A case of upper brainstem infarction developing symptomatic narcolepsy after the administration of anti-convulsant drugs]

A 52-year-old woman, who had ischemic infarction in the ventral upper brainstem due to subarachnoid hemorrhage in October 1986, had recurrent sleep and cataplexy attacks from May 1987. She was receiving valproate and phenytoin daily since 1986. The diagnosis of narcolepsy was made based on the clinical symptoms and EEG findings showing REM sleep during a sleep attack. Both sleep and cataplexy attack increased in parallel with an increase of the dose of anti-convulsant drugs and disappeared immediately after the discontinuation of the treatment. The findings that suggest that the administration of anti-convulsant drug as well as the brainstem vascular lesion was deeply involved in the development of narcolepsy in this case.     

Clinical, behavioural and polysomnographic correlates of cataplexy in patients with narcolepsy/cataplexy

BACKGROUND: Cataplexy is the main motor symptom of narcolepsy/cataplexy and is considered a form of rapid eye movement (REM) sleep motor dyscontrol appearing during wakefulness and elicited by emotions. This study examined the relationship between the frequency of cataplectic attacks in patients with narcolepsy/cataplexy and (a) the clinical and behavioural characteristics of cataplectic attacks, including the emotional tone of trigger events, and (b) the polysomnographic characteristics of daytime sleepiness, nocturnal sleep structure and indices of motor disorders during sleep. METHODS: A consecutive series of 44 first-diagnosed drug-naive patients with narcolepsy/cataplexy, fulfilling the International Classification of Sleep Disorders, 2nd edition (ICSD-2) clinical and polysomnographic diagnostic criteria, were interviewed to estimate the frequency and clinical characteristics of cataplectic attacks and the occurrence of REM sleep behaviour disorder (RBD). All patients also underwent a video-polysomnographic recording to assess their sleep parameters and indices of altered motor control during sleep. RESULTS: Patients were divided into two groups on the basis of the frequency of cataplectic attacks, namely high-frequency (n=30) or low-frequency (n=14) depending on whether they estimated they had more or less than one attack per month. High-frequency patients (with a larger proportion of men) reported attacks more often affecting mainly the head, jaw and shoulder muscles and experienced more events among those listed as possible triggers of attacks. Sixty-one percent of patients reported RBD and 43% had an RBD episode at video-polysomnography regardless of the frequency of cataplectic attacks or gender. Lastly, the frequency of periodic leg movements (PLM) per hour was higher in men than women and increased with age. CONCLUSIONS: Patients with more than one cataplectic attack per month had more frequent involvement of head, jaw and shoulder muscles and were mainly men. The proportions of patients with clinically assessed RBD and an RBD episode documented by video-polysomnography, as well as conspicuous values of PLM per hour, are fairly consistent with those reported in recent small-group studies. Therefore, it seems legitimate to argue that RBD and PLM are nocturnal manifestations intrinsic to narcolepsy/cataplexy and that the gender-related differences in the frequency of attacks and the value of PLM per hour may be indicative of a larger difference in the clinical and polysomnographic characteristics of narcolepsy/cataplexy than hitherto suspected.     

Two cases of childhood narcolepsy mimicking epileptic seizures in video-EEG/EMG

Narcolepsy is characterized by excessive sleepiness, hypnagogic hallucinations, and sleep paralysis, and can occur with or without cataplexy. Here, we report two children with narcolepsy presenting with cataplexy mimicking epileptic seizures as determined by long-term video-electroencephalography (EEG) and electromyography (EMG) monitoring.Case 1 was a 15-year-old girl presenting with recurrent episodes of “convulsions” and loss of consciousness, who was referred to our hospital with a diagnosis of epilepsy showing “convulsions” and “complex partial seizures”. The long-term video-polygraph showed a clonic attack lasting for 15?s, which corresponded to 1–2?Hz with interruption of mentalis EMG discharges lasting for 70–300?ms without any EEG changes. Narcolepsy was suspected due to the attack induced by hearty laughs and the presence of sleep attacks, and confirmed by low orexin levels in cerebrospinal fluid (CSF). Case 2 was an 11-year-old girl presenting with recurrent episodes of myoclonic attacks simultaneously with dropping objects immediately after hearty laughs, in addition to sleep attacks, hypnagogic hallucinations, and sleep paralysis. The long-term video-polygraph showed a subtle attack, characterized by dropping chopsticks from her hand, which corresponded to an interruption of ongoing deltoid EMG discharges lasting 140?ms without any EEG changes. A diagnosis of narcolepsy was confirmed by the low orexin levels in CSF.These cases demonstrate that children with narcolepsy may have attacks of cataplexy that resemble clonic or myoclonic seizures.     

Efficacy of trazodone in narcolepsy

A 25-year-old man with narcolepsy and cataplexy experienced partial relief of symptomatology following administration of methylphenidate. Moreover, the latter caused extreme agitation and aggression. However, administration of the antidepressant agent trazodone resulted in almost complete alleviation of the narcoleptic and cataplectic attacks within 48 h after initiation of therapy. Trazodone, a novel antidepressant agent may be useful in the long-term management of individuals suffering from narcolepsy.     

Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures

The efficacy of gamma-hydroxybutyrate (GHB) versus placebo for treating narcolepsy was evaluated in 20 patients with narcolepsy, 10 men and 10 women, using a double-blind counterbalanced crossover design. Each patient completed a daily sleep-wake log and questionnaire during a 14-day baseline, a 29-day placebo period, a 29-day GHB period (50 mg GHB/kg/night given 25 mg/kg h.s. and 25 mg/kg 3 hr later), and a 6-day washout period after each treatment. Cataplexy frequency was significantly lower during GHB treatment than during placebo treatment (p = 0.022). Compared to baseline values, the number of cataplexy attacks per day declined by 52% and 69% during GHB treatment weeks 1 and 4, respectively. The number of subjective arousals from sleep was less with GHB than with placebo (p = 0.035), and the number of sleep attacks was not significantly different during GHB versus placebo treatment. GHB did not have a significant effect on subjective estimates of sleep onset latency, total sleep time, Stanford Sleepiness Scale ratings at morning wake-up, methylphenidate usage, or the number of naps per day. The results indicate that GHB is efficacious for reducing the frequency of cataplexy attacks and subjective nocturnal arousals in patients with narcolepsy within the first 4 weeks of treatment.     

Narcolepsy-cataplexy in a female dog

Narcolepsy in human beings is a life-long illness afflicting 100,000–150,000 Americans. No current treatment for this neurological disorder is satisfactory and a definitive approach to the disease requires an animal model of narcolepsy. This report summarizes data on a female toy poodle which has a canine form of narcolepsy-cataplexy. At approximately 4 mo of age, the dog presented cataplectic attacks. Physical examination disclosed no systemic factors to account for such atonic episodes. Observation indicated that attacks were frequently partial, involving only the neck musculature and hind legs. However, such attacks could develop into complete cataplexy, causing postural collapse and areflexia, although extrinsic eye muscles and the muscles of respiration were spared. Presentation of food, water, or a plaything were the most frequent elicitors of attacks. During 41 hr of EEG, EOG, and EMG monitoring in conjunction with behavioral observation, the dog exhibited normal polygraphic wakefulness, slow-wave sleep and REM sleep. Unambiguous sleep onset REM periods and cataplectic attacks were also observed. These pathological manifestations are analogous to those characteristic of human narcolepsy. The diagnosis of canine narcolepsy was further confirmed by two negative trials with neostigmine (ruling out myasthenia) and two positive trials with imipramine (cataplexy in human narcolepsy responds to imipramine treatment). The dog will be bred either with a littermate or a similarly afflicted male in an attempt to produce a population of afflicted dogs.     

Successful treatment of narcolepsy with propranolol: a case report.

A patient with severe narcolepsy and cataplexy had been treated with a high dosage of methylphenidate hydrochloride, but the drug was not effective. To relieve the patient's cardiac arrhythmia, which was assumed to be secondary to drug therapy, we withdrew methylphenidate therapy and started propranolol hydrochloride therapy. When the dosage of propranolol was increased to a level consistent with maximum beta-adrenergic receptor blockade, the attacks were eliminated.     

Analysis of onset location,laterality and propagation of cataplexy in canine narcolepsy

Hypocretin deficiency is involved in most cases of human narcolepsy. Although cataplexy is pathognomonic of narcolepsy, mechanisms of induction of cataplexy are largely unknown. Patterns of occurrence of cataplectic attacks (i.e. onset location, laterality, and propagation of attacks) in hypocretin receptor 2-mutated narcoleptic Dobermans were characterized in order to understand the basic mechanism of this abnormal sleep-related atonia. Most cataplexy attacks were bilateral (98%) and were initiated in the hind legs (80%). Progression of attacks was also seen (49%) and atonia during propagation was most often bilateral (94%). Involvement of abnormal inactivation of bilateral pathways to the spinal motoneurones due to a deficiency in hypocretin neurotransmission is suggested in the occurrence of cataplexy.     

Normal levels of cerebrospinal fluid hypocretin-1 and daytime sleepiness during attacks of relapsing-remitting multiple sclerosis and monosymptomatic optic neuritis

There is emerging evidence that multiple sclerosis (MS), the hypothalamic sleep-wake regulating neuropeptide hypocretin-1 (hcrt-1) and the sleep disorder narcolepsy may be connected. Thus, the major pathophysiological component of narcolepsy is lack of hcrt-1. Dysfunction of the hypocretin system has been reported in MS case reports with attacks of hypothalamic lesions, undetectable cerebrospinal fluid (CSF) hcrt-1 and hypersomnia, but not found during remission in small samples. Finally, daytime sleepiness, the major symptom of narcolepsy, is reported in several MS populations, and there are case reports of co-existent narcolepsy and MS. However, it is unknown whether hcrt-1 and daytime sleepiness generally change during MS attacks. We therefore analyzed whether daytime sleepiness (using the Epworth Sleepiness Scale (ESS)) and CSF hcrt-1 levels differed between MS attack and remission, in 48 consecutively referred patients with relapsing-remitting MS (RRMS) or monosymptomatic optic neuritis (MON). Twenty-seven patients were in attack and 21 in remission. ESS was normal both during attacks (5.4 +/- 3.0) and remission (5.8 +/- 2.6), and mean CSF hcrt-1 was normal (456 +/- 41 pg/ml). No statistically significant differences were found between attack and remission. MRI scans revealed no hypothalamic lesions. The results show that the hypocretin system is intact and sleepiness is not typical in RRMS and MON without hypothalamic lesions on MRI.     

Status cataplecticus induced by abrupt withdrawal of clomipramine

Introduction: Cataplexy is one of the main narcoleptic symptoms and is characterized by sudden loss of muscle tone triggered by emotional stimuli while consciousness is mantained. Clomipramine is an effective treatment of cataplexy. Cataplexy that occurs repeatedly for hours or days is referred to as status cataplecticus.Patients: We report three adults with narcolepsy in whom cataplexy was chronically and effectively treated with clomipramine (75-150 mg/day). For diverse reasons, these three patients had an abrupt withdrawal of clomipramine, and after 2-9 days patients showed an invalidant status cataplecticus characterized by a marked increase of the frequency, duration and severity of their cataplectic attacks that were now elicited by mild emotional stimuli. After introduction of anticataplectic agents (clomipramine in two patients and fluoxetine in one patient), status cataplecticus was resolved in less than a week.Conclusion: In patients with narcolepsy, abrupt withdrawal of chronic treatment with clomipramine may be associated with status cataplecticus. This condition may be resolved with the reintroduction of anticataplectic agents.     

The treatment of accessory symptoms in narcolepsy: a double-blind cross-over study of a selective serotonin re-uptake inhibitor (femoxetine) versus placebo

A randomized, double-blind cross-over trial was carried out in 10 patients with narcolepsy to evaluate the effect of 600 mg femoxetine versus placebo. In comparison to placebo, femoxetine treatment resulted in a significant decrease in both the number and severity score of cataplectic attacks per day. There were also significantly fewer attacks of sleep paralysis, whilst the effects on nightmare and hypnogenic hallucinations were minor. The frequency of sleep attacks decreased slightly during femoxetine treatment, but the overall estimated sleep time during the day and excessive daytime sleepiness remained un-affected. An ambulatory sleep recording for 48 h one week after the start of the femoxetine and placebo period showed that femoxetine treatment resulted in a significant decrease in the total time spent in REM sleep. The side-effects of femoxetine were restricted to transient nausea in 2 patients. It is concluded that femoxetine or other selective serotonin reuptake inhibitors may be a useful alternative for narcoleptic patients who experience troublesome side-effects with tricyclic antidepressants.     

A putative link between childhood narcolepsy and obesity

BACKGROUND AND PURPOSE: While there have been anecdotal observations of binge eating in childhood-onset narcolepsy, the possible relationship between increased weight gain and childhood-onset narcolepsy has not been evaluated. PATIENTS AND METHODS: A retrospective, case-control design was used to compare the body mass index (BMI) of 31 narcolepsy children at the time of diagnosis with that of healthy, age- and gender-matched controls. RESULTS: The median BMI in the narcolepsy subjects was 22.93 as compared to that in controls of 20.36 (P=0.001). BMI did not differ significantly between narcolepsy subjects who had received prior psychotropic medications and those who had not. The mean BMI of 22 of 31 narcolepsy subjects who had not received psychotropic medications prior to diagnosis was also significantly higher than that of controls (25.1, SEM 1.53 versus 21.1, SEM 0.56; P=0.008 ). CONCLUSION: The tendency for increased weight gain is intrinsic to childhood narcolepsy and is manifested relatively early in the course of the disorder. Correlation of this finding with hypocretin and leptin metabolism may further understanding of the pathogenesis of narcolepsy.     

Familial narcolepsy

BACKGROUND AND PURPOSE: Narcolepsy is a disease characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness, provoked by an emotional trigger, e.g. laughter), sleep paralysis (isolated loss of muscle tone associated with rapid eye movement [REM] in normal sleep) and hypnagogic-hypnopompic hallucinations (vivid dreaming occurring at the time of sleep onset and awakening that can be difficult to distinguish from reality). MATERIAL AND METHODS: The authors present eleven patients with suspected narcolepsy, who were members of a five-generation family with many cases of episodic excessive daytime sleepiness. Some of them experienced sleep attacks which were occasionally associated with a sudden loss of muscle tone (cataplexy), as well as with sleep paralysis and hypnagogic hallucinations. All probands had magnetic resonance (MR) of the brain performed, along with routine blood tests, EEG, polysomnography, examination of the level of hypocretin in the cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales. RESULTS: Narcolepsy was diagnosed in nine patients. Improvement in their clinical state was observed during the treatment with modafinil.     

Status cataplecticus misdiagnosed as recurrent syncope

A 76-year-old patient, since the age of 45, presented with frequent attacks often triggered by emotional stimuli and characterised by forward head drop and a fall to the ground without loss of consciousness. Clinically these episodes were misinterpreted as pseudoseizures and treated with clomipramine for more than 20 years. In spite of this chronic therapy, during the last year, the attacks presented with a daily recurrence and, moreover, after arbitrary clomipramine withdrawal, they increased in frequency until they became subcontinuous. Videopolygraphic analysis, multiple sleep latency test (MSLT) and human leukocyte antigen (HLA) association studies were suggestive of narcolepsy and the recurrent episodes, diagnosed as status cataplecticus, recovered after citalopram administration.     

Pseudo-narcolepsy: case report.

This report describes the case of a 44-year-old woman presenting to a Sleep and Alertness clinic with symptoms of narcolepsy. The patient had clinical and polysomnographic features of narcolepsy, which disappeared after disclosure of severe psychological stress. Following a discussion of the differential diagnosis of narcolepsy, alternative diagnoses are considered. The authors suggest that the patient had a hysterical conversion disorder, or "pseudo-narcolepsy." Careful inquiry into psychological factors in unusual cases of narcolepsy may be warranted.     

Idiopathic recurring stupor: a case with possible involvement of the gamma-aminobutyric acid (GABA)ergic system.

A patient had recurrent spontaneous episodes of stupor or coma in the absence of toxic, metabolic, or structural brain damage. Ictal electroencephalography showed fast 14 Hz background activity; sleep studies excluded narcolepsy. Flumazenil (Anexate), a benzodiazepine antagonist, promptly resolved the episodes and normalized the electroencephalogram. Radioreceptor binding studies showed the presence of a ligand to the central benzodiazepine receptor in plasma and cerebrospinal fluid during the episodes, suggesting a gamma-aminobutyric acid (GABA)ergic system involvement in the origin of the attacks.     

Degenerative pontine lesions in patients with familial narcolepsy

Background and purposeNarcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness provoked by an emotional trigger, e.g. laughter), sleep paralysis and hypnagogic-hypnopompic hallucinations. Most cases are sporadic; familial narcolepsy contributes to only 1–5% of all cases. While most cases of narcolepsy are idiopathic and are not associated with clinical or radiographic evidence of brain pathology, symptomatic or secondary narcolepsy may occur occasionally in association with lesions caused by tumours, demyelination or strokes of the diencephalon, midbrain, and pons. There are some examples of non-specific brainstem lesions found in magnetic resonance imaging (MRI) in patients with idiopathic narcolepsy.Material and methodsThe authors present eleven patients from a five-generation family with many members who suffer from episodic excessive daytime sleepiness. Narcolepsy was diagnosed in 9 patients. Sleepiness was frequently associated with cataplexy, hypnagogic-hypnopompic hallucinations and sleep paralysis. Improvement in their clinical state was observed during the treatment with modafinil. All probands had MRI of the brain, routine blood tests, EEG, polysomnography, examination of the level of hypocretin in cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales.ResultsIn 9 patients with narcolepsy, decreased thickness of the substantia nigra was found and in six of them degenerative lesions in the pontine substantia nigra were also noticed.ConclusionsThe significance of these changes remains unclear. No data have been published until now concerning the presence of any brain lesions in patients with familial narcolepsy.     

Clinical and sleep laboratory study of narcoleptic symptoms in multiple sclerosis

Seventy white patients with a diagnosis of MS and typed for their HLA-A, B, C, and DR were studied. A clinical interview and a questionnaire were used to evaluate the presence of narcoleptic symptoms. The prevalence of sleep attacks, cataplexy, and sleep paralysis was significantly elevated among these patients. However, no difference was seen between DR2 and non-DR2 subjects with regard to the incidence of narcoleptic symptoms. Nine DR2 patients complaining of both sleep attacks and cataplexy were studied in the sleep laboratory for five consecutive naps, but no polygraphic evidence of narcolepsy was found.     

Methysergide in the treatment of narcolepsy.

Five patients with narcolepsy (four with the allied symptom of cataplexy) were treated with the serotonin antagonist methysergide. All patients had as good control of their sleep attacks while on methysergide therapy as on a control period of dextroamphetamine therapy. The cataplexy was less well controlled by methysergide than by dextroamphetamine, but improved when compared to a period without medication. Two patients developed severe calf claudication while on methysergide.     

REM alpha rhythm: diagnostic for narcolepsy?

SUMMARY: A young man, in whom narcolepsy was subsequently diagnosed, had the simultaneous onset of quadriparesis and a rapid eye movement (REM)-sleep polysomnographic pattern. During this REM-sleep pattern, a waking alpha EEG rhythm, appearing when he was asked to close his eyes, immediately attenuated when he was instructed to open his eyes, after which the REM-sleep pattern persisted. The juxtaposition of REM sleep patterns and reactive alpha rhythms are likely unique to sleep paralysis and may prove valuable in diagnosing narcolepsy.