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PubMed1991

Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.

Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.

Animals↗

PubMed2005

[The neurophysiology of cataplexy].

Cataplexy and excessive daytime sleepiness are the leading symptoms of narcolepsy. Electrophysiological studies in humans do not show a clear association between cataplexy and rapid eye movement (REM) sleep. Even a decrement of the H reflex is not specific for cataplexy and may be caused by unspecific triggers such as coughing. Cholinomimetics, which may induce status cataplecticus, do not influence REM sleep, thus evidencing a REM-independent mechanism. Recent studies demonstrate a lack of the neuropeptide hypocretin in the CSF of narcoleptics. Hypocretin controls wakefulness and the motor and autonomous systems. In hypocretin-1 and -2 knockout mice, sudden stops of motor activity could be observed in emotional situations that were accompanied by sudden shifts from wakefulness to REM sleep and could be terminated by application of anticataplectic medication. The lack of hypocretin not only causes a noradrenergic-cholinergic imbalance in the midbrain but also influences motoneurons directly by juxtacellular hypocretin-containing membranes. Intravenous application of hypocretin in a dog with hypocretin deficiency in the CSF caused a dose-dependent decrease of cataplexies. An understanding of the neuronal mechanisms responsible for cataplexies is essential for the development of new anticataplectic medications.

Animals↗

PubMed1999

Locus coeruleus neurons: cessation of activity during cataplexy.

Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, emotionally significant stimuli. We now report that locus coeruleus neurons cease discharge throughout cataplexy periods in canine narcoleptics. Locus coeruleus discharge rates during cataplexy were as low as or lower than those seen during rapid-eye-movement sleep. Prazosin, an alpha1 antagonist, and physostigmine, a cholinesterase inhibitor, both of which precipitate cataplexy, decreased locus coeruleus discharge rate. Our results are consistent with the hypothesis that locus coeruleus activity contributes to the maintenance of muscle tone in waking, and that reduction in locus coeruleus discharge plays a role in the loss of muscle tone in cataplexy and rapid-eye-movement sleep. Our results also show that the complete cessation of locus coeruleus activity is not sufficient to trigger rapid-eye-movement sleep in narcoleptics.

Adrenergic alpha-Antagonists↗

PubMed1999

Dopamine D3 agonists into the substantia nigra aggravate cataplexy but do not modify sleep [corrected].

We have recently demonstrated that local perfusion of dopaminergic D2/D3 agonists into the ventral tegmental area (VTA) significantly aggravates cataplexy and increases sleep in narcoleptic Dobermans. We further assessed the roles of the mesostriatal dopaminergic system and found that local perfusion of quinpirole and 7-OH-DPAT into the substantia nigra (SN) significantly aggravated cataplexy, while perfusion of a D2/D3 antagonist significantly reduced cataplexy. Neither a D1 agonist nor a D1 antagonist modified cataplexy. SN perfusion of quinpirole did not significantly modify sleep, while VTA perfusion significantly increased the drowsy state. Although autoregulation of the VTA and SN dopaminergic neurons are involved in the regulation of cataplexy, both structures have distinct roles for the regulation of sleep.

Animals↗

PubMed1999

Dopamine D3 agonists into the substantia nigra aggravate cataplexy but do not modify sleep.

Animals↗

PubMed2004

Activity of dorsal raphe cells across the sleep-waking cycle and during cataplexy in narcoleptic dogs.

Cataplexy, a symptom associated with narcolepsy, represents a unique dissociation of behavioural states. During cataplectic attacks, awareness of the environment is maintained, as in waking, but muscle tone is lost, as in REM sleep. We have previously reported that, in the narcoleptic dog, noradrenergic cells of the locus coeruleus cease discharge during cataplexy. In the current study, we report on the activity of serotonergic cells of the dorsal raphe nucleus. The discharge patterns of serotonergic dorsal raphe cells across sleep-waking states did not differ from those of dorsal raphe and locus coeruleus cells recorded in normal rats, cats and monkeys, with tonic discharge in waking, reduced activity in non-REM sleep and cessation of activity in REM sleep. However, in contrast with locus coeruleus cells, dorsal raphe REM sleep-off neurones did not cease discharge during cataplexy. Instead, discharge continued at a level significantly higher than that seen in REM sleep and comparable to that seen in non-REM sleep. We also identified several cells in the dorsal raphe whose pattern of activity was the opposite of that of the presumed serotonergic cells. These cells were maximally active in REM sleep and minimally active in waking and increased activity during cataplexy. The difference between noradrenergic and serotonergic cell discharge profiles in cataplexy suggests different roles for these cell groups in the normal regulation of environmental awareness and muscle tone and in the pathophysiology of narcolepsy.

Action Potentials↗

PubMed1994

Symptomatic cataplexy in pontomedullary lesions.

Cataplexy is a cardinal manifestation of the narcolepsy syndrome. Although symptomatic narcolepsy is well described, isolated cataplexy is extremely rare. We reviewed clinical and radiologic data in two patients with isolated symptomatic cataplexy and associated CNS disease. In an HLA-DR2-positive patient with chronic progressive MS, we confirmed cataplexy by observation of reported spells. MRI revealed diffuse white-matter lesions involving the medial medulla, pons, and subcortical white matter; protriptyline provided symptomatic relief. A second patient with a pontomedullary pilocytic astrocytoma developed infrequent but recurrent cataplectic attacks in association with sleep fragmentation due to nocturnal cough and nausea. MRI revealed an enhancing lesion involving the dorsal pons and medulla. Genetic predisposition and sleep fragmentation may precipitate symptomatic cataplexy in patients with structural pontomedullary lesions.

Adult↗

PubMed1997

HLA DR15 (DR2) and DQB1*0602 typing studies in 188 narcoleptic patients with cataplexy.

Narcolepsy is considered a homogeneous clinical entity when excessive daytime sleepiness and cataplexy are present. Cataplexy is a polymorphic symptom that can be very mild and is thus subjectively defined. The Multiple Sleep Latency Test (MSLT) is widely used as a diagnostic test for narcolepsy. A short mean sleep latency and multiple sleep onset REM periods (SOREMPs) are typically observed in narcoleptic patients. The discovery of a tight association of narcolepsy with HLA class II antigens offers a unique opportunity to explore the respective value of the MSLT or of the presence of clear-cut cataplexy in defining an etiologically homogeneous group of narcoleptic patients. In this study, we carried out HLA typing for DR15(DR2) and DQB1*0602 in 188 narcoleptic patients with cataplexy in three ethnic groups (24 Asians, 61 Blacks, and 103 Caucasians). These results confirm the importance of DQB1*0602 typing rather than DR15 (DR2) typing in Black narcoleptic patients and demonstrate that the presence of clear-cut cataplexy is a better predictor for DQB1*0602 positivity than the presence of abnormal MSLT results.

Asian People↗

PubMed1996

Resolution of partial cataplexy in multiple sclerosis by treatment with weak electromagnetic fields.

Cataplexy, an ancillary symptom of narcolepsy, involves the sudden loss of muscle tone without altered consciousness usually brought on by sudden excitement or emotional influence and extreme exertions (Guilleminault et al., 1974; Parks et al., 1974; Guilleminault, 1976; Aldrich, 1992; 1993; Scrima, 1981; Baker, 1985). Attacks of generalized cataplexy produce complete atonic, areflexic partial or complete paralysis of striated muscles commonly involving the leg muscles resulting in collapse of the knees and falling while milder forms often termed partial cataplexy may manifest by sagging of the face, eyelid, or jaw, dysarthria, blurred vision, drooping of the head, weakness of an arm or leg, buckling at the knees, or simply a momentary sensation of weakness that is imperceptible to observers (Guilleminault, 1976; Aldrich, 1993). The duration of cataplexy is usually a few seconds, although severe episodes can last several minutes and rarely several hours or days in the case of "status cataplecticus" (Parkes et al., 1974; Guilleminault, 1976; Billiard & Cadilhac, 1985; Aldrich, 1992; 1993). This report concerns a 51 year old man with chronic progressive multiple sclerosis who exhibited daily episodes of partial cataplexy which resolved within 3 weeks after he received treatment with picotesla electromagnetic fields.

Brain↗

PubMedDate not supplied

Cataplexy treated with escitalopram--clinical experience.

BACKGROUND: Narcolepsy with cataplexy is a debilitating sleep disease of which some symptoms can be treated with antidepressants. The antidepressant escitalopram is considered the most specific serotonin reuptake inhibitor. PATIENTS AND METHODS: Ten patients (5 men and 5 women, age range 18-77 years) suffering from narcolepsy with cataplexy occurring at least weekly were treated with escitalopram 5 or 10 mg a day for 28-98 days. These patients were barred from taking any drugs influencing cataplexy and also had no other diseases affecting sleep or vigilance. RESULTS: The mean number of cataplexies per week in 8 compliant patients declined significantly from 6.7 (+/-SD=7.2) to 0.3 (+/-0.6), P=0.02 (Sign test). Cataplexy completely disappeared in 6 patients. Subjective daytime sleepiness, power of concentration, quality of night sleep and mood remained unchanged. During the treatment, two patients had ejaculation disturbances. Two patients withdrew from the therapy (one because of ejaculation disturbance, the other for unknown reason). CONCLUSION: Escitalopram proved to have anticataplectic effects in this small-scale open-label study.

Adolescent↗

PubMed2000

Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy.

The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of CG-3703 (16 mg/kg) significantly reduced cataplexy and daytime sleep. The anticataplectic effects of CG-3703 were not associated with changes in general behavior, heart rate, blood pressure, rectal temperature, blood chemistry and thyroid function. Although drug tolerance for the effects on cataplexy and sleep were observed during the second week of chronic drug administration, therapeutic efficacy on cataplexy was improved with individual dose adjustment (final dose range: 16 to 28 mg/kg, p.o.). These results suggest that TRH analogs could be a promising new form of treatment for human narcolepsy.

Animals↗

PubMed2001

Narcolepsy and obesity: remission of severe cataplexy with sibutramine.

An overweight patient (body mass index of 34 kg/m(2)) with narcolepsy associated with cataplexy is described. Polysomnography did not indicate obstructive sleep apnea. Her obesity was treated with sibutramine, a norepinephrine, serotonin and dopamine reuptake inhibiting medication and her severe cataplexy remitted. Clinicians must be aware that sibutramine may suppress cataplexy when evaluating excessive daytime sleepiness in an overweight patient taking this anti-obesity medication. Therefore a negative history of cataplexy in these cases may be misleading and narcolepsy may be overlooked in the differential diagnosis. Sibutramine should be discontinued before polysomnography and multiple sleep latency testing but may be a useful medication in the management of obese narcoleptic patients with cataplexy. With the discovery of decreased hypocretin 1 levels in humans with narcolepsy, a neuropeptide that modulates sleep and feeding, the association between narcolepsy and obesity requires more attention.

Journal Article↗

PubMed2002

CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia.

We measured cerebrospinal fluid (CSF) hypocretin-1 levels in 11 patients with narcolepsy-cataplexy, five with narcolepsy without cataplexy and 12 with idiopathic hypersomnia (IHS). All patients were Japanese. As reported in Caucasian patients, undetectable or very low hypocretin-1 levels were observed in most (9 out of 11) Japanese narcolepsy--cataplexy patients. Our hypocretin-deficient narcoleptics included three prepubertal cases within few months after the disease onset. All nine hypocretin-deficient patients were human leuckocyte antigen (HLA) DR2 positive, while two who had normal CSF hypocretin-1 levels were HLA DR2 negative. In contrast, none of the narcolepsy without cataplexy and IHS subjects had undetectable low levels. Low CSF hypocretin-1 is therefore very specific for HLA DR2 positive narcolepsy-cataplexy, and the deficiency is likely to be established at the early stage of the disease.

Adult↗

PubMed2002

Clinical aspects of narcolepsy-cataplexy across ethnic groups.

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.

Adolescent↗

PubMed1993

Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers.

Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.

Adrenergic Agents↗

PubMed1991

HLA DR2 in narcolepsy with sleep-onset REM periods but not cataplexy.

To determine the association of HLA DR2 in patients with narcolepsy without cataplexy, a case-control study was performed. Patients receiving the diagnosis of narcolepsy without cataplexy had excessive daytime sleepiness (EDS) and polysomnographic findings consistent with narcolepsy but no clinical evidence of cataplexy. Of 28 patients identified, 12 agreed to return for HLA typing. Respondents did not differ from nonrespondents in demographic, clinical, or sleep laboratory data. The comparison group was 503 individuals, those 30 years and older, on the Michigan Kidney Transplant Registry. The odds ratio obtained from logistic regression indicated a strong association between narcolepsy without cataplexy and HLA DR2. To control for potential confounding variables, multivariate models were constructed to explore the joint effects of HLA DR2 and each one of the covariates (age, sex, and race), their possible combinations, and the effect of all three covariates. The odds ratios decreased minimally and the association between the disease and HLA DR2 remained significant.

Adult↗

PubMed1989

Central alpha 1 adrenoceptor subtypes in narcolepsy-cataplexy: a disorder of REM sleep.

The present study suggests the specific involvement within the central nervous system of an alpha 1 adrenoceptor subtype in a behavior, the control of cataplexy, a pathological analogue of rapid eye movement (REM) sleep atonia. Experiments have shown that prazosin, an alpha 1 antagonist, dramatically aggravates canine narcolepsy-cataplexy through a central mechanism, and that [3H]prazosin binding sites are increased in the amygdala of narcoleptic dogs. However, the corresponding Scatchard plots were curvilinear and best fit was obtained with a two-site model, suggesting the existence of two [3H]prazosin binding sites. These two sites (high and low affinity [3H]prazosin binding sites) met the criteria for authentic receptors and were respectively very similar to the alpha 1a and alpha 1b (high and low affinity for WB4101, respectively) subtypes recently described in the rat and rabbit. Our results of in vivo pharmacology and in vitro [3H]prazosin binding in canine narcolepsy now clearly implicate the low affinity [3H]prazosin binding site (alpha 1b) in canine narcolepsy: (1) Prazosin, an alpha 1 antagonist with similar affinity for both subtypes, was much more potent in increasing cataplexy than WB4101, a compound with more affinity for the alpha 1a receptor. (2) Chlorethylclonidine and phenoxybenzamine, two irreversible blockers of the alpha 1 receptors with more affinity for the alpha 1b receptors, aggravate cataplexy for up to two weeks. (3) The alpha 1 receptor upregulation previously reported by our group in the amygdala of narcoleptic dogs was due to a selective increase in the low affinity [3H]prazosin binding sites. A role for noradrenaline in REM sleep regulation has been suspected for many years, but has never been clearly elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed2005

Studies of humoral immunity to preprohypocretin in human leukocyte antigen DQB1*0602-positive narcoleptic subjects with cataplexy.

BACKGROUND: Canine models for narcolepsy have mutations of the hypocretin receptor 2 gene, and preprohypocretin knockout murine lines exhibit narcoleptic-like behaviors. Human narcolepsy with cataplexy is associated with human leukocyte antigen DQB1*0602 and reduced hypocretin levels in cerebrospinal fluid, suggesting an autoimmune diathesis. We tested the hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have immunoglobulin (Ig)G reactive to human preprohypocretin and its cleavage products. METHODS: Serum samples of 41 DQB1*0602-positive narcoleptic subjects with cataplexy and 55 control subjects were studied, as were 19 narcoleptic and 13 control samples of cerebrospinal fluid. We tested for IgG reactive to preprohypocretin and its major cleavage products (including hypocretin 1 and 2), using immunoprecipitation assays (IP), immunofluorescence microscopy (IF) of Chinese hamster ovarian cells expressing preprohypocretin, and Western blots. RESULTS: There was no evidence for IgG reactive to preprohypocretin or its cleavage products in CSF of subjects with narcolepsy as measured by IPs, Western blots, and IF. Although the IP with CSF and the C-terminal peptide showed significant differences by two methods of comparison, the control subjects had higher counts per minute than narcoleptic subjects, which was opposite to our hypothesis. CONCLUSIONS: The hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have IgG reactive to preprohypocretin or its cleavage products was not supported.

Adult↗