|Seiji Nishino (2007), Scholarpedia, 2(9):2425.||doi:10.4249/scholarpedia.2425||revision #91548 [link to/cite this article]|
Narcolepsy is a neurological disease of unknown etiology (prevalence = 1 in 2,000) characterized by excessive daytime sleepiness (EDS) that is often profound. About 95% of narcoleptic cases are sporadic, but it also occurs in familial forms.
Symptoms of Narcolepsy
Narcolepsy usually occurs in association with cataplexy and other symptoms, which commonly include hypnagogic or hypnopompic hallucinations, sleep paralysis, automatic behavior, and disrupted nocturnal sleep. Symptoms most often begin between adolescence and young adulthood, however it may also occur earlier in childhood or not until the third or fourth decade of life. Quality of life studies suggest that the impact of narcolepsy is equivalent to that of Parkinson's disease. Although EDS is not specific for narcolepsy and is seen in other primary and secondary EDS disorders (such as sleep apnea syndrome), cataplexy is generally regarded as pathognomonic. Occurrence of cataplexy is tightly associated with impairment of hypocretin/orexin neurotransmission, and it rarely occurs as an isolated symptom. Cataplexy occasionally occurs in conjunction with other neurological conditions, such as Nieman-Pick Type C disease, but the pathophysiological links in these neurological conditions with the hypocretin abnormalities are presently not well established.
Sleepiness or excessive daytime sleepiness (EDS)
The EDS of narcolepsy presents itself with an increased propensity to fall asleep, nod, or easily doze in relaxed or sedentary situations, or a need to exert extra effort to avoid sleeping in these situations. Additionally, irresistible or overwhelming urges to sleep occur from time to time during wakeful periods, commonly in untreated patients with narcolepsy. These so-called "sleep attacks" are not instantaneous lapses into sleep, as is often thought by the general public, but represents the episodes of profound sleepiness experience by those with marked sleep deprivation. The EDS of narcolepsy (as in other sleep disorders) can also cause related symptoms, including poor memory, reduced concentration, and irritability. Narcoleptic subjects feel refreshed after a short nap, but this does not usually last long and they become sleepy again within a few hours. Narcolepsy may therefore consist of an inability to maintain wakefulness combined with the intrusion of REM sleep associated phenomena (hallucinations, sleep paralysis and possibly cataplexy) into wakefulness.
Cataplexy is the partial or complete loss of bilateral muscle tone in response to a strong emotion. Reduced muscle tone may be minimal, occuring in a few muscle groups and causing minimal symptoms (such as bilateral ptosis, head drooping, slurred speech or dropping things from the hand) or it may be so severe that total body paralysis occurs, resulting in complete collapse. Cataplectic events usually last from a few seconds to 2 or 3 minutes, but occasionally continues longer, however, the patient is usually alert and oriented during the event despite their inability to respond. Positive emotions such as laughter can more commonly trigger cataplexy than negative emotions, but any strong emotion is a potential trigger. Additionally, startling stimuli, stress, physical fatigue, or sleepiness may also be important triggers or factors that exacerbate cataplexy.
In a broader classification, diagnosing narcolepsy does not require cataplexy if REM sleep abnormalities (i.e., sleep onset REM sleep periods [SOREMPs] during multiple sleep latency test [MSLT]) are objectively documented. According to epidemiologic studies, cataplexy is found in 60% to 100% of patients with narcolepsy. This large range is due to the fact that the definition of narcolepsy may vary among each study. The onset of cataplexy is most frequently simultaneous with or within a few months of the onset of EDS, but in some cases, cataplexy may not develop until many years after the initial onset of EDS.
Hypnagogic or hypnopompic hallucinations
These phenomena may be visual, tactile, auditory or multi-sensory events, usually brief but occasionally continuing for a few minutes that occur at the transition from wakefulness to sleep (hypnagogic) or from sleep to wakefulness (hypnopompic). Hallucinations may contain elements of dream sleep and consciousness combined, and are often bizarre or disturbing to patients.
Sleep paralysis is the inability to move, lasting from a few seconds to a few minutes, during the transition from sleep to wakefulness or from wakefulness to sleep. Episodes of sleep paralysis may alarm patients, particularly those who experience the sensation of being unable to breathe. Although accessory respiratory muscles may not be active during these episodes, diaphragmatic activity continues and air exchange remains adequate.
Other commonly reported symptoms include automatic behavior, such as "absent-minded" behavior or speech that is often nonsensical and which the patient does not remember, and fragmented nocturnal sleep, such as frequent awakenings during the night.
Hypnagogic hallucinations, sleep paralysis and automatic behavior are not specific to narcolepsy and occur in other sleep disorders (as well as in healthy individuals), however, these symptoms are far more common and occur with much greater frequency in narcolepsy.
Polysomnography, nocturnal and daytime sleep studies
Nocturnal polysomnography is not essential in the diagnostic work-up when straightforward cataplexy accompanies EDS. However, it remains an important part of the evaluation process primarily to identify the presence of other conditions that occur in narcolepsy at a higher than normal rate (obstructive sleep apnea, periodic limb movement syndrome and REM sleep behavior disorder). Additionally, SOREMPs during nocturnal polysomnography may be witnessed and is also supportive for the diagnosis.
Daytime nap studies (in the form of the MSLT) usually demonstrate substantially reduced sleep latency and SOREMPs in patients with narcolepsy. Average MSLT sleep latencies for narcolepsy with cataplexy is approximately 2 to 3 minutes, however, substantial variability across and within patients can, at times, be seen. A mean sleep latency of less than 8 minutes during MSLT is used for the 2nd revision of the International Classification of Sleep Disorders (ICSD). SOREMPs are also not specific to narcolepsy, but the occurrence of 2 or more of these events during the MSLT in the setting of objectively marked sleepiness and without any other explanation for their occurrence (such as: sleep deprivation, REM-suppressant medication rebound, altered sleep schedule, obstructive sleep apnea or delayed sleep-phase syndrome), are suggestive of narcolepsy.
Cerebrospinal fluid (CSF) hypocretin-1 assessment
It has been recently found that many (about 90%) of narcolepsy-cataplexy patients have very low or undetectable levels of hypocretin-1/orexin A in CSF. Such low levels of CSF hypocretin-1 are relatively specific for narcolepsy-cataplexy, but are also seen in a few other neurological conditions, such as a subset of Guillain-Barré syndrome and Ma2 positive paraneoplastic syndrome. Since these conditions are clinically distinct from narcolepsy, low CSF hypocretin levels remain of diagnostic value for narcolepsy. When used to assess patients for narcolepsy, CSF hypocretin-1 measures appear to be a more specific test than the MSLT. As a result, a low CSF hypocretin-1 level (less than 110 pg/ml) was also included for the 2nd revision of ICSD. Previously, no specific and sensitive diagnostic test for narcolepsy based on the pathophysiology of the disease was available, and the final diagnosis was often delayed for several years after the disease onset. Many patients with narcolepsy and related EDS disorders are therefore likely to obtain immediate benefit from this new specific diagnostic test. It should be noted that blood measures of hypocretin-1 may also be possible, but are not yet available.
Histocompatibility Human Leukocyte Antigen (HLA) testing
A very strong, but incomplete correlation exists between narcolepsy (with cataplexy) and the HLA subtype DQB1* 0602. However, this subtype is very common in the general population (approximately 20% in the combined US population) and thus is neither specific nor sensitive for narcolepsy. HLA testing is therefore, not useful in confirming or excluding the diagnosis of narcolepsy, and in fact, may lead a clinician to inappropriate diagnostic conclusions.
Pathophysiology of Narcolepsy
The following facts suggest that narcolepsy is primarily a "disease of REM sleep": (1) the similarity between cataplexy and REM sleep atonia, (2) the presence of frequent episodes of hypnagogic hallucinations and of sleep paralysis, and (3) the propensity for narcoleptics to go directly from wakefulness into REM sleep [i.e., SOREMs]. This hypothesis may, however, be too simplistic and does not explain the presence of sleepiness during the day and the short latency to both NREM and REM sleep during nocturnal and nap recordings. A more probable hypothesis is that narcolepsy results from the disruption of the control mechanisms of both sleep and wakefulness, that is from vigilance-state boundary problems (sleep/wake state instability). This concept also fits well with the fact that sleep and wake of narcoleptic subjects are very fragmented, and that they can not maintain long bouts of wakefulness during the daytime and usually experience insomnia at night due to the sleep fragmentation.
Deficiency in hypocretin (orexin) transmission in narcolepsy
Narcolepsy has been described in several animal species including dogs and most recently in the genetically engineered mouse and rat models. Canine narcolepsy is a naturally occurring model, described both in 17 different breeds and in familial forms (Doberman, Labrador and Dachshund). In Doberman pinschers and Labrador retrievers, the disease is transmitted as an autosomal recessive trait with complete penetrance.
In 1999, using positional cloning and gene targeting strategies, the pathogenesis of narcolepsy was identified in animals. The lack of the hypothalamic neuropeptide hypocretin/orexin ligand (preprohypocretin/orexin gene) in knockout mice, or mutations in one of the two hypocretin/orexin receptor genes (hypocretin receptor 2 gene) in autosomal recessive canine narcolepsy, were observed to result in narcolepsy. After extensive screening (especially in familial and early-onset human narcolepsy), it was demonstrated that mutations in hypocretin-related genes are rare in humans; only a single case, with early-onset at 6 months of age, was found to be associated with a single point mutation in the preprohypocretin gene.
Despite the lack of genetic abnormalities in the hypocretin system, it was found that the large majority (85-90%) of patients with narcolepsy-cataplexy have low or undetectable hypocretin-1 ligand in their cerebrospinal fluid (CSF) (Figure. 1). This hypocretin deficiency is tightly and positively associated with the occurrence of cataplexy and HLA-DQ1*0602. Postmortem human studies have confirmed hypocretin ligand deficiency in the narcoleptic brain (Figure. 1). Hypocretin deficiency has also been observed in sporadic cases of canine narcolepsy (7 out of 7 currently studied), suggesting that the pathophysiology in these animals mirrors that of most human cases.
Although it is evident that the occurrence of cataplexy is tightly associated with hypocretin-deficiency (and HLA positivity) in narcolepsy, the pathophysiological mechanisms underlying the relationship between cataplexy and emotion are largely unknown.
It should also be noted that even when a very strict criteria for cataplexy is applied, about 10% of narcolepsy-cataplexy patients have normal CSF hypocretin-1. Whether or not hypocretin neurotransmission is abnormal in these rarer cases is currently unknown. Considering the fact that hypocretin production and hypocretin neurons appear to be normal in hypocretin receptor 2-mutated narcoleptic Dobermans, it is possible that deficiencies in hypocretin receptors and a downstream pathway may exist in some of these patients. However, currently, this cannot be tested.
The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e., symptomatic narcolepsy) such as the inherited disorder Prader Willi syndrome, tumors, head trauma, and other inflammatory and degenerative diseases. Reduced CSF hypocretin-1 levels were seen in many symptomatic narcolepsy cases of EDS with various etiologies, and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and with an improvement of the hypocretin status.
HLA, immune system, and etiology of narcolepsy
A remarkably high HLA association with narcolepsy was discovered in the early 1980's. The most specific marker of narcolepsy in a number of different ethnic groups studied to date is DQB1*0602. This association is seen in an average of approximately 90% of those with unequivocal cataplexy.
The strong association between HLA type and narcolepsy with cataplexy raises the possibility that narcolepsy is an autoimmune disease. However, there is no strong evidence of inflammatory processes or immune abnormalities associated with narcolepsy, and studies have not found classical autoantibodies or an increase in oligoclonal CSF bands in narcoleptics. Typical autoimmune pathologies (erythrocyte sedimentation rates, serum immunoglobulin levels, C-reactive protein levels, complement levels and lymphocyte subset ratios) are apparently normal in narcoleptic patients. No neuron-specific and organ-specific autoantibodies, including hypocretin peptides, have been identified in narcolepsy patients (HLA DQB1*0602 positive and negative).
Therefore, causes/mechanisms of the hypocretin ligand deficiency in human narcolepsy remains unknown, but it is believed to be a result of acquired cell death of hypocretin neurons. This is likely because: (1) the onset of most sporadic cases of human narcolepsy is around puberty, later than those for the genetic animal models, (2) the only known human hypocretin gene mutation had a very early onset at 6 months of age, (3) the substances that colocalize in hypocretin neurons, such as dynorphine and neuronal activity-regulated pentraxin (Narp), are also lost in hypocretin-deficient narcolepsy, and (4) postnatal ablation of hypocretin neurons in mice induces a phenotype that most resembles human narcolepsy. The mechanisms of the hypocretin cell death, especially in relation to HLA positivity, should therefore be determined to prevent and/or rescue the disease.
Treatments of Narcolepsy
Non-pharmacological treatments (i.e., by behavioral modification) are often reported to be useful additions to the clinical management of narcoleptic patients. Regular napping usually relieves sleepiness for 1 to 2 hours and is the treatment of choice for some patients, but this often has negative social and professional consequences. Exercising to avoid obesity, keeping a regular sleep-wake schedule, and having a supportive social environment are also helpful. In almost all cases, however, pharmacological treatment is needed, and 94% of patients were reported to be using medications in a recent survey by a patient group organization.
For EDS, amphetamine-like CNS stimulants or modafinil, a nonamphetamine stimulant whose mechanism of action is debated, are most often used. These compounds possess wake-promoting effects in narcoleptic subjects as well as in the general population. For consolidating nighttime sleep, benzodiazepine hypnotics, gamma hydroxybutyrate (GHB) or sodium oxybate (NaGHB) are occasionally used, and nighttime administration of GHB reduces EDS and cataplexy during the daytime. GHB was classified as a schedule I controlled substance in 2000, but has recently been approved for the treatment of narcolepsy. Since amphetamine-like stimulants and modafinil have little effect on cataplexy, tricyclic antidepressants (such as imipramine or clomipramine) are used as these compounds reduce REM sleep. GHB is also used for the treatment of cataplexy, but the mechanisms of GHB action remain unknown (the antidepressants and GHB are also effective for the other REM sleep phenomena). Most of these compounds (amphetamines, modafinil and antidepressants) are known to act on monoaminergic systems. Animal data suggests that these compounds are effective for EDS and/or cataplexy, regardless of hypocretin receptor dysfunction and ligand deficiency, and they are likely to act on down-stream pathways of the hypocretin neurotransmission. A series of anatomical and functional findings suggest that these monoaminergic systems are likely to mediate the effects of hypocretin on vigilance and muscle tonus control. In addition, the loss of hypocretin input would possibly induce monoaminergic dysfunction.
Current pharmacological treatments are symptomatic treatments and do not cure the disease. Hypocretin/orexin peptides (or its mimetic) are the most promising agent for this ligand deficient condition. Unfortunately however, large molecular peptides do not penetrate to the brain efficiently, and oral administration is not applicable for neuropeptides. Therefore, non-peptide agonists need to be developed. Since most hypocretin receptors are G-protein coupled, 7-transmembraine receptors (as most neuropeptide receptors are), this method may become possible in the near future. Cell transplantation and gene therapy (preprohypocretin /orexin gene transfer using various vectors) might also be used to cure the disease in the near future.
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