Narcolepsy

Sergio Claudio Podesta.

Physician Neurologist.

Sleep Medicine Specialist.

Narcolepsy is a condition characterized by cardinal signs and symptoms clear description of which dates back over a hundred years (1), however, even today, worldwide, it remains underdiagnosed.

It usually begins around the second decade of life and affects both sexes equally.

Clinical features include excessive daytime sleepiness with irresistible sleep attacks, cataplexy, hypnagogic or hypnopompic hallucinations and sleep paralysis. It should be mentioned that this tetrad is observed only in one third of patients, being most frequent forms of presentation incomplete or progressive.

Narcolepsy is a condition which is inherited predisposition to acquire it, is chronic and depending on the severity can be disabling when not set the proper treatment.

Since the eighties, studies of the HLA system have allowed to have more diagnostic tools, since a high percentage of narcoleptic patients share a specific offense of alleles.

At present, treatment is symptomatic both hypersomnia and for cataplexy, but recent research in the field of orexins and hypocretins to visualize a future etiologic therapeutic.

Narcolepsy has a prevalence of about 0.6 to 1.2/mil in the general population (2.3). In the graph below, we compare their frequency with other neurological disorders of nature to demonstrate the ignorance of the condition. It has almost the same prevalence as multiple sclerosis and is much more common than myasthenia gravis and amyotrophic lateral sclerosis, rarely absent entities in differential diagnosis.

Figure 1: Narcolepsy (prevalence compared / 00000). Billiard, 1989 (2).

Onset of symptoms usually occurs in puberty and adolescence, occasionally, in later childhood. There is a bimodal distribution (2), most often in the second decade of life and to a lesser extent, about a quarter.

Narcoleptic patients spend an extended period of time between onset of symptoms and accurate diagnosis in the series being studied more numerous, more than ten years (4). Reason is partly that excessive daytime sleepiness is not usually taken by patients as a symptom, then delaying medical consultation. On the other hand, hypersomnia is not infrequently attributed to depression or digestive disorders and episodes of cataplexy is not unusual to be misinterpreted as seizures.

Our series (5) of just over one hundred patients diagnosed over the age of eighteen years of the laboratory in the institution, shows, first of the low proportion of narcoleptic subjects studied, having evaluated today more than 10000 patients various pathologies. Second, the age at onset has a predominantly unimodal distribution with a peak evident in the second decade of life.

A) Figure 2: Age of onset of first symptoms

B) Figure 3: Latency of diagnosis (in years).

(Casuistry staff)

Analysis of diagnostic latency showed an average of twenty-four, with ranges of between one fifty-nine years. Anecdotes serve as a reference, such as two patients whose complaints were insomnia and hypersomnia, or that most of them had received at some point in their evolution antidepressant medication and / or epileptic, or for two women who had undergone cholecystectomy course having digestive disorders were responsible for their excessive sleepiness.

Clinical Picture

Excessive daytime sleepiness that afflicts these patients, of varying severity (sometimes debilitating), interferes with their daily activities and is aggravated in the course of the day by the intrusion of irresistible sleep attacks in the most unlikely circumstances.

Cataplexy is a symptom that can sometimes be absent at the start of the condition, and involves the sudden loss of muscle tone to which the patient attends conscientiously. Can be generalized to involve the whole body (with the consequent fall in the subject) or partial, limited to a brief dysarthria, sluggish head or limb. A note to remember is that triggers cataplexy compared to stimuli that provoke emotion or surprise the individual. It has shown an increase in dopamine D2 receptors and alpha adrenergic receptor-1-b in the amygdala (6.7), an increase of M2 muscarinic receptors in pontine reticular formation (8) and alpha-2 adrenergic receptors in the locus coeruleus (9). The limbic system stimulation by emotion or surprise and its impact on brain stem structures, may explain the sluggishness that characterizes cataplexy.

There are other symptoms, more fickle in presentation and in its persistence such as hypnagogic hallucinations and sleep paralysis. Both can appear and disappear in the course of evolution and, if filed, are observed in the transitional periods between wakefulness and sleep or vice versa. Cataplexy, hallucinations and sleep paralysis are equivalent of REM sleep that are incorporated in unexpectedly during wakefulness. The hallucinatory episodes are more heavily on visual, such as a dream invasion, although patients also describe a lesser extent auditory events and somesthetic type. Sleep paralysis, which is explained by a sudden inhibition of alpha motor neuron, is described by them as highly distressing experience, and that in full awareness of being awake, there is only chance to breathe and move the extraocular muscles.

Other frequently observed anomalies. Contrary to what might be expected, narcoleptic patients have poor nighttime sleep, fragmented and unstable type, with numerous passages arousal and light sleep stages, a fact corroborated in hipnogramas evoke nights in the Sleep Laboratory. It is also possible to observe its evolution, episodes of recurrent nightmares and bizarre stereotyped motor behavior during the evening (events of "REM sleep without atonia").

Diagnosis

The diagnosis is mainly clinical because the symptoms are categorical. The history should emphasize the characteristics of hypersomnia capital-symptom time of onset, evolution and fluctuations. The suspect before an interrogation directed to induce the physician to confirm the disease.

The preparation of agendas patient prolonged for a fortnight or a month to discover his sleep habits, their rhythmicity, the number of nocturnal awakenings, their subjective estimation of the quality of your sleep. Then, exploration in the sleep laboratory sample nighttime sleep objectively and determines the degree of daytime sleepiness.

Polysomnography during the course of one night can rule out other anomalies that fragment sleep continuity, cause sleepiness (sleep apnea syndrome, syndrome of periodic movements of legs, disturbances of circadian rhythms, etc..).

During the morning and later afternoon, the patient remains in his room and he made ​​a Test Multiple Sleep Latency (MSLT) methodology through five naps regulated, to define the severity of hypersomnia, assess the appearance of REM sleep episodes during the day and dream activity report. In children, it was impossible that may occur to systematize the latency test naps can be extended to record twenty-four hours which is analyzed then the intrusion of REM sleep episodes during periods of wakefulness.

Finally, the definition of Group II HLA antigens by serology and PCR, confirm if the polysomnographic and MSLT data were not conclusive.

Etiology

The predisposition to narcolepsy is a genetic but the outbreak appears to depend on many factors. 95% of patients with cataplexy share a specific HLA allele group II (DQB1 * 0602), however this also appears in the general population at a frequency not dismissed from 12 to 35% (10). Recent observations have a blanket of doubt that their presence is necessary and sufficient condition for developing the condition. Firstly, the disease is rarely transmitted from generation to generation, then in the case of homozygous twins usually only one is usually affected (both share in a proportion of 25 to 30%). Also, there have been speculation that narcolepsy could answer autoimmune nature as it has been found associated for example, Multiple Sclerosis (we have one such patient in our series). Although no direct evidence, some authors hypothesize that neurons hipocretínicas could be the target of any such process, thus leading to cell destruction (11).

The literature also cites the role of exogenous factors in its determinism, such as sudden changes in patterns of sleep / wake, stress, illness or grief (12).

Narcolepsy and hypocretins

The most relevant findings in relation to the pathophysiology of narcolepsy are recently departed reference and basic research on the canine model (where feasible cause cataplexy episodes similar to those of humans). Over the years, have crossed generations of Labrador Beagle Pinscher and to study the anomaly. Autosomal recessive canine narcolepsy has been linked to Canarc gene-1 (homologous to human but located in different gene). A recent development in the pathogenesis of narcolepsy is the identification of an abnormality in hypocretin receptor (Hcrtr2) in the canine model.

The hypocretins are hypothalamic neuropeptides, and reduced levels (or lack thereof), would explain both excessive daytime sleepiness and cataplexy.

Hypersomnia cessation would result, on one side of the hypocretin causes inhibition on basal brain hipnogénicos systems, and secondly, the stimulation generated by the mechanisms of cholinergic and monoaminergic wake.

Peripheral motor neurons, which receive inhibitory stimuli (glycine) and excitatory (norepinephrine and serotonin) would be affected in the absence of hypocretin would be released as the first and absent the latter, a fact that would explain the cataplexy.

Genetic manipulations in mice aimed at preventing the synthesis of hypocretin determined hypersomnia and cataplexy episodes similar to those observed in human narcolepsy. Similar observations have been reported recently in humans, resulting in dosages undetectable CSF hypocretin in narcoleptic patients (13). Pathologic Analysis endorse such a presumption, as there has been a significant reduction in hypothalamic dorsomedial hipocretínicas cells with a consequent increase in gliosis reaction (14).

Figure 4: Reduction in cell hipocretínicas

dorsomedial hypothalamus in human narcolepsy (14).

Figure 5: Gliosis of hypothalamus and thalamus in

narcoleptic patients and normal controls (14).

Clinical variants

In some patients, the clinical picture and evaluation in the sleep laboratory confirmed the presence of narcolepsy, but it is among his record the occurrence of episodes of cataplexy, a fact that does not mean that your progress can come to develop it.

There are forms associated, especially periodic movements of legs syndrome and obstructive sleep apnea.

The forms are rare symptomatic presentation. Certain brain stem tumors, severe head trauma, encephalitis or cerebral ischemia have been reported, among other causes as responsible for narcolepsy (15,16). In our case we have three symptomatic patients with narcolepsy, one with a severe post-traumatic atrophy and cerebellar pedúnculopontina.

Figs. 6 and 7 post-traumatic Narcolepsy (personal case), cerebellar atrophy and note pedunculopontina (17).

Treatment

The treatment of narcolepsy remains in the field currently symptomatic. The treatment is twofold, first used sleep hygiene and sometimes, when these are not enough, drugs are used. Are treated separately hypersomnia, cataplexy and stabilization of nighttime sleep.

The first measures to be considered are those concerning night sleep hygiene (regular hours of sleep and wakefulness) and an indication of short naps, no more than twenty miutos during the day (for retrieving appropriate levels of wakefulness). On many occasions, either by impediments (labor or social) to make naps, or excessive sleepiness, stimulant medication should be used. Currently tend to be neglected amphetamine derivatives (Pemoline and Methylphenidate) in pursuit of the use of Modafinil. This, the mechanism of action remains uncertain, it seems to stimulate the secretion of hypocretin (18) and is used in doses greater than 600mg/day not.

When cataplexy is a symptom that strongly affects the patient, the use of antidepressants (clomipramine, viloxazine, fluoxetine) tends to reduce the number of episodes.

The instability of nighttime sleep, characterized by fragmented sleep is an observable throughout the course of the disease and the use of benzodiazepines is one of the entries in order to mitigate it.

Conclusions

Narcolepsy is a condition not uncommon and the illness of sleep and wakefulness that causes more severe hypersomnia. Unfortunately, as was already mentioned, its presence is not always present in the differential diagnosis in clinical practice, despite signs and symptoms have unequivocal.

While currently the treatment is conditioned and has limitations, the bond with the HLA system and the findings on orexins dysfunction mechanisms allow in a near future, the production of synthetic hypocretin to transform etiological symptomatic treatment.

Slope will investigate why neurons are affected hipocretínicas hypothalamic and explain the impact of exogenous factors in the desencadenamiemto of the disease.

Literature

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2) Billiard M, Deauvilliers Y, Carlander B.: The Narcolepsie. In: Le normal et sommeil pathologique. Ed: Billiard M, Masson, 1998: 278-292.

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10) Mignot E. et al. DQB1 * 0602 and DQA1 * 0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasians and black Americans. Sleep, 17, S60-S67, 1994.

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A mutation in a case of early onset narcolepsy and a generalized Absence of hypocretin peptides in human narcoleptic brains. Nat Med.2000Sep; 6 (9) :991-7.

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14) Thannickal T, Moore R, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel J. Reduced Number of Neurons in Human Narcolepsy hypocretin. Neuron, Vol 27, 469-474, September, 2000.

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17) Podesta C, Massaro M, Mazzola ME. Symptomatic Narcolepsy. Minutes of Physiology "2001 Sleep Odyssey Congress," Punta del Este, Uruguay, 2001: 232.

1999 Aug 20;98(4):437-51 . 18) RM Chemelli et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999 Aug 20, 98 (4) :437-51.