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At least 541 records · Page 30Linked to original sources
PubMed2004

Neuropeptides in hypothalamic neuronal disorders.

A few examples of hypothalamic, peptidergic disorders leading to clinical signs and symptoms are presented in this review. Increased activity of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) and decreased activity of the vasopressin neurons in the biological clock and of the thyroxine-releasing hormone (TRH) neurons in the PVN contribute to the signs and symptoms of depression. In men, the central nucleus of the bed nucleus of the stria terminalis (BSTc) is about twice as large and contains twice as many somatostatin neurons as in women. In transsexuals this sex difference is reversed, pointing to a role of this structure in gender. Luteinizing hormone-releasing hormone (LHRH) neurons are formed in the fetal olfactory placade and migrate along the terminal nerve fibers into the hypothalamus. In Kallmann's syndrome the migration process of the LHRH (gonadotropin-releasing hormone) neurons is aborted, which explains the joint occurrence of hypogonadotropic hypogonadism and anosmia in this syndrome. In postmenopausal women, the neurons of the infundibular nucleus hypertrophy and become hyperactive because of the disappearance of the estrogen feedback and contain hyperactive peptidergic neurons. Climacteric flushes may be caused by hyperactivity of the neurokinin-B or LHRH neurons in this nucleus. The hypocretin (orexin) neurons in the perifornical area are involved in sleep. In narcolepsy with cataplexy, a loss of these neurons, probably due to an autoimmune process, is found. Obese subjects with a mutation in the gene that encodes for leptin, the preproghrelin gene, or the alpha-melanocyte-stimulating hormone (alpha-MSH) gene have been described. Decreased numbers and activity of the oxytocin neurons in the PVN may be responsible for the absence of satiety in Prader-Willi syndrome. Moreover, a glucocorticoid receptor polymorphism is associated with obesitas and dysregulation of the hypothalamus-pituitary-adrenal axis. In contrast, two single nucleotide polymorphisms (SNPs) of the AGRP gene have been associated with anorexia nervosa.

Animals↗
PubMed1999

The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.

Narcolepsy is a disabling sleep disorder affecting humans and animals. It is characterized by daytime sleepiness, cataplexy, and striking transitions from wakefulness into rapid eye movement (REM) sleep. In this study, we used positional cloning to identify an autosomal recessive mutation responsible for this sleep disorder in a well-established canine model. We have determined that canine narcolepsy is caused by disruption of the hypocretin (orexin) receptor 2 gene (Hcrtr2). This result identifies hypocretins as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients.

Amino Acid Sequence↗
PubMedDate not supplied

A functional autoantibody in narcolepsy.

Narcolepsy is widely believed to have an autoimmune basis, but conventional immunological approaches have failed to detect a serum autoantibody marker. Since cholinergic hyperactivity is a feature of narcolepsy-cataplexy, we transferred IgG from nine patients with narcolepsy and nine healthy controls to mice and assessed the effect on smooth muscle contractile responses to cholinergic stimulation. IgG from all narcolepsy patients significantly enhanced bladder contractile responses to the muscarinic agonist carbachol and to neuronally released acetylcholine compared with control IgG (p<0.0001), whereas contraction of the sympathetically innervated vas deferens was unaltered. Our findings provide direct evidence for the autoimmune hypothesis of narcolepsy.

Adult↗
PubMedDate not supplied

Treatment of narcolepsy with L-tyrosine.

8 patients with narcolepsy were treated with oral tyrosine. Within six months all were free from daytime sleep attacks and cataplexy.

Administration, Oral↗
PubMed1997

[Excessive daytime sleepiness].

When it is not due to an extrinsic origin, somnolence may be the main symptom of various diseases. Among these causes of excessive daytime sleepiness, obstructive sleep apnea syndrome is noteworthy for its very important prevalence, estimated at 4% in adult males. Due to repeated upper airway obstructions during sleep, this disease is efficiently treated by continuous positive airway pressure applied through a nasal masks during sleep. Another syndrome, periodic limb movements during sleep may also lead to a sleep fragmentation at the origin of daytime sleepiness. Its treatment is principally based on dopaminergic agonists. Narcolepsy-cataplexy and idiopathic hypersomnia are two causes of excessive daytime sleepiness in young people. The first is as frequent as multiple sclerosis and the second is ten times less frequent. The treatment of these two diseases is now based on a new French drug: modafinil(Modiodal). Sleep pathology still has only a small place in medical training. Excessive daytime sleepiness is therefore often misdiagnosed. In addition to their major risk of work or road accidents, numerous untreated patients continue to suffer from this very unpleasant symptom, at the origin of a major social handicap.

Adult↗
PubMed2003

Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats.

Narcolepsy, a disabling neurological disorder characterized by excessive daytime sleepiness, sleep attacks, sleep fragmentation, cataplexy, sleep-onset rapid eye movement sleep periods and hypnagogic hallucinations was recently linked to a loss of neurons containing the neuropeptide hypocretin. There is considerable variability in the severity of symptoms between narcoleptic patients, which could be related to the extent of neuronal loss in the lateral hypothalamus. To investigate this possibility, we administered two concentrations (90 ng or 490 ng in a volume of 0.5 microl) of the neurotoxin hypocretin-2-saporin, unconjugated saporin or saline directly to the lateral hypothalamus and monitored sleep, the entrained and free-running rhythm of core body temperature and activity. Neurons stained for hypocretin or for the neuronal specific marker were counted in the perifornical area, dorsomedial and ventromedial nucleus of the hypothalamus. More neuronal nuclei (NeuN) cells were destroyed by the higher concentration of hypocretin-2-saporin (-55%) compared with the lower concentration (-34%) in the perifornical area, although both concentrations lesioned the hypocretin neurons almost equally well (high concentration=91%; low concentration=88%). The high concentration of hypocretin-2-saporin also lesioned neurons in the dorsomedial nucleus of the hypothalamus and ventromedial nucleus of the hypothalamus. Narcoleptic-like sleep behavior was produced by both concentrations of the hypocretin-2-saporin. The high concentration produced a larger increase in non-rapid eye movement sleep amounts during the normally active night cycle than low concentration. Neither concentration of hypocretin-2-saporin disrupted the phase or period of the core temperature or activity rhythms. The low concentration of unconjugated saporin did not significantly lesion hypocretin or neurons and did not alter sleep. The high concentration of unconjugated saporin produced some loss of neuronal nuclei-immunoreactive (NeuN-ir) neurons and hypocretin immunoreactive neurons, but only a transient increase in non-rapid eye movement sleep. These results led us to conclude that the extent of hypocretin neuronal loss together with an accompanying loss of cells in the lateral hypothalamus may explain the differences in severity of symptoms seen in human narcolepsy.

Animals↗
PubMed1986

[Value of mazindol in Gélineau's disease. Apropos of 10 cases].

Ten narcoleptic patients were treated daily with Mazindol 2-6 mg for 42.2 months (31-63 months). The response was excellent on narcoleptic attacks in 6 and on cataplexy in 7 cases. However, the nocturnal sleep disturbance persisted unchanged. The improvement was poor in 1 case and inexistant in 1 subject. Minor side effects (dry mouth) occurred in 3 cases, and urinary retention obliged to stop the medication in 2 cases.

Adolescent↗
PubMed1992

The more unusual sleep disturbances of childhood.

The sleep patterns of children often cause anxiety to their parents. Some disturbances are unusual, and therefore may cause diagnostic difficulties. Sleep walking and night terrors can be confused with epileptic seizures. The sudden sleep of narcolepsy can lead to false accusations, when in fact the episodes are beyond the child's control. The associated phenomena of cataplexy, hypnogogic hallucinations and sleep paralysis can be particularly alarming, especially if they occur in the absence of narcolepsy. The overlap between narcolepsy and the Kleine-Levin syndrome is confirmed. Although of a different nature the sleep apnoea syndrome is equally important from the point of view of diagnosis and treatment.

Child↗
PubMed2003

Sleep disorders in childhood.

Childhood sleep-wake disorders are common and associated with significant impairment of quality of life. The recent discovery of hypocretin deficiency as the pathophysiologic basis for narcolepsy-cataplexy is likely to spur the development of hypocretin analogs for definitive treatment [82,83]. The link between disrupted sleep and daytime learning and childhood inattention is a challenging area of mind-brain interaction in which further progress is likely, once methodologic issues have been sorted out. The recent recognition of genetic influences in the control of circadian rhythms also may spur the development of specific therapies for circadian rhythm disorders. In many ways, sleep medicine is benefiting from recent progress in the basic neurosciences, genetics, and technology.

Child↗
PubMed2002

[Narcolepsy and epidural obstetrical analgesia ].

We report the case of a parturient with a history of narcolepsy that delivered under epidural anaesthesia without any complication. Patients with narcolepsy might be at risk of delayed recovery or of apneic episodes after general anaesthesia while narcolepsy-cataplexy fits might be more frequent during regional anaesthesia. Avoiding sedative premedication and continuing medical therapy on the day of surgery are recommended to avoid these complications.

Adult↗
PubMed2003

Niemann-Pick type C disease associated with peripheral neuropathy.

Niemann-Pick type C disease is an autosomal-recessive, inherited neurovisceral lipid storage disorder. This disease results from either protein NPC1 or HE1 deficiency, which leads to cholesterol metabolism disturbance and is characterized by early hepatosplenomegaly and progressive ataxia, dystonia, cataplexy, dysarthria, and dementia. We describe a 3 1/2-year-old patient with Niemann-Pick type C disease, who presented with regression in both cognitive and motor domains. Almost 10 months before admission to the hospital, the child developed progressive speech and behavioral changes, as well as gait disturbances with frequent falls. The examination demonstrated hepatosplenomegaly, ataxia, and vertical gaze palsy. Nerve conduction velocities demonstrated mild demyelinating peripheral neuropathy. Bone marrow examination revealed foam cells, and cholesterol esterification studies found massive accumulation of unesterified cholesterol and very low intracellular esterification of exogenous lipoprotein-derived cholesterol. These results indicate Niemann-Pick type C disease. Peripheral neuropathy is a rare complication in patients with Niemann-Pick type C disease, which certainly contributes to their neurologic deterioration.

Child, Preschool↗
PubMed1993

[Sleepiness. Experimental models].

Some experimental models of sleepiness are reviewed. The model of the narcoleptic dog is the best one to study the mechanisms of cataplexy. Idiopathic sleepiness can be experimentally studied by acting upon either circadian or homeostatic regulation of sleep. The paradoxical sleep rebound which occurs after its previous suppression has been explained by different theories which are summarized. Finally, the decrease of waking which follows either lesion or pharmacological alterations is useful to develop new molecules which can increase waking, in a safe manner.

Animals↗
PubMed1993

Autoimmune hypothesis in narcolepsy.

Since the discovery of an almost 100% association of HLA-DR2 with narcolepsy-cataplexy, many efforts have been made to demonstrate the intervention of immune factors in the pathogeny of the disease. Some epidemiological features could support this hypothesis: age of onset around 25, triggering factors, association with multiple sclerosis. Molecular studies at the DNA level have, up to now, failed to uncover an abnormal gene in the HLA system, which would imply that the DR2 antigen acts through its role in the immune response. However, results have been largely inconclusive as far as classical features of autoimmunity in blood and CSF are concerned. In canine narcolepsy, a linkage with a human immunoglobulin-related gene has recently been shown, and may constitute a counterpart of the HLA association in man. Thus, the hypothesis of a transient and discrete autoimmune aggression may be ruled out.

Animals↗
PubMed1993

[The effects of modafinil (300mg) on sleep, sleepiness and arousal in narcoleptic patients].

CNS stimulants are the most widely used drugs to treat narcolepsy which is characterized by the excessive daytime sleepiness and typically associated with cataplexy. However, a number of side effects may often arise with this therapeutic approach. Thus, investigating new drugs which are efficient but well tolerated is of utmost importance in the treatment of narcolepsy. Although modafinil, an alpha-1 adreno-receptor agonist, has been reported to bring substantial awakening properties in animals, the studies performed in man, particularly in narcoleptic subjects, are few. In the present study, we evaluated the effects of a 300 mg daily dose of modafinil on sleepiness and psychomotor performance of 16 narcoleptic subjects. The major effect of modafinil in narcoleptic subjects was a decrease of daytime sleepiness and corresponding improvement of performances involving attentive functions. However, the learning effect in psychomotor tests may mask the drug effect.

Adolescent↗
PubMed1996

Narcolepsy in children.

Childhood narcolepsy is frequently under-diagnosed. Hypersomnolence may not always be accompanied by cataplexy, sleep paralysis, or hypnagogic hallucinations in the early stages. Pathophysiologic considerations revolve around an altered central nervous system catecholamine-acetylcholine balance. Both idiopathic and symptomatic forms have been described. Serial polysomnography and multiple sleep latency tests may be required to establish a definitive diagnosis. The long-term management requires the provision of both pharmacological and non-pharmacological forms of therapy.

Adolescent↗
PubMed2003

International Study on Syncope of Uncertain Etiology 2: the management of patients with suspected or certain neurally mediated syncope after the initial evaluation rationale and study design.

STUDY DESIGN: Multi-centre, prospective observational study. OBJECTIVES: Main objective is to verify the value of implantable loop recorder (ILR) in assessing the mechanism of syncope and the efficacy of the ILR-guided therapy after syncope recurrence. INCLUSION CRITERIA: Patients who met the following criteria are included: suspected or definite neurally mediated syncope based on initial evaluation; >/=3 syncope episodes in the last 2 years; severe clinical presentation of syncope requiring treatment initiation in the judgement of the investigator and age >30 years. EXCLUSION CRITERIA: Patients with one or more of the following are excluded: carotid sinus syndrome; suspected or definite heart disease and high likelihood of cardiac syncope; symptomatic orthostatic hypotension diagnosed by standing blood pressure measurement; loss of consciousness different from syncope (e.g. epilepsy, psychiatric, metabolic, drop-attack, TIA, intoxication, cataplexy) and subclavian steal syndrome. END-POINTS: The primary end-points are the ECG-documented syncopal events and the syncope recurrences after application of ILR-guided therapy. SAMPLE SIZE AND DURATION: A minimum of 400 patients will be enrolled during an anticipated period of 3 years.

Clinical Protocols↗
PubMed2003

Clinical aspects and pathophysiology of narcolepsy.

UNLABELLED: Narcolepsy is a chronic debilitating sleep disorder first described in the late 19th century. It is characterized by two major symptoms, excessive daytime sleepiness and cataplexy, and two so-called auxiliary symptoms, hypnagogic hallucinations and sleep paralysis. The final diagnosis relies on polysomnography showing the presence of sleep onset rapid eye movement periods (SOREMPs) during the multiple sleep latency test. The presence of HLA DQA1*0102-DQB1*0602 is supportive of the diagnosis. The pathophysiology of the disorder is still unknown but an imbalance between monoamines and acetylcholine is generally accepted. Recent findings in narcoleptic dogs, a natural model of narcolepsy, and in knockout mice revealed that a mutation of type 2 hypocretin receptor plays a major role in the etiology of narcolepsy. Up to now, no mutation has been found in humans except a case of early onset and atypical narcolepsy. However, a marked reduction of hypocretin type 1 has been found in the cerebrospinal fluid (CSF) of a majority of patients and a global loss of hypocretins was noted in post-mortem brain tissue of narcoleptic subjects. Conversely, no hypocretin neuron degeneration has been observed in the genetic form of narcolepsy in dogs but no trace of hypocretin was seen in the brain or the CSF in cases of sporadic canine narcolepsy. This suggests that different hypocretinergic mechanisms are involved in sporadic and genetic forms of canine narcolepsy. Treatment has not evolved significantly over the last few years. However, new drugs, such as hypocretin agonists, are currently being developed. SIGNIFICANCE: After the discovery of the type 2 hypocretin receptor mutation in canine narcolepsy and the finding of a CSF hypocretin-1 deficiency in human narcolepsy, the major stream of research has involved the hypocretinergic system. However, other lines of research deserve to be pursued simultaneously, in view of comprehensive advancements in the understanding of narcolepsy.

Animals↗
PubMed2001

Low cerebrospinal fluid hypocretin levels found in familial narcolepsy.

OBJECTIVE: This report describes abnormal hypocretin neurotransmission in a case of familial narcolepsy. BACKGROUND: Narcolepsy is a chronic, often-disabling central nervous system disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep features including cataplexy, a loss of muscle tone triggered by emotion. The cause of human narcolepsy is unknown. Several familial cases have been described, but most cases are sporadic (95%). An abnormality of hypocretin neurotransmission has been found in a majority of sporadic cases. METHODS: Hypocretin-1 levels were measured in the cerebrospinal fluid of the narcoleptic proband of a family with several affected members. RESULTS: The proband was found to have a hypocretin-1 deficiency. CONCLUSION: Abnormal hypocretin neurotransmission is found in familial, as well as sporadic, narcolepsy.

Journal Article↗