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Synonyms and keywords: Narcolepsy, Cataplexy, Hypocretin/Orexin, Human Leukocyte Antigen (HLA), Rapid eye movement (REM) sleep, Gamma hydroxybutyrate
Narcolepsy is a debilitating lifelong rapid eye movement (REM) sleep disorder that has a typical onset during adolescence or early adulthood and is characterized by a classic tetrad of Excessive Daytime Sleepiness (EDS), cataplexy (sudden symmetric loss of muscle tone during wakefulness that is evoked by strong emotions), sleep paralysis and hypnagogic hallucinations (hallucinations while falling asleep). Other features include frequent irresistible sleep attacks, fragmented night sleep, loss of concentration and memory, hypnopompic hallucinations (hallucinations during waking up) and blurry vision. Narcolepsy is of two types: narcolepsy type 1 (formerly narcolepsy with cataplexy) and narcolepsy type 2 (formerly narcolepsy without cataplexy). Narcolepsy can have severe consequences for the patient with impairments in academic, social and occupational performances. Problems may include social stigma associated with the disease, reduced quality of life, difficulty in obtaining an education and keeping a job and socioeconomic consequences. It can restrict patients from having certain careers and activities. Narcolepsy is often under-diagnosed and 5-10 years of delay is common before making a firm diagnosis.
The earliest account of narcolepsy was described by Thomas Willis (1621-1675) in patients, "with a sleepy disposition who suddenly falls fast asleep." The first-ever descriptions of narcolepsy were reported by Westphal (1877) and Fisher (1878) in Germany. They also observed a hereditary factor; the mother of Westphal's patient and a sister of Fisher's patient had similar features. French physician Jean-Baptiste-Édouard Gélineau (1880) described this condition in a wine merchant as neurosis or a functional condition. He gave narcolepsy its name, which is the English form of the French word narcolepsie, and also recognized this disorder as a specific clinical entity. The term narcolepsy is derived by combining the Greek narke numbness, stupor and lepsis attack, to seize. [Source: entry Narcolepsy. In the Online Etymology Dictionary. Douglas Harper, Historian. 18 Sep 2007.  Cataplexy from the Greek kataplexis (fixation of the eyes), was first named by Loëwenfeld (1902). Kinnier Wilson (1928) first coined the term, "sleep paralysis." Large case series of narcolepsy were reported by Addie (1926), Wilson (1927), and Daniels (1934). Review of narcolepsy-cataplexy by Daniels is considered by many as one of the most insightful clinical reviews published. The classic description of narcolepsy tetrad was possible due to further work by Yoss and Daly at the Mayo clinic in 1957 and Bedrich Roth in Prague. Various methods were initially proposed in the treatment of narcolepsy until Prinzmetal and Bloomberg introduced amphetamines in 1935. After the discovery of tricyclic antidepressants in 1957, Akimoto, Honda, and Takahashi used imipramine in the treatment of human cataplexy. Methylphenidate was introduced by Yoss and Daly in the 1960s. REM sleep at the onset of sleep attack in narcoleptic patients was first ever recorded and reported by Vogel (1960), an observation extended by Rechschaffen and Dement in 1967. Hishikawa (1968) studied the EEG of narcoleptic patients. These authors together first articulated the now classical hypothesis of dissociated REM sleep and explained some symptoms of narcolepsy. Their discovery established a multiple sleep latency test as a standard diagnostic test for narcolepsy in 1970. Further research work by Nathaniel Kleitman at the University of Chicago and William Dement and Dr. Christian Guilleminault at Stanford University in the 1970's helped in establishing this classical hypothesis of dissociated REM sleep in narcolepsy. Various causes or lesions were proposed for narcolepsy. Tumors situated in relation to the third ventricle were suggested as a possible cause of narcolepsy by Wilson. Von Economo first recognized the posterior hypothalamus as a crucial region governing wakefulness. Canine narcolepsy in various breeds of dogs was identified in 1973, by Knecht and Mitler. The first epidemiological studies of narcolepsy were performed by Roth (1980) and Dement (1972-73). Link with the HLA-DQB1*0602 gene on chromosome 6 was established in 1980s. As many HLA associated disorders are also autoimmune in nature, it raised the possibility that narcolepsy may be an autoimmune disorder. Hypocretins (orexins) were identified in 1990s. In 1998, DeLecea and Sakurai identified hypocretins/orexins almost simultaneously with a difference of a few weeks. Hypocretin deficiency was associated with human narcolepsy by Nishino and Ripley in 2000.
The pathophysiology of narcolepsy is only partly understood with the involvement of both genetic and environmental factors. 75% discordance rate for narcolepsy in all described monozygotic twins supports the hypothesis that narcolepsy is a multifactorial disorder. Narcolepsy is considered to arise from multiple hits: the environmental factors, genetic predisposition, and triggering events lead to the selective, immune-mediated destruction, silencing or dysfunction of orexin-producing neurons. One study, published in 2018, described the presence of autoreactive CD4+ and CD8+ T cells in narcolepsy. Three subsequent publications further supported the hypothesis of a pivotal role of specific T cells in the neuronal damage seen in narcolepsy. The exact mechanism leading to the loss of the hypocretin producing neurons in most patients with narcolepsy and cataplexy is unknown. The loss of these neurons is highly selective, sparing the melanin-concentrating hormone (MCH) producing neurons, also in the lateral hypothalamus. This observation supports the prevailing hypothesis of narcolepsy being an autoimmune disorder. The autoimmune hypothesis is further supported by a strong association between narcolepsy, HLA-DQB1*06:02 allele, and polymorphisms in other immune-related genes. In addition, the incidence of narcolepsy follows a specific seasonal pattern, indicating an infectious trigger, although this observation was not found in all studies. Although circumstantial evidence supporting the autoimmune pathogenesis of narcolepsy is strong, direct evidence supporting this hypothesis is lacking with no clear signs of inflammatory processes in the central nervous system (CNS) of patients with narcolepsy and a clear increase in the incidence of narcolepsy in patients suffering from other autoimmune disorders has not been observed on a consistent basis. Immune modulating therapy did not show any improvement in the symptoms or alter the course of narcolepsy, even when administered close to the onset of disease, except for a single exceptional case report.
Hypocretins (the alternative name is orexins, from the Greek orexis for appetite) is neuroexcitatory peptides that promote wakefulness, stabilize behavioral states, couple the consciousness of wakefulness with the postural muscle tone, which is generally associated with it. Sakurai, T. et al. (1998) proposed that primary function of hypocretin (orexin) was related to food intake, because administration of hypocretin 1 in rodents lead to increased food intake. Research on the role of hypocretin (orexin) neurons in rodents revealed that stimulation of these neurons increases the probability of transitions from sleep to wakefulness while silencing of hypocretin neurons induces sleep during the inactive phase in rodents. Additional crucial and complex functions of hypocretins besides regulation of sleep and wakefulness include autonomic regulation, emotional processing, energy homeostasis, metabolic and endocrine functions, as well as consummatory and reward associated behaviors. Blouin and Fried (2013) reported that hypocretin and melanin-concentrating hormone levels in humans are linked to emotions and social interactions. They identified that concentrations of hypocretins in the brains of participants were highest during social interactions, or when participants experienced either positive emotion or anger, and were lowest before sleeping or when they were experiencing pain. Orexin A and B are small neuropeptides, which excite target neurons through orexin receptors type 1 and 2, respectively. The hypocretin system in humans comprises of almost 70,000 neurons that produce hypocretin in the lateral and posterior hypothalamus. These neurons project to almost the entire neuraxis. Hypocretin neurons have excitatory connections to wakefulness-promoting areas of the brain, including dopaminergic (ventral tegmental area and ventral periaqueductal grey matter), serotonergic (raphe nuclei), adrenergic (locus ceruleus), and histaminergic (tuberomammillary nucleus) regions in the brainstem and midbrain, among others. Loss of this crucial system leads to a general hypoarousal state, with a lower threshold required to fall asleep, which results in the symptoms of narcolepsy and disrupts function of multiple frontal, limbic, diencephalic and brainstem networks.
The regulation of transitions from sleep to wakefulness and distinct regions promoting sleep and wakefulness with mutually inhibitory connections resulting in a switching mechanism to avoid intermediate sleep and wake states explains the hypersomnia phenotype of narcolepsy patients. The normal hypocretin system of neurons stabilizes the switching mechanism by stimulating the wakefulness when the pressure of sleep rises during the day. Abnormal hypocretin system in narcolepsy patients with hypocretin deficiency results in an unstable switch mechanism, with uncontrolled daytime sleep attacks and excessive daytime sleepiness (EDS). After the discovery of the hypocretin neuropeptides, Lin, L. et al. (1999) identified an autosomal recessive loss of function mutation in HCRTR2 (also known as OXR2, which encodes hypocretin receptor 2), which was the cause of narcolepsy in Doberman pinschers. Chemelli, R. M. et al. (1999) reported in the same year that mice lacking hypocretin had a narcolepsy like phenotype. These studies on canines and mice lead to the discovery that narcolepsy patients lacked hypocretin. Hypocretin (orexins) deficiency (Hypocretin is profoundly decreased in CSF of narcolepsy patients) causes the disease, but hypocretin genes are not mutated, suggesting a more complex cause in humans. Immunostaining of hypocretin (orexin) neurons in humans revealed a concomitant loss of other markers (besides hypocretin) of hypocretin producing neurons (e.g, dynorphin, NARP) in the brains of narcolepsy patients, which supported the common belief that entire hypocretin neurons are missing from the brains of narcolepsy patients. Patients with narcolepsy are born with hypocretin producing neurons, but deficiency of hypocretin develops later in life and is closely linked to the onset of symptoms of narcolepsy. Postmortem brain analysis in a three autopsy series in patients with narcolepsy showed substantial (75-95%) or complete elimination of hypocretin-producing neurons in the lateral hypothalamus. It is also possible that some of these neurons are undetectable (due to silencing of orexin expression) but are not lost irreversibly.
Postmortem analysis did not reveal any effect on the other adjacent neurons of the lateral hypothalamus (such as melanin-concentrating hormone (MCH) producing neurons). Histopathology of the brain tissue showed increased gliosis but no inflammatory or neurodegenerative changes. Both Valko, P. and John, J. along with their respective teams independently reported in 2013, that narcolepsy patients have an increased number of histamine neurons (usually >50% higher than in healthy individuals) in their hypothalamic tuberomammillary nucleus, which is possibly a compensatory response to the loss of excitatory drive due to orexins. The immune-mediated process might also be the underlying reason for this increase in the number of histamine producing neurons in humans. Neuronal firing and release of histamine are maximal during wakefulness, which is usually diminished as a consequence of loss of histamine producing neurons or the inhibition of signaling of these neurons. Several studies in patients with narcolepsy and other central hypersomnias reported no differences in levels of histamine or its metabolite tele-methylhistamine, compared to healthy controls, suggesting that despite an increased number of histamine producing neurons in the brains of narcolepsy patients, the cerebrospinal fluid (CSF) levels of histamine and its metabolite are not useful biomarkers for narcolepsy. Narcolepsy patients with and without cataplexy may have normal levels of orexin in the CSF, while some patients with hypothalamic damage and subsequent low or absent levels of orexin in the CSF may not have any symptoms of narcolepsy or cataplexy. This observation suggests that a deficiency in orexin is not (always) necessary nor (always) sufficient to cause narcolepsy in humans.
Genetic and epigenetic factors
Studies conducted in twins for narcolepsy revealed only ~25% (20-35%) of concordance rate in monozygotic twins and concordance rate in other first-degree relatives was 1-2%, which suggests that genetic factors play an important role in the pathogenesis of narcolepsy with cataplexy. Only 1-2% cases of narcolepsy are familial. Less than 2% of patients with narcolepsy have more than 1 affected family member, while multiplex families (families with more than 2 members) are rare. Up to 11% of first-degree relatives of patients with narcolepsy have also reported symptoms of this disease. Variants of genes, which encode MHC class II are the main genetic risk factors of this disorder. Narcolepsy has a close association with the human leukocyte antigen (HLA) class II (HLA genes encode MHC molecules that present antigenic peptides to CD4+ helper T cells) region. HLA-DQB1*06:02 is expressed in 86–98% of patients with narcolepsy type 1 and in ~40–50% of patients with narcolepsy type 2. HLA-DQB1*06:02 allele is the main genetic risk factor for narcolepsy with cataplexy. Other human leukocyte antigen (HLA) class II alleles are also associated with narcolepsy, although to a lesser extent than HLA-DQB1*06:02. Some individuals in the general population (5-38%) can also express HLA-DQB1*06:02, while only 1 individual out of 1,000 carriers of this allele will eventually develop narcolepsy. Almost all patients with narcolepsy type 1 (except at least 2%) carry the HLA-DQB1*06:02 alleles, whether this represents a fundamentally different disease or a similar disease with only a minor variation is unknown. Although the latter explanation is supported by the finding of an over represented, very rare HLA-DPB1*09/10 alleles in narcolepsy patients without HLA-DQB1*06:02 alleles, which suggests similar disease mechanism in these patients, except antigen, is presented by a different MHC molecule.
Association between HLA-DQB1*06:02 positivity in the general population and shorter REM sleep latency, suggest that this EEG finding during sleep might represent a (first) biomarker of an increased risk of developing narcolepsy. Jewish, Sardinian and Saudi populations have a low frequency of this allele (< 5%), which might explain rare cases of narcolepsy in these populations. Higher frequency of HLA-DQB1*06:02 allele in Northern European (25%) and African American (38%) populations explains higher prevalence of narcolepsy in these populations. Extremely high linkage is present between HLA‑DQB1*06:02 and HLA-DQA1*01:02, which suggests that patients carrying HLA-DQB1*06:02 alleles also carry HLA-DQA1*01:02 on the same chromosome. HLA-DQA1*01:02 can also be carried by other HLA-DQB1 alleles, but the risk of narcolepsy in those cases is increased only slightly or remains unchanged. Other genes, which encode MHC class II proteins (e.g, variants of HLA-DQ and HLA-DP) can also predispose individuals to develop narcolepsy, although to a lesser extent. HLA-DQB1*03:01 allele increases the risk of narcolepsy by 1.5‑fold while the onset of narcolepsy in Asian carriers of this allele was 2 years earlier than those who were non-carriers. HLA-DPB1 alleles also affect the risk of developing narcolepsy. HLA-DPB1*05:01 predispose individuals to develop narcolepsy, while HLA-DPB1*04:01 and HLA-DPB1*04:02 protect against the development of narcolepsy.
Weak association between human leukocyte antigen (HLA) class I genes (A, B and C) and narcolepsy has also been reported, which suggests that pathogenesis of narcolepsy involves cytotoxic immune mechanism (response mediated either by cytotoxic CD8+ T cells or natural killer (NK) cells) and these patients might have an increased genetic susceptibility to infections. Human leukocyte antigen (HLA) class I genes encode MHC class I molecules that present antigenic peptides to CD8+ T cells. Genome-wide association study (2010) identified protective alleles in both human leukocyte antigen (HLA) class I and class II genes, which might explain the role played by these protective alleles in causing the delay (or absence) of the evolution of narcolepsy seen in some patients. Genome-wide association study also reported an association between susceptibility to narcolepsy and polymorphism in TRAC (which encodes the T cell receptor α-constant domain), further supporting the hypothesis that narcolepsy is an immune-mediated disease. Associations between the narcolepsy and polymorphisms in other immune related genes have also been reported, including P2RY11 (modulates an autoimmune response to the infection and encodes P2Y receptor 11), TNFSF4 (which encodes tumor necrosis factor (TNF) ligand superfamily member 4), the chemokine receptor CCR1-CCR3 region and CTSH (which encodes pro-cathepsin H). No consistent associations were reported on performing gene sequencing studies in patients with familial narcolepsy, although mutations were identified in MOG (which encodes myelin oligodendrocyte glycoprotein), HCRT (which encodes the hypocretin, orexin), and P2RY11 genes, which modulate the immune response. These rare mutations point towards an entirely different pathogenesis of the disease.
Narcolepsy occasionally occurs in association with autoimmune diseases, such as celiac disease, multiple sclerosis and systemic lupus erythematosus (SLE) and paraneoplastic syndromes, which suggests that narcolepsy may have an autoimmune pathogenesis. Cvetikovic-Lopes, V. (2010) and Bergman, H. (2014) reported the presence of a few types of autoantibodies in the sera of narcolepsy patients. Although this finding is nonspecific as these antibodies were also detected in the sera from healthy controls and patients with other sleep disorders. Most of the studies, with a few exceptions, trying to find circulating autoantibodies as an evidence of autoimmunity and a possible underlying cause of hypocretin deficiency in patients with narcolepsy, yielded negative results. Antibodies against tribbles homolog 2 (TRIB2), which is a protein produced by many cells including hypocretin neurons, have been identified in many patients with narcolepsy, usually less than one year after the onset of disease.  These autoantibodies have also been found in patients with autoimmune uveitis. However, TRIB2 antibodies were not reported in patients with narcolepsy associated with H1N1 influenza immunization. Most likely, TRIB2 autoantibodies do not have a direct causative role in narcolepsy, because these autoantibodies have also been found in other neuronal populations and cell types. Other autoantibodies have been detected in the sera of patients with narcolepsy including antibodies against the common carboxy-terminal epitope of the neuropeptide glutamic acid-isoleucine and α‑melanocyte stimulating hormone (NEI/αMSH). The anti-NEI/αMSH antibodies bind to melanin concentrating hormone (MCH) producing neurons, which are connected at functional levels with hypocretin neurons and regulate sleep processes. Ahmed, S. S. et al. (2015) reported autoantibodies against hypocretin (orexin) receptor 2 (HCRTR2) in 17 out of 20 Finnish patients with narcolepsy.
In both of these studies, the autoantibodies were also reported in some healthy controls and in the sera of patients with other sleep-related disorders (e.g., sleep apnea, idiopathic hypersomnia, parasomnias, major depressive disorder, and restless legs syndrome), which argues against a causal relationship of these autoantibodies with narcolepsy. Katzav, A. et al. (2013) reported passive transfer of narcolepsy into mice with intracerebral and intraventricular administration of anti‑TRIB2 antibodies or anti-NEI/αMSH antibodies, which revealed changes in sleep patterns suggesting some functional relevance. Injection of anti-NEI/αMSH antibodies induced a strong increase in sleep fragmentation, which is an important symptom of narcolepsy. No other symptoms of narcolepsy were reported in these mice, so clear evidence pointing towards the role of these autoantibodies in the development of narcolepsy is still missing. These autoantibodies could possibly be due to neuronal damage (owing to an immune-mediated process) or could be present before the onset of disease and confer a higher risk of developing narcolepsy in some individuals. Anti-Ma encephalitis can destroy hypocretin neurons, leading to narcolepsy like symptoms, but screening of anti-Ma antibodies in patients with narcolepsy did not reveal the presence of these antibodies. Blood samples from patients with narcolepsy identified CD4+ helper T cells with reactivity towards hypocretin. However, whether the presence of CD4+ helper T cells is specific to narcolepsy or these cells trigger the disease or they appear in response to the destruction of hypocretin neurons is not clear yet. Although the presence of these cells strongly supports the autoimmune hypothesis of narcolepsy.
In 2009, Dauvilliers, Y., Abril, B., and Mas, E. reported that patients with narcolepsy respond to immunomodulatory treatment. Luo, F. et al. (2018) suggested that molecular mimicry of a particular piece of the influenza haemagglutinin protein might trigger an autoimmune process targeting orexin neurons. Further support for hypothesis that an autoimmune process contributes to narcolepsy includes the occasional presence of inflammatory findings in cerebrospinal fluid (e.g, pleocytosis and oligoclonal bands), although evidence for the presence of disease specific antibodies is lacking. Increased levels of CD4+ T cells (helper T cells), some cytokines (Tumor necrosis factor (TNF) and interferon-gamma (IFNγ)), and activation of CD4+ and CD8+ T cells (cytotoxic T cells), have been reported in the serum and to some extent also in the cerebrospinal fluid (CSF) of patients with narcolepsy. However, studies assessing the levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF) in the serum of patients with narcolepsy revealed inconsistent results. Some studies reported differences in the levels of interleukin 4 (IL-4) and CC-chemokine ligand 3 (CCL3) in the cerebrospinal fluid (CSF) between patients with narcolepsy and healthy controls. However, there was no consistent alteration of cytokine levels in patients with narcolepsy and cataplexy, even very close to the onset of symptoms. Autoreactive CD4+ and CD8+ T cells have been identified in patients with narcolepsy, which specifically target antigens expressed by orexin neurons.
75% discordance rate for narcolepsy in all described monozygotic twins points to a contribution of environmental factors. Reported association between the risk of narcolepsy and season of birth in some but not all studies suggested that early life exposure to viruses, bacteria or toxins might alter the immune system development and thereby predispose individuals to narcolepsy. Subsequent exposure of these predisposed individuals to these or other environmental factors (infections) might trigger or reactivate an immune response leading to the destruction of orexin neurons. Symonds, C. (1922), Redlich, E. (1924), and Mankowski, B. (1926) initially reported a temporal association between influenza or epidemic encephalitis lethargica and the onset of narcolepsy. Aran, A. et al. (2009) reported elevated titers of antistreptococcal antibodies in patients with recent-onset narcolepsy, which suggested an association of narcolepsy with other upper respiratory tract infections, particularly β-hemolytic streptococcal infections. Increased levels of antistreptococcal antibodies were reported in patients with narcolepsy compared to healthy controls, with higher titres in individuals with a recent onset of narcolepsy. Ambati, A. et al. (2015) reported an increased Beta-hemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular (mediated by cytotoxic T cells) immune responses to streptococcal antigens in samples of Swedish narcolepsy patients. Further support towards the role of streptococcal infections and the development of narcolepsy was provided with a reported association between infection with streptococcus pyogenes and other neurological disorders and some autoimmune neuropsychiatric disorders in children that target basal ganglia neurons.
The most important reported association of narcolepsy with infections involves the influenza A virus (subtype H1N1). In 2009-2010, a statistically significant six to a ninefold increase in the risk of narcolepsy was reported in the northern European countries (eg, Finland, Sweden, Norway), Ireland, France and the United Kingdom, subsequent to vaccination campaign (with the Pandemrix vaccine) against the pandemic H1N1 influenza. The highest risk of developing narcolepsy after immunization with the Pandemrix vaccine was reported in individuals less than 20 years of age, but the risk was also slightly increased in adult patients. Although the relative risk was generally three to twelve-fold high, the incidence of narcolepsy remained low with only 1 reported case per 16,000 individuals that were immunized. This inflation of association between Pandemrix vaccine and narcolepsy might be explained by increased media attention and detection as well as inclusion bias, while the true association is probably lower. However, this increased risk of narcolepsy due to immunization with the Pandemrix vaccine was observed in most countries, regardless of media coverage. This association was not observed with any other influenza vaccines that targeted H1N1 influenza A virus (e.g, Arepanrix, an almost identical vaccine used in South America and Canada), which might be explained due to the differences in vaccine content of different influenza vaccines. Childhood onset of narcolepsy might also be related to the H1N1 influenza infections pandemic of 2010-2011, which suggests that H1N1 influenza virus infection itself or some influenza vaccines might trigger the development of narcolepsy. Narcolepsy has also been reported to occur following other vaccinations (e.g, Post Tick-borne encephalitis virus vaccination narcolepsy with cataplexy), these associations could be coincidental or not causal.
A case-control study (2007) of the environmental risk factors for narcolepsy in the United States showed that the strongest risk factor for narcolepsy was self-reported flu during the previous year. Han, F., Lin, L., and Li, J. (2013) reported a peak in the incidence of H1N1 influenza infections in China in late 2009, due to absence of the influenza vaccination, which was subsequently followed by a threefold increase in the incidence of narcolepsy during the winter of 2009–2010, compared with both previous and subsequent years. This observation suggested a temporal association between the peak in the infections due to the H1N1 influenza A virus and a peak in the incidence of narcolepsy, 3 to 6 months later. Return of the incidence of narcolepsy back to baseline in the following years suggested an association between infection with the 2009 H1N1 influenza virus strain and the onset of narcolepsy. A review of Chinese data before 2009 revealed a seasonal pattern in the onset of narcolepsy with most cases of sleepiness being reported within 6 months after the winter season. Although a peak in the incidence of narcolepsy was reported in China, it was not observed in Taiwan despite exposure to the same epidemic. Whether infection with H1N1 influenza A virus was the underlying factor for the development of narcolepsy in Northern European patients remains unknown, but one study argued against this hypothesis, as only 2.2% of narcolepsy patients with immunization history with Pandemrix vaccine had infection specific antibodies against the H1N1 influenza A virus. Lankford, D. (1994) and Silber, M. H. (2005) reported occurrence of narcolepsy after traumatic brain injury.
Epidemiology and Demographics
The prevalence of narcolepsy in white individuals from North America and Europe is estimated to be ~200–500 cases per million individuals. Although prevalence in most Asian populations is similar to white populations, possible differences specific to each population do exist. The highest prevalence of narcolepsy occurs in Japanese population (1,600 cases per million individuals), while the lowest prevalence occurs in Arabic and Jewish populations (2–40 cases per million individuals). African-Americans have a prevalence of 420 cases of narcolepsy per million individuals. The differences of prevalence between populations is possibly explained by the exposure to environmental factors (e.g infections) or the prevalence of genetic risk factors. African-Americans usually have lower than average socioeconomic status, which could also influence the prevalence of narcolepsy, as lower socioeconomic status in general causes an increased risk of infections and morbidity. The global prevalence of narcolepsy in the overall population is 25-50 cases (0.025%-0.05%) per 100,000 individuals. The exact incidence of narcolepsy with cataplexy remains unknown, because of uncertainties regarding the narcoleptic borderland (particularly narcolepsy type 2). Narcolepsy can occur in both men and women, although in some studies, it affected more male than female individuals, which may be due to contribution by genetic and environmental factors. Whether this higher risk of narcolepsy in males compared to females (1.6–1.8 males per 1 female) is due to a true sex effect or referral bias is unknown, because most of the epidemiological studies included too few cases to look at sex differences. Male patients in European populations with narcolepsy showed a later onset of the daytime sleepiness symptoms but with a shorter delay to diagnosis. Morbidity and mortality data of middle-aged and elderly narcoleptics indicating increased mortality in patients with narcolepsy remains controversial. Although narcolepsy can occur at any age (ranging from 3 years of age to 80 years), most cases of narcolepsy usually start in adolescence, with a small second peak of onset occurring at around 35 years of age (ranging from 30 to 39 years of age). In some patients (10-15%), narcolepsy may start before the age of 10 years. However, childhood-onset narcolepsy was systematically studied only in rare studies before the current century. Long diagnostic delay of 8 to 12 years from the onset of disease can underestimate the prevalence of narcolepsy. However, in recent years, more cases (especially in children) have been diagnosed sooner after onset, probably due to increasing awareness of the disease.
Narcolepsy can have an acute, chronic, or a progressive course, which possibly reflects different pathophysiologic mechanisms. In the acute course, symptoms usually develop within a few days or weeks after a triggering event (e.g, immunization, stress, head trauma). In the chronic course, onset of symptoms is difficult to determine, while in progressive course onset of different symptoms is separated by years or even decades. In a series of studies regarding the clinical spectrum of narcolepsy with cataplexy, cataplexy and excessive daytime sleepiness (EDS) both developed at the same time in 49% of the study participants, while cataplexy developed after excessive daytime sleepiness (EDS) in 43% of patients. Cataplexy developed before excessive daytime sleepiness (EDS) in only 8% of the study participants. These studies revealed that the usual interval between the onset of excessive daytime sleepiness (EDS) and onset of cataplexy is usually less than 2 to 3 years but it can exceed up to 40 to 50 years. Narcolepsy patients without cataplexy can enter remission as it can be a transient presentation, whereas remission in patients with narcolepsy with cataplexy is very unlikely (remission of narcolepsy with cataplexy has been reported only once in a patient who received immunotherapy soon after the onset of disease. Symptoms of narcolepsy often improve over time and the severity of both, excessive daytime sleepiness (EDS) and cataplexy usually decrease with increasing age, possibly due to coping mechanisms.
According to an estimation, as many as 3 million people worldwide are affected by narcolepsy. Narcolepsy is as widespread as Parkinson's disease or multiple sclerosis and it is more prevalent than cystic fibrosis, but it is a less well-known disease. Narcolepsy can be mistaken for depression, epilepsy, or as a side effect of some medication. There is strong evidence that narcolepsy is a familial disorder and may run in the families; 8-12% of people with narcolepsy usually have a close relative with this neurologic disorder. There is an average delay of 15 years between onset and correct diagnosis which may contribute substantially to the disabling features of the disorder. Cognitive, educational, occupational, and psychosocial problems have a reported association with the excessive daytime sleepiness of narcolepsy. These problems are especially damaging in teenagers, who are developing their self-image, getting an education, and making their occupational choices in the meantime. While cognitive impairment does occur in patients with narcolepsy, it may only be a reflection of the excessive daytime sleepiness (EDS).
Diagnosis is relatively easy when all the symptoms of narcolepsy are present. But if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult.
Two tests that are commonly used in diagnosing narcolepsy are the polysomnogram and the multiple sleep latency test. These tests are usually performed by a sleep specialist. The polysomnogram involves continuous recording of sleep brain waves and a number of nerve and muscle functions during nighttime sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may awaken often during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness.
For the multiple sleep latency test, a person is given a chance to sleep every 2 hours during normal wake times. Observations are made of the time taken to reach various stages of sleep. This test measures the degree of daytime sleepiness and also detects how soon REM sleep begins. Again, people with narcolepsy fall asleep rapidly and enter REM sleep early.
DSM-V Diagnostic Criteria for Narcolepsy
Narcolepsy patients usually have a variable combination of symptoms, related to sleep and wakefulness, as well as cognitive, motor, emotional, psychiatric, autonomic and, metabolic disturbances reflecting the hypothalamic origin of the disease.
Excessive daytime sleepiness
Excessive daytime sleepiness (EDS) is usually most disabling and the leading symptom of narcolepsy, which typically presents as an inability to stay awake or as a subjective feeling of sleepiness with difficulty in sustaining attention, even after adequate night time sleep. Excessive daytime sleepiness (EDS) is typically irresistible, often already present in the morning hours and patients experience sleep attacks with rapid transition into sleep, often at inappropriate times and places. Khatami, R. et al. (2016) reported involuntary napping in 80% of 1,079 European patients with narcolepsy. These episodes of overwhelming, excessive daytime sleepiness (EDS) predominantly occur in monotonous situations but can also occur in active patients. Naps are usually but not invariably short (with a duration of 15 to 20 minutes), refreshing (only for a few hours), and are also associated with oneiric experiences. These daytime naps can occur several times during the day, may occur without warning and can be physically irresistible. Patients with excessive daytime sleepiness (EDS) can develop automatic behaviors (e.g, writing over the border of a piece of paper, abnormal behaviors upon waking such as putting salt in the coffee or driving to the wrong destination). These so-called automatic behaviors are experienced as blackouts because patients can be amnesic during these episodes. Resisting sleep might increase the risk of developing such behaviors in patients with narcolepsy, but they can also manifest with nonspecific symptoms such as hypoacusis, headache, and sensory or visual disturbances. Excessive daytime sleepiness (EDS) must be distinguished from fatigue, which is reported by up to 60% of patients with narcolepsy and is more resistant to therapy than excessive daytime sleepiness (EDS). Fatigue also increases the burden of excessive daytime sleepiness (EDS) by impairing daytime activity, which is a major measure to combat excessive daytime sleepiness (EDS). Narcolepsy patients are usually unable to maintain vigilance during the daytime with an inability to maintain sleep states during the night time (nocturnal sleep may be fragmented with frequent awakenings), but the total amount of sleep is usually not increased over the course of the day. Narcolepsy patients have sleep instability with increased transitions between non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and increased transitions from non-rapid eye movement (NREM) sleep to wakefulness, which further supports the hypothesis of hypocretin involvement in stabilizing sleep stages. Narcolepsy patients can also have REM sleep behavior disorder (defined as REM sleep without muscle atonia and increased intermittent activity of muscles during REM sleep), also linked to hypocretin deficiency. Additional associated clinical symptoms include dream enactment, increased motor activity during sleep, and disturbed sleep.
Cataplexy, the only specific symptom of narcolepsy (generally considered to be unique to narcolepsy), is an episodic condition, defined as brief episodes of bilateral loss of muscle tone triggered by strong emotions with a normal state of consciousness. The person suffering from cataplexy remains conscious throughout the episode. Partial attacks of cataplexy are very short, usually lasting only 2 to 10 seconds unless the trigger remains present. Muscle atonia manifests as face drooping, sagging of the jaw, eyelid closure, passive tongue protrusion, dysarthria, and bilateral loss of motor control of the extremities. In children, atonia of the facial muscles (also known as facies cataplectica) with mouth opening and tongue protrusion can also be observed. Cataplexy can range from slight muscle weakness (e.g, limpness at the neck or knees, inability to speak clearly) to complete body collapse. Cataplectic immobility (complete inability to move) is reported by only a few patients. Although one-third of patients report falls, injuries are rare. Typically, deep tendon reflexes (DTRs) are transiently abolished but can persist in patients who suffer from partial or mild episodes. Babinski sign, which is upward movement (dorsiflexion) of the big toe after stimulation of the sole of the foot, rather than normal downward movement (plantar flexion) in adults, can appear transiently while Parkinson disease-related tremor might persist.
Partial attacks of cataplexy can evolve over seconds to complete attacks, which usually have a duration of fewer than 2 minutes; cataplexy attack duration of more than 5 minutes is unusual and often related to the withdrawal of anti-cataplectic drugs. Unilateral dominance of symptoms is atypical, and cataplexy attacks that involve single muscles are exceptional. The frequency of cataplexy attacks can vary from dozens per day to a few per year. Hyperkinesias, in the form of tonic (tongue protrusion, facial grimacing or extension of the neck), phasic (facial muscles twitching), and repetitive motor activities, are sometimes superimposed on muscle atonia and can be misdiagnosed as epilepsy or a movement disorder. These positive motor phenomena are usually more common at the onset of disease and in children.
Four other classic symptoms of narcolepsy, which may not occur in all patients, are cataplexy, sleep paralysis, hypnogogic hallucinations, and automatic behavior. Episodes of cataplexy may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear, and may last from a few seconds to several minutes. Sleep paralysis is the temporary inability to talk or move when waking up. It may last a few seconds to minutes. This is often frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening. Automatic behavior means that a person continues to function (talking, putting things away, etc.) during sleep episodes, but awakens with no memory of performing such activities. It is estimated that up to 40 percent of people with narcolepsy experience automatic behavior during sleep episodes. Daytime sleepiness, sleep paralysis, and hypnagogic hallucinations also occur in people who do not have narcolepsy, more frequently in people who are suffering from extreme lack of sleep.
In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not.
Although these are the common symptoms of narcolepsy, many (although less than 40% of people with narcolepsy) also suffer from insomnia for extended periods of time. This is most often from
- An excess of sleep.
- Use of self-medications such as energy drinks, or caffeinated drinks.
The symptoms of narcolepsy, especially the excessive daytime sleepiness and cataplexy, often become severe enough to cause serious problems in a person's social, personal, and professional life.
Normally, when an individual is awake, brain waves show a regular rhythm. When a person first falls asleep, the brain waves become slower and less regular. This sleep state is called non-rapid eye movement (NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again. This sleep state, called REM sleep (rapid eye movement sleep), is when most remembered dreaming occurs. Associated with the EEG observed waves during REM sleep muscle atonia is present (called REM atonia).
In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Thus, narcolepsy is a disorder in which REM sleep appears at an abnormal time. Also, some of the aspects of REM sleep that normally occur only during sleep — lack of muscular control, sleep paralysis, and vivid dreams — occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep. This has several consequences:
- Nighttime sleep does not include much deep sleep, so the brain tries to "catch up" during the day, hence EDS
- May visibly fall asleep at any moment (such motions as head bobbing are common)
- People with narcolepsy fall quickly into what appears to be very deep sleep
- They wake up suddenly and can be disoriented when they do (dizziness is a common occurrence)
- They have very vivid dreams, which they often remember
- People with narcolepsy may dream even when they only fall asleep for a few seconds.
The drowsiness is normally treated using amphetamine-like stimulants such as methylphenidate, racemic amphetamine, dextroamphetamine, and methamphetamine, or modafinil, a new stimulant with a different pharmacologic mechanism.
Other medications used are codeine and selegiline. Another drug that is used is atomoxetine (Strattera), a non-stimulant and Norepinephrine reuptake inhibitor (NRI), that has little or no abuse potential. In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS to a low or non-existent level. Cataplexy is frequently treated with tricyclic antidepressants such as clomipramine, imipramine, or protriptyline. Venlafaxine, a newer antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy. Gamma-hydroxybutyrate (GHB), a medication recently approved by the US Food and Drug Administration, is the only medication specifically indicated for cataplexy. Gamma-hydroxybutyrate has also been shown to reduce symptoms of EDS associated with narcolepsy. While the exact mechanism of action is unknown, GHB is thought to improve the quality of nocturnal sleep.
Treatment is tailored to the individual based on symptoms and therapeutic response. The time required to achieve optimal control of symptoms is highly variable, and may take several months or longer. Medication adjustments are also frequently necessary, and complete control of symptoms is seldom possible. While oral medications are the mainstay of narcolepsy treatment, lifestyle changes are also important. The main treatment of excessive daytime sleepiness in narcolepsy is with a group of drugs called central nervous system stimulants. For cataplexy and other REM-sleep symptoms, antidepressant medications and other drugs that suppress REM sleep are prescribed.
In addition to drug therapy, an important part of treatment is scheduling short naps (10 to 15 minutes) two to three times per day to help control excessive daytime sleepiness and help the person stay as alert as possible. Daytime naps are not a replacement for nighttime sleep.
Ongoing communication between the health care provider, patient, and the patient's family members is important to optimal management of narcolepsy.
Coping with Narcolepsy
Learning as much about narcolepsy as possible and finding a support system can help patients and families deal with the practical and emotional effects of the disorder, possible occupational limitations, and situations that might cause injury. A variety of educational and other materials are available from sleep medicine or narcolepsy organizations.
Support groups exist to help persons with narcolepsy and their families.
Individuals with narcolepsy, their families, friends, and potential employers should know that:
- Narcolepsy is a life-long condition that may require continuous medication.
- Although there is no cure for narcolepsy at present, several medications can help reduce its symptoms.
- People with narcolepsy can lead productive lives if they are provided with proper medical care.
- If possible, individuals with narcolepsy should avoid jobs that require driving long distances or handling hazardous equipment or that require alertness for lengthy periods.
- Parents, teachers, spouses, and employers should be aware of the symptoms of narcolepsy. This will help them avoid the mistake of confusing the person's behavior with laziness, hostility, reject ion, or lack of interest and motivation. It will also help them provide essential support and cooperation.
- Employers can promote better working opportunities for individuals with narcolepsy by permitting special work schedules and nap breaks.
Doctors generally agree that lifestyle changes can be very helpful to those suffering with narcolepsy. Suggested self-care tips, from the National Sleep Foundation, University at Buffalo, and Mayo Clinic, include:
- Take several short daily naps (10-15 minutes) to combat excessive sleepiness and sleep attacks.
- Develop a routine sleep schedule – try to go to sleep and awaken at the same time every day.
- Alert your employers, coworkers and friends in the hope that others will accommodate your condition and help when needed.
- Do not drive or operate dangerous equipment if you are sleepy. Take a nap before driving if possible. Consider taking a break for a nap during a long driving trip.
- Join a support group.
- Break up larger tasks into small pieces and focusing on one small thing at a time.
- Take several short walks during the day.
- Carry a tape recorder, if possible, to record important conversations and meetings.
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