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12% of night nurses surveyed claimed to have suffered from a totally incapacitating paralysis that may be related to sleep paralysis, and contribute to impaired levels of safety on the night shift. The incidence of this paralysis is shown to be age-related, largely confined to the early hours of the morning, and to increase over consecutive night shifts.
Narcolepsy is characterized by excessive sleepiness and episodes of cataplexy brought on by emotional excitation. Cataplexy and sleep paralysis have been hypothesized to be produced by the triggering during waking of brain stem cholinergic mechanisms normally acting to induce atonia in REM sleep. We hypothesized that narcoleptics have an abnormal number of LDT and/or PPN cholinergic neurons. A comparison was made of cholinergic cell numbers in the brain stems of normal and narcoleptic canines. Cholinergic neurons were identified by NADPH-diaphorase histochemistry. We found increased numbers of cholinergic neurons at the R6-R7 level of the LDT and PPN in narcoleptic canines. This abnormality can explain alterations in cholinergic receptor number, acetylcholine release, and the occurrence of cataplexy and sleep paralysis that characterize narcolepsy.
A new antodepressant drug, clomipramine hydrochloride, closely related to imipramine hydrochloride, was used to treat four patients suffering from cataplexy, sleep paralysis, and hypnagogic hallucinations. Attacks of cataplexy were associated with rapid-eye-movement (REM) electroencephalographic patterns. Cloripramine, in doses of 25 to 75 mg/day, completely stopped all attacks of cataplexy, sleep paralysis, and hypnagogic hallucinations within 48 hours of initial therapy. The patients have been free of symptoms for periods of 10 to 21 months. Side effects included impotence in the male patients, but no hematologic, cardiovascular, hepatic, or renal toxic effects were observed. Available evidence suggests that such drugs inhibit those brain stem systems that control the toxic components of REM sleep.
A questionnaire survey has been made of the life effects of narcolepsy in 180 patients, 60 each from North American, Asian and European populations, with 180 similarly distributed age and sex matched controls. Life-effects were attributed by the patients to the primary symptoms of excessive daytime drowsiness, sleep attacks, cataplexy, vivid hypnagogic hallucinations and sleep paralysis, and also to other frequent symptoms such as visual problems (blurring, diplopia) and memory impairment. Occupational problems were prevalent (over 75%) and included statistically significant deleterious effects upon performance, promotion, earning capacity, fear of or actual job loss and increased disability insurance. Driving was greatly affected and patients fell asleep at the wheel more frequently (66%), had near or actual accidents from drowsiness or falling asleep at the wheel (67%), and could experience cataplexy (29%) or sleep paralysis (12%) while driving. Work or home accidents attributed to sleepiness or sleep (49%) or related to smoking (49%) were much more common in patients. There were also deleterious effects on education, recreation and personality related to disease. Narcolepsy can produce a variety of life-effects probably more serious and pervasive than, for instance, those of epilepsy, therefore emphasizing the importance of early diagnosis and treatment.
The authors examined HLA antigens in 124 narcoleptics. In addition to narcolepsy, 122 patients suffered also from cataplexy. The two patients without cataplexy suffered also from sleep paralysis and hypnagogic hallucinations. These two symptoms were also present in many of the other patients. HLA group DR2 was found in 120 patients including all six symptomatic cases. In four patients HLA DR2 was not present. Two of these were fully pronounced narcolepsy-cataplexy cases whereas the two other did not suffer from cataplexy. Since several other cases with negative DR2 have already been published it is necessary to admit the existence of DR2-negative narcolepsy, albeit very rare. Among 5 patients with isolated sleep paralysis HLA DR2 was present in one familial and 1 sporadic case. The authors further discuss some aspects of the classification of narcolepsies in the light of recent HLA studies as well as their delimitation from idiopathic hypersomnia.
STUDY OBJECTIVES: The objectives of this study were to compare severity and clinical presentation for narcolepsy-cataplexy across various ethnic groups. A large sample of narcoleptic patients was also used to further describe symptomatology and natural history for this sleep disorder. DESIGN: Retrospective review of clinical data ascertained from the Stanford Sleep Inventory, polysomnography and MSLT data, as well as clinical notes. Ethnicity was narrowly defined as African (Black) Americans, Caucasians, Asians, and Latinos when both parents and the subject identified with a given ethnic group. SETTING: N/A. PARTICIPANTS: We compared the severity and clinical presentation of narcolepsy in 64 African Americans, 353 Caucasians, 32 Asians, 26 Latinos, and 9 subjects of mixed ethnicity. Subjects were recruited through the Stanford center for narcolepsy research. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A striking similarity in symptomatology, age of onset, and disease severity was found across ethnic groups. Mean age of onset for sleepiness, hypnagogic hallucinations, sleep paralysis and cataplexy were 19.20, 19.50, 20.11 and 23.02 years old. We also found that narcoleptic patients have slightly but significantly elevated body mass index relative to normative data (106.6% of matched controls, p<0.005) and are born slightly more frequently during the month of March. A tight correlation between our previously validated cataplexy scale and DQB1*0602 positivity was observed. Two thirds of patients reported having cataplexy with laughing, 92% of those being DQB1*0602 positive independent of ethnicity. CONCLUSIONS: These results confirm the similarities in clinical presentation and natural history of narcolepsy-cataplexy in a large number of patients of various ethnic groups and cultural backgrounds.
A randomised, double-blind, placebo-controlled study of L-tyrosine was done in ten subjects with narcolepsy and cataplexy. Of twenty-eight visual analogue scales rating mood and arousal, the subjects' ratings in the tyrosine treatment (9 g daily) and placebo periods differed significantly for only three (less tired, less drowsy, more alert). Ratings of daytime drowsiness, cataplexy, sleep paralysis, night-time sleep, overall clinical response, and measurements of multiple sleep latency and tests of speed and attention did not differ significantly between tyrosine and placebo periods. Dietary supplementation with tyrosine 9 g daily for 4 weeks seems to have a mild stimulant action on the central nervous system but this effect is not clinically significant in the treatment of the narcoleptic syndrome.
CLINICAL DATA: Narcolepsy is a poorly known disease, though not exceptional, with a prevalence of 25 to 35 per 100,000 according to various surveys. Its onset can be anytime from childhood to the fifties with a peak in the second decade. It is characterized by two cardinal symptoms, irresistible sleep episodes and cataplexy or sudden loss of muscle tone triggered by emotional situations. The other symptoms, referred to as accessory due to their inconstancy, are hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Its diagnosis relies on the identification of the cardinal symptoms. Laboratory tests are required to confirm the diagnosis before initiation of a life-long treatment. Theses test include: all-night and daytime polysomnography documenting sleep-onset REM periods, HLA typing, showing the association with HLA DQB1*0602, and, in unclear cases only, measurement of cerebro-spinal fluid (CSF) hypocretine-1 showing values below 110pg/ml, highly specific of narcolepsy with cataplexy. Pathophysiology owes a lot to the existence of a natural canine model, the narcoleptic dog. Irresistible sleep episodes and cataplexy exhibit different pharmacological control, the former depending on dopaminergic systems and the latter on noradrenergic systems. The most remarkable findings of the last twenty years are the close association with HLA DQB1*0602, the identification of a mutation of hypocretin receptor 2 in the narcoleptic dog and the absence of CSF hypocretin-1 in 90% of patients. An autoimmune mechanism is suggested but not evidenced. THREE-FOLD TREATMENT: First line treatment of irresistible sleep episodes in modafinil, Cataplexy or tricyclic antidepressants or sodium oxybate, and disturbed nocturnal sleep by hypnotics or sodium oxybate. Current therapeutic research is oriented towards hypocretin agonists and immunosuppressors.
STUDY OBJECTIVES: Narcolepsy is a neurological disorder whose clinical features include excessive daytime sleepiness, hypnagogic hallucinations, cataplexy, sleep paralysis, and disrupted nocturnal sleep. It has been shown that there may be quite a long interval between the onset of symptoms, and the correct diagnosis. We tested the hypothesis that given their severe symptomatology, these patients would have been diagnosed more often with a variety of psychiatric and neurologic conditions than controls in the year prior to confirmation of their narcolepsy diagnosis. DESIGN: Using the Province of Manitoba Health database, we compared the diagnoses made in the year prior to initial sleep disorder center evaluation of 77 patients with narcolepsy (33 males, 44 females) and 1,155 matched control subjects from the general population. SETTING: Sleep disorders center in University-based teaching hospital PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients were much more likely than controls to be diagnosed with mental disorders (Odds ratio (OR) = 4.0645; 95% confidence limit (CL) = 2.4671-6.6962; p<0.0001) and nervous system disorders (OR= 5.0495; CL = 3.0606 -8.3309; p<0.0001) and there was a trend towards more injuries in these patients (OR =1.6316; CL = 0.9857-2.7007; p=0.0514). We found that cases were statistically much more likely than controls to have received a diagnosis for neurotic disorders (17% of cases), depression (16%), personality disorders (3%) and adjustment reaction (4%). Although the cases had twice as many doctor visits as the controls (9.3 +/- 0.97 (sem) vs. 4.8 +/- 0.17 p<0.0001), only 38% of them had received a diagnosis of narcolepsy in the year prior to sleep specialist evaluation. Neurologists had the highest "success rate" for correct diagnosis: neurologists diagnosed narcolepsy in 55% of the cases they had seen. The other medical practitioners diagnosed narcolepsy in a much smaller percentage of the cases they had seen: 23.5% for internists (excluding neurologists), 21.9% for general practitioners, 11.1% for psychiatrists, and 0% for pediatricians. CONCLUSIONS: In the year prior to documentation of narcolepsy in a sleep disorders center, patients with narcolepsy were diagnosed with a wide variety of mental and neurologic disorders. Our findings are supportive of either the coexistence of these disorders in narcolepsy patients or a high frequency of missed diagnosis by their clinicians. The latter may help explain the very long interval between onset of symptoms and correct diagnosis.
Narcolepsy is a disabling disorder characterised by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Traditionally, a wide variety of substances are used in the symptomatic pharmacological treatment of narcolepsy. Several generally more-tolerated substances have been added to the therapeutic repertoire after extensive testing in large patient populations during recent years. This review addresses the state-of-the-art knowledge about the pharmacological treatment of narcolepsy along with the personal view of the authors. The recent discovery that narcolepsy is caused by deficient hypocretin (orexin) transmission opens a perspective on causal therapy.
A mutation in the HCRT locus was proved in 18-yrs old male suffering from narcolepsy-cataplexy. He has demonstrated cataplectic attacks (brief spells of head dropping provoked by laughter) as well as imperative sleep in spells of several minutes up to one hour since the age of six months. He has suffered from severe bulimia since five years; later hypnagogic hallucinations, sleep paralysis and unquiet nocturnal sleep accompanied by periodic limb movements appeared. Symptoms are partially controlled with methylphenidate and either imipramine, clomipramine or fluoxetine. Periodic leg movements poorly responded to L-DOPA and clonazepam treatment. He is HLA-DQB1*0602 negative. Repeated MSLT (over 16 years followed-up period) showed extremely short latency with predominant SOREMPs and also nocturnal PSG recordings revealed fragmented sleep with SOREMPs. This case report demonstrates that hypocretin (orexin) mutations in human can produce the full narcolepsy phenotype and validates data recently reported in dog and mouse models suggesting a role for hypocretin (orexin) in the pathophysiology of narcolepsy and the regulation of REM sleep.
The parasomnias comprises a group of disorders that intrude into the sleep process and are not primarily disorders of sleep and wake states per se. These disorders are manifestations of central nervous system activation usually transmitted through skeletal muscle or autonomic nervous system channels (ICSD 1990). The parasomnias are divided into four groups: Arousal disorders (sleepwalking, night terrors, and confusionnal arousal), sleep-wake transition disorders (rhythmic movement disorder, sleep starts), REM sleep parasomnias (nightmares, sleep paralysis, hallucinations, and REM sleep behavior disorders), and other parasomnias (sleeptalking, nocturnal enuresis, and nocturnal bruxism.
Narcolepsy is a potentially invalidating disorder of the sleep and wakefulness structure, characterized by attacks of sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed night sleep. The diagnosis is mainly based on the history. Additional sophisticated examinations, such as nocturnal polysomnography, are primarily indicated to rule out other causes of excessive daytime somnolence. The recently detected high correlation between a certain HLA status and cataplexy has led to new pathogenetic concepts. The primary aim of the therapy is to keep the patient at work rather than attempting a symptom free state. Measures to organize his day with planned naps should precede the use of medication. Besides stimulants against daytime somnolence and tricyclic antidepressants to suppress cataplectic attacks, some new drugs have been administered successfully against the various symptoms of narcolepsy in recent years.
Narcolepsy is a common but underdiagnosed sleep disorder characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep: cataplexy, sleep paralysis and hypnagogogic hallucinations. Sleep onset REM periods (SOREMPs) are diagnostic. Within the last five years the pathogenesis has become clearer: narcolepsy is associated with almost total absence of the neuropeptides hypocretin-1 and -2 in the hypothalamus and CSF. A low level of CSF hypocretin is now recognized as a new diagnostic tool. This review provides updated knowledge of narcolepsy.
Narcolepsy is a syndrome of unknown origin characterized by the irresistible urge to sleep. Other important features are disturbed nocturnal sleep and abnormal manifestations of REM sleep such as cataplexy, sleep paralysis, and abnormal sleep-onset REM periods. Narcolepsy is not a rare condition. With a prevalence between 2 and 10 per 10,000 individuals, it is about as common as multiple sclerosis. Like multiple sclerosis, narcolepsy can be disabling and have profound consequences for job capability, public safety, sense of self-worth, and social image.
The neurophysiologic basis of near death experience (NDE) is unknown. Clinical observations suggest that REM state intrusion contributes to NDE. Support for the hypothesis follows five lines of evidence: REM intrusion during wakefulness is a frequent normal occurrence, REM intrusion underlies other clinical conditions, NDE elements can be explained by REM intrusion, cardiorespiratory afferents evoke REM intrusion, and persons with an NDE may have an arousal system predisposing to REM intrusion. To investigate a predisposition to REM intrusion, the life-time prevalence of REM intrusion was studied in 55 NDE subjects and compared with that in age/gender-matched control subjects. Sleep paralysis as well as sleep-related visual and auditory hallucinations were substantially more common in subjects with an NDE. These findings anticipate that under circumstances of peril, an NDE is more likely in those with previous REM intrusion. REM intrusion could promote subjective aspects of NDE and often associated syncope. Suppression of an activated locus ceruleus could be central to an arousal system predisposed to REM intrusion and NDE.
Three patients had longstanding (37 to 50 years), highly disabling narcolepsy, poorly controlled by treatment. The clinical histories were typical, consisting of sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, disturbed nocturnal sleep, and HLA-DR2 tissue typing. Polygraphic findings confirmed the diagnosis. Neurologic examination, spinal fluid, and evoked potentials were normal. On MRI scanning, all three patients showed overlapping bilateral and symmetric brainstem T2 hyperintensities circumscribed to the ventrolateral aspect of the midrostral pons. The nature of the lesions remains uncertain but their location corresponded to the pontine oral reticular formation, where the neuronal network generating REM sleep is located. This is the first report of MR signal abnormalities in patients with idiopathic narcolepsy and suggests a causal relationship between the disease and the central pontine lesions.
OBJECTIVE: To demonstrate the utility of accurate clinical and electroencephalographic characterization of provoked cataplexy spells in the diagnosis of narcolepsy. METHODS: Four individuals, three with suspected and one with known narcolepsy, were clinically assessed during split-screen, video polysomnographic monitoring sessions after cataplectic events were induced by emotional provocation. RESULTS: The subjects experienced a total of nine cataplectic-like events, one occurring spontaneously (sleep paralysis) in association with a hypnagogic hallucination. During all events, the patients appeared to be sleeping with polysomnographic rapid eye movement sleep patterns, but when questioned they were able to give appropriate verbal responses. The diagnosis of narcolepsy was substantiated in all cases using standard overnight polysomnograms and multiple sleep latency tests. CONCLUSION: The diagnosis of narcolepsy can be greatly enhanced by documenting cataplexy with thorough clinical assessment and demonstration of typical rapid eye movement sleep patterns during provoked spells in the course of polysomnographic monitoring sessions.