasive sleep monitoring system that identifies wake and sleep patterns of newborn mice using a simple piezoelectric transducer (PZT). Using this system, we have succeeded in detecting age-dependent occurrences and changes in sleep fragmentation of orexin/ataxin-3 narcoleptic mice (a narcoleptic mouse model with postnatal hypocretin/orexin cell death) across the disease onset. We also detected REM sleep/cataplexy patterns (i.e., immobility with clear heartbeat [IMHB] signals due to the flaccid posture) by the PZT system, and found that sudden onset of REM sleep-like episodes specifically occur in narcoleptic, but not in wild type mice, suggesting that these episodes are likely cataplexy. In contrast, gradual onset of IMHB likely reflects occurrence of REM sleep. In summary, we have shown that the PZT system is useful as a non-invasive sleep and behavior monitoring system to analyze the developmental aspects of sleep and movement disorders in mice models.

Pharmacological management of narcolepsy and cataplexy in pediatric patients.

Narcolepsy is a neurological disorder frequently occurring from childhood and persisting through adolescence and adulthood. Individuals suffering from narcolepsy exhibit excessive daytime somnolence, sleep attacks, cataplexy, dysomnia, metabolic perturbations including weight gain, and problems in social interaction and academic performance. The prevalence of narcolepsy in childhood is not known but can be estimated from adult studies to be greater than 20-60 per 100,000 in Western countries. The 2009 (A) H1N1 vaccination campaign led to an increase of narcoleptic cases both in children and in adults, supporting the autoimmune hypothesis of the disease. This article focuses on the epidemiology, etiology, and particularities of treatment in pediatric narcolepsy and details the effects of the drugs used to treat this condition, including recent trends in the field. Future therapeutic directions are also discussed. At present, medications used to treat children or adolescents have shown efficacy mostly based on clinical experience, given the lack of level 1 evidence-based studies in the pediatric population. Therefore, most compounds used in adult narcolepsy to target clinical symptoms such as wake-promoting or anticataplectic agents are prescribed off-label in pediatric patients. Published research shows the benefit of drug therapy for narcoleptic children, but these must be dispensed with caution in the absence of well conducted clinical trials.