INVITED REVIEW SERIES: TRANSLATING RESEARCH INTO PRACTICE
Sleepiness that cannot be overcome: Narcolepsy and cataplexy
The Author: Fang Han, MD, is Professor and sleep specialist in the Department of Respiratory Medicine, Peking University People's Hospital, with research interests in respiratory regulation in sleep apnoea and genetic studies on narcolepsy. He serves as the President of the Chinese Sleep Research Society.
SERIES EDITORS: JOHN E HEFFNER AND DAVID CL LAM
Fang Han, Department of Respiratory Medicine, The Peking University People's Hospital, Beijing 100044, China. Email: email@example.com
Narcolepsy–cataplexy syndrome is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. It is strongly associated with the genetic marker, human leucocyte antigen (HLA) DQB1*06:02. A deficit in the endogenous hypocretin/orexin system due to neuronal degeneration in the lateral hypothalamus, induced by an autoimmune-mediated process, is the primary pathophysiology associated with the human disease. The important finding of an association with hypocretin genes in animal models of narcolepsy has led to the establishment of cerebrospinal fluid hypocretin measurements as a new diagnostic test for human narcolepsy. This is a fascinating story of translation of basic science research into clinical practice in sleep medicine during the past decade. Recent advances have shed light on the associations between respiratory medicine and narcolepsy–cataplexy research. The first is that upper airway infections, including H1N1 and/or streptococcal infections, may initiate or reactivate an immune response that leads to loss of hypocretin-secreting cells and narcolepsy in genetically susceptible individuals. The second is that an increased incidence of sleep disordered breathing among narcoleptic subjects may relate to the impairment of central control of breathing, linked to hypocretin deficiency or carriage of HLADQB1*06:02, in animals and human subjects with narcolepsy, respectively, indicating neural dysfunction in an area where respiratory and sleep–wake systems are closely interrelated.
Excessive daytime sleepiness (EDS) or hypersomnia is defined as the inability to stay awake and alert during the major waking episodes of the day and results in unintended lapses into drowsiness or sleep.1 It has critical implications for human productivity and safety, as EDS can result in reduced quality of life, impairment of mood and cognitive function, and increased risk of motor-vehicle accidents. The problem is estimated to affect up to 9% of the general population,2 and 15–30% of patients are suffering from sleep disorders. It is one of the most common complaints evaluated by sleep specialists. For this reason, all respiratory physicians should know the causes of sleepiness, and many who are interested in obstructive sleep apnoea–hypopnoea syndrome (OSAHS) will manage patients with other causes of sleepiness.3
Besides sleep apnoea, the main non-respiratory sleep disorder causing EDS is narcolepsy–cataplexy syndrome. All narcoleptic subjects present with chronic sleepiness. Cataplexy, typically presenting as an abrupt and reversible decrease or loss of muscle tone usually elicited by strong emotions, is the most specific symptom. Narcolepsy–cataplexy syndrome is the best-understood hypersomnia, due in large part to the elucidation of the role of hypocretin (orexins) in the pathophysiology of human narcolepsy–cataplexy.4–7 This was based on the discovery that hypocretin genes were associated with animal models of narcolepsy,4,5 followed by the findings of strikingly low levels of hypocretin-1 in cerebrospinal fluid (CSF)6 and loss of hypocretin-producing neurons in the hypothalamus on post-mortem examination of human subjects with narcolepsy.7 This has led to the development of new diagnostic tests, and possibly, to targeted treatments. Low CSF levels of hypocretin were included in the diagnostic criteria for narcolepsy in the second revision of the International Classification of Sleep Disorders.1 It is now well recognized that more than 95% of patients with definite cataplexy who carry the human leucocyte antigen (HLA) DQB1*06:02 can be predicted to have a deficiency of CSF hypocretin.8 This tight association with HLA DQB1*06:02 also implies that an autoimmune process may lead to the destruction of hypocretin-secreting cells, with the possible involvement of infectious agents. Because hypocretins are involved in various hypothalamic functions,9 hypocretin-deficient narcolepsy–cataplexy could possibly be used as a model disorder to further our understanding of rapid eye movement (REM) sleep and the regulation of sleepiness in humans. New evidence from animal and human studies suggests that narcolepsy–cataplexy are associated with a deficiency in the regulation of breathing and an increased incidence of sleep apnoea.10–16
The major breakthrough in narcolepsy research during the past decade is a fascinating story of translation of basic science and clinical investigative discoveries into the improvement of patient care. This review presents an overview of the clinical aspects of human narcolepsy–cataplexy17 and will focus on recognition of the disease and on new basic science and clinical insights that help us to understand current research into elucidation of the pathophysiology of human narcolepsy–cataplexy syndrome.
Narcolepsy affects 0.03–0.16% of the general population in various ethnic groups.18–21 There is a spectrum of narcolepsy phenotypes, including narcolepsy with cataplexy, narcolepsy without cataplexy and rare cases of secondary narcolepsy.1 The prevalence of narcolepsy with cataplexy is between 25 and 50 per 100 000.22 Information on incidence is limited, with one study finding an incidence of narcolepsy with cataplexy of 0.74 per 100 000 person-years.21 The majority of patients begin to show symptoms in the second decade of life, and the distribution is bimodal, with a large peak around puberty and a smaller peak between 35 and 45 years of age.23 An earlier onset of disease has been noted among Chinese subjects.23 Although it was originally thought that there was no strong gender disparity in the prevalence of narcolepsy, newer data suggest that men are more commonly affected, with narcolepsy occurring 1.6 times more frequently than in women.22,24 Most cases of narcolepsy in humans are sporadic. Up to 5% are familial cases, and the risk of a first-degree relative developing narcolepsy–cataplexy is 1–2%, which is 10–40 times higher than that for the general population.25
The classic tetrad of narcolepsy symptoms include sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Not all symptoms occur in all patients, and they may vary in frequency and intensity over time. EDS and cataplexy are the cardinal symptoms of narcolepsy, with EDS often being the most disabling symptom. It is well recognized that patients experience recurring sleepiness and cataplectic attacks as a homogeneous clinical entity, and this is now known to be associated with hypocretin deficiency.8
EDS is the most common symptom and usually the first to occur. It persists throughout the patient's life. EDS presents as unwanted episodes of sleep during monotonous sedentary activities and also in bizarre situations where the patients are fully involved in a task such as eating, walking, talking, cycling or driving. Sleepiness is most often relieved by short naps, and there is a refractory period of a couple of hours before the next episode occurs. The duration of the sleep attacks can vary from a few seconds to over an hour. The episodes of overwhelming sleepiness are repeated several times every day, and the short naps are very often associated with dreaming.
Cataplexy, which is a unique characteristic of narcolepsy, is the best diagnostic marker of the disease. It is characterized by sudden episodes of bilateral muscle weakness provoked by strong emotions, particularly positive emotions such as joking, laughing or pleasant surprise, and less frequently by negative emotions such as anger. Most often, it is mild and occurs as a simple buckling of the knees, dropping of the head, flickering of facial muscles, sagging of the jaw or weakness in the arms. Slurred speech or mutism also frequently occurs. Cataplectic episodes usually last for a few seconds to several minutes; ‘status cataplecticus’ comprising continual cataplectic episodes lasting several hours occasionally occurs in children with recent-onset narcolepsy,24 or more often upon withdrawal of anti-cataplectic drugs.26 The frequency of cataplexy shows wide interpersonal variation, from rare events over long periods in some patients to numerous attacks per day in others. All antigravity muscles may be affected, but the diaphragm and eye muscles are not. Cataplexy worsens with poor sleep and fatigue and often improves with advancing age. In most patients, it is better controlled, and only in rare cases does it disappear completely. Awareness is preserved throughout the attacks, unless the patient subsequently falls asleep or begins to have hypnagogic hallucinations. Falls and injury are rare, and patients are often aware of these attacks and take action to find support or will sit down when they perceive that an attack is coming on. Clinicians should specifically ask about incomplete forms of cataplexy, because the patient might not necessarily perceive these as being pathological. Neurological examination performed at the time of an attack shows a suppression of the patellar reflex.27,28
Patients with narcolepsy–cataplexy may suffer from hallucinations and sleep paralysis, either at the onset of sleep or upon awakening. More than 50% of patients report disturbed nocturnal sleep and poor sleep quality. These symptoms, however, also occasionally occur in normal people and in patients with other sleep disorders, and therefore are not diagnostic.29 Narcolepsy–cataplexy is often a co-morbidity associated with other sleep disorders such as REM sleep behaviour disorder,30 sleep disordered breathing (SDB),16 other parasomnias and periodic limb movement disorder.31 Narcolepsy–cataplexy can have major negative effects on all aspects of life, including the patient's education, work performance, ability to drive safely, relationships, mood and overall well-being.32
The diagnosis of narcolepsy is primarily based on clinical symptomatology, with daytime sleepiness occurring almost daily for at least 3 months, and with a clear history of cataplexy.1 Additional tests to assist diagnosis include nocturnal polysomnography followed by a daytime multiple sleep latency test (MSLT) and measurement of hypocretin-1 concentrations in CSF. The diagnostic criteria for narcolepsy include a mean daytime sleep latency of <8 min, with two or more sleep-onset REM periods during the MSLT and/or CSF hypocretin-1 levels of 110 pg/mL or lower, or a third of mean control values.1 In addition, the hypersomnia should not be better explained by another sleep disorder, medical or neurological disorder, mental disorder, or medication or substance use.
As the diagnosis of patients with cataplexy is generally straightforward, neither the MSLT nor CSF hypocretin-1 measurements will affect treatment plans. In fact, in the second revision of the International Classification of Sleep Disorders, an MSLT is not required for the diagnosis of narcolepsy if definite cataplexy is clearly present. However, confirmation of the diagnosis with objective data is still recommended before commencement of potentially lifelong therapy in patients with cataplexy.1 In addition, to assess whether a patient has had sufficient sleep before the MSLT, a nocturnal polysomnogram is also useful for the diagnosis of other concomitant sleep disorders associated with EDS, such as periodic limb movement disorder and SDB. The MSLT is currently the accepted standard for obtaining objective information regarding the severity of excessive sleepiness and the occurrence of sleep-onset REM periods, which are both consistent with a diagnosis of narcolepsy. However, the diagnostic value of a single MSLT for narcolepsy is limited by the fact that approximately 15% of patients with narcolepsy–cataplexy may have normal, or more frequently, borderline MSLT results. On the other hand, typical narcolepsy-like MSLT results have been observed in a small number of patients with SDB and even normal subjects.
Almost all patients with typical cataplexy carry HLA-DQB1*06:02, and this marker is also present in a high proportion of the normal population, therefore HLA typing can only support, not determine a diagnosis, and it is not included in the second revision of the International Classification of Sleep Disorders as being diagnostic for narcolepsy. A CSF hypocretin-1 concentration of <110 pg/mL is highly specific (99%) and sensitive (87%) for narcolepsy–cataplexy and is more specific than the MSLT. As the probability of low CSF hypocretin-1 levels in HLA-DQB1*06:02-negative patients without cataplexy is estimated to be much less than 1%, and almost all patients with narcolepsy and low CSF hypocretin-1 levels are positive for HLA-DQB1*06:02, this marker could be a useful indicator of hypocretin deficiency. CSF hypocretin-1 measurements are highly recommended in situations where it is difficult to conduct or interpret the MSLT, for example, in young children who are unable to follow the MSLT instructions, individuals with severe or complex psychiatric, neurological or medical disorders that could compromise the validity of the MSLT results and those using drugs (e.g. anti-cataplectics or stimulants) that substantially alter sleep latency and the occurrence of REM sleep.17,33
Narcolepsy–cataplexy is commonly confounded with other forms of hypersomnia, such as narcolepsy without cataplexy, SDB, idiopathic hypersomnia, recurrent hypersomnia, hypersomnia associated with depression and chronic sleep deprivation.34 The presence of cataplexy is a key factor in distinguishing narcolepsy–cataplexy from other forms of hypersomnia. The refreshment value of short naps is of considerable diagnostic value, as this may differentiate patients with narcolepsy from those with idiopathic hypersomnia, who take long and unrefreshing naps. Some patients with narcolepsy without cataplexy, especially children, may develop true cataplexy later in the course of the illness. Symptomatic or secondary narcolepsy due to other medical disorders may occur with cataplexy, and detailed neurological examinations, including brain magnetic resonance imaging scans, may be used to identify the causes. Cataplexy must be differentiated from cataplexy-like episodes such as psychiatric conditions or epileptic variants. It may also be misdiagnosed as syncope, drop attacks, atonic attacks or attacks of a histrionic nature, when cataplexy is a predominant symptom. The presence of other sleep disorders such as SDB or periodic limb movement disorder does not preclude a diagnosis of narcolepsy if cataplexy is present.
As the definitive cause of narcolepsy–cataplexy has yet to be identified, its management must focus on relief of symptoms. Non-pharmacological treatments include optimization of nocturnal sleep duration, keeping a regular sleep–wake schedule, planning scheduled daytime naps, having a supportive social environment and exercising to avoid obesity. Driving restrictions are another important consideration. Almost all patients will require medications, especially for EDS and cataplexy. These include traditional amphetamine-like central nervous system stimulants and modafinil for daytime sleepiness and sleep attacks, REM-suppressing antidepressants (mostly noradrenergic) for cataplexy and other REM sleep intrusion phenomena, and hypnotics for disturbed nocturnal sleep. Sodium oxybate has been reported to be effective in controlling daytime sleepiness, cataplexy and disturbed night-time sleep.17
PATHOPHYSIOLOGY AND HYPOCRETIN DEFICIENCY
Genetic predisposition and environmental factors are both considered important for the development of narcolepsy. The nature of the possible environmental trigger that could influence the severity of narcolepsy or the likelihood of developing the disease is unknown. Extensive efforts over the past 30 years to gain a better understanding of the genetic basis of the disease have shown that susceptibility to narcolepsy is strongly associated with a specific HLA allele, DQB1*06:02, and that this marker is consistently present in 90 to 100% of patients across different ethnic groups.35 This association is thought to be a sensitive but not particularly specific risk factor, because 15–25% of individuals in the general population carry the associated HLA haplotype. Recent genome-wide association scans showed that HLA DQB1*06:03 was a new HLA class II haplotype that was strongly protective against narcolepsy.36 There are reports indicating that other non-HLA immune-related polymorphisms may also confer susceptibility to narcolepsy.37–39
Elucidation of the major pathophysiology of narcolepsy–cataplexy has been based on the discovery of its link with dysregulation of hypocretin. Hypocretin is a peptide derived from prepro-orexin, a single protein precursor encoded by a gene localized to human chromosome 17q2.40 Two variants, hypocretins 1 and 2 (orexins-A and -B), are exclusively synthesized in the lateral hypothalamus and act on two orexin receptors, OX1R and OX2R, which have been cloned.41 The cells containing hypocretin connect diffusely with monoamine-related cell groups in the locus ceruleus, raphe nucleus, tuberomammillary nucleus and ventral tegmental area, corresponding to noradrenaline, serotonin, histamine and dopamine secretion, respectively,42,43 and have been linked to multiple regulatory functions, including sleep/wake cycles, food intake and pleasure-seeking behaviour.43
Clues suggesting the possible involvement of hypocretin in narcolepsy initially came from animal studies. Mice lacking either the hypocretin gene (prepro-orexin knockout mice) or hypocretin neurons (hypocretin/ataxin-3 transgenic mice), as well as mice and dogs with null mutations in the OX2R gene, share a narcolepsy-like phenotype, including altered sleep–wake regulation and sudden onset of muscle atonia.4,5,44–46 In contrast, most human cases of narcolepsy are not due to mutations in either the hypocretin ligand or hypocretin receptor genes. Systematic screening of mutations in the hypocretin system in patients with narcolepsy–cataplexy has so far identified only one patient with a mutation in hypocretin genes.47 The first clear link between hypocretin dysfunction and human narcolepsy came from the study by Nishino et al.,6 which showed that lumbar CSF hypocretin-1 levels were below the detection limit (40 pg/mL) in narcoleptic patients, whereas in control subjects, the mean concentration was 280 pg/mL. These findings have been extended and replicated by other groups,8,48–51 confirming that 85–90% of patients with narcolepsy–cataplexy have low or undetectable levels of hypocretin-1 ligand in their CSF.
Further pathological evidence of selective hypocretin deficiency has come from immunohistochemical and in situ hybridization studies, which revealed an 85 to 95% reduction in the number of hypocretin-secreting neurons in the brains of human narcoleptics at post-mortem examination.7,47 Interestingly, adjacent melanin-concentrating hormone neurons, which are intermixed with hypocretin cells, were unaffected. Human narcolepsy–cataplexy is the direct consequence of degeneration of hypocretin neurons. The mechanisms responsible for the loss of orexinergic neurons are yet to be determined. An autoimmune-mediated process targeting hypocretin-producing neurons has been proposed, as indicated by evidence that includes the strong association with HLADQB1*06:02;35 the identification of Trib2 reactive autoantibodies;52 the association with polymorphisms in the T-cell receptor alpha locus and the purinergic receptor subtype 2Y11 (P2RY11) loci in genome-wide association studies;53–55 and a suggested association with streptococcal and H1N1 infections, as well as H1N1 vaccinations, an association also supported by the robust seasonality of disease onset.56–58 Cases of successful immunotherapy using intravenous immunoglobulins,59 plasmapheresis60 and alemtuzumab administration, with prolonged suppression of CD4+ T-cells to prevent progression of the disease61 and even recovery of CSF hypocretin levels have been reported.62 These findings may shed light on the therapeutic use of hypocretin or hypocretin analogues, hypocretin gene therapy, transplantation of hypocretin neurons, stem cell precursors or engineered cells to produce hypocretin peptides for treatment of the debilitating symptoms of narcolepsy–cataplexy.17
NARCOLEPSY–CATAPLEXY: WHY IT IS IMPORTANT FOR RESPIROLOGISTS
Upper airway infections: Implication in the pathophysiology
Narcolepsy–cataplexy is considered to be an emerging autoimmune disease triggered by infections. Unexplained fevers and influenza infections in the preceding year were associated with a 3.9-fold and 1.8-fold increased risk of narcolepsy–cataplexy, respectively.63 The onset of narcolepsy is highly correlated with seasonal and annual patterns of upper airway infection, with a six-fold higher incidence in April than in December, suggesting it most typically occurs 5–6 months after winter.57 Two types of upper airway infections, influenza A (including H1N1) and/or Streptococcus pyogenes (S. pyogenes) infections, may initiate or reactivate an immune response that leads to loss of hypocretin-secreting cells and narcolepsy in genetically susceptible individuals.
S. pyogenes infections are known to be associated with the onset of other brain-related autoimmune diseases. S. pyogenes infections result in the release of superantigens that bridge HLA and T-cell receptor molecules independently of antigen presentation, allowing the global stimulation of a broad range of T-cell clones. There is evidence suggesting S. pyogenes infections are prime candidates as potential autoimmune triggers of narcolepsy. Aran et al.56 showed that about 65% of Caucasian patients with onset of narcolepsy within the previous year, as compared with 26% of age-matched controls, had high titres of anti-streptolysin O antibody (>200), which is a marker of S. pyogenes infections, primarily of the throat. This finding was complemented by epidemiological findings showing a 5.4-fold higher risk of narcolepsy among individuals reporting a physician-diagnosed streptococcal throat infection before the age of 21 years.64 As upper airway infections often involve multiple viral and bacterial co-infections or superinfections, S. pyogenes may increase the risk of narcolepsy, in conjunction with influenza or other upper airway infections. Even among patients with post-H1N1 infection-related narcolepsy, 69% of the 12 published cases were positive for anti-streptolysin O antibody, suggesting a role for previous streptococcal throat infections.58
Cases of narcolepsy with cataplexy have been reported following 2009 H1N1 influenza vaccination or infection.58,65–68 Studies in Sweden and Finland reported a 6–9-fold increased risk of narcolepsy in children and adolescents after pandemic H1N1 influenza vaccination with Pandemrix (GlaxoSmithKline, Middlesex, UK), an H1N1 vaccine with squalene/α-tocopherol (AS03) adjuvant. Cases have also been reported in France and Canada, where a similar vaccine was used. Although the small numbers of children and adolescents with narcolepsy precluded any meaningful conclusions from population based cohort studies, there was, however, evidence suggesting that exposure to H1N1 infections per se may also increase susceptibility to narcolepsy in children.57 In China, the occurrence of childhood cases increased 3-fold following the winter of 2009–2010, independent of vaccination. In this context, it is notable that the great H1N1 pandemic of 1918 was followed by cases of seasonal encephalitis, ‘von Economo encephalitis lethargica’, which led to extreme somnolence and ophthalmoplegia (associated with lesions of the posterior hypothalamus and upper brainstem), insomnia and sleep inversion (associated with lesions of the anterior hypothalamus), psychosis and chorea-type movement disorders (reminiscent of Sydenham's chorea, associated with lesions of the basal ganglia).69 Two mechanisms could be involved in narcolepsy triggered by H1N1 vaccination or infection, a specific immune response to H1N1 (and subsequent molecular mimicry), or generalized stimulation of the immune system mediated by the vaccine, as AS03 adjuvant vaccines have been shown to induce a somewhat stronger immune response.70
Narcolepsy–cataplexy and sleep apnoea
Narcolepsy–cataplexy and OSAHS are both conditions associated with the primary symptom of EDS. An increased incidence of OSAHS has been observed among subjects with narcolepsy, with values ranging from 9.8–19% based on polysomnography studies.14,16 A recent report based on larger sample of patients16 indicated a prevalence of OSAHS (apnoea-hypopnoea index > 15) of 26% among narcolepsy–cataplexy patients with a mean age of 45 years. A higher apnoea-hypopnoea index and lower minimal oxygen saturation during sleep were noticed in a group of non-obese young narcoleptic patients (mean age 20 years), and the prevalence of an apnoea-hypopnoea index > 5 (16% vs 5%) and apnoea-hypopnoea index > 15 (5% vs 0%) were both higher than that in the age- and gender-matched control group.14 Even among first-degree relatives of narcoleptic patients, males and females were at higher risk of OSAHS.71 The exact mechanisms linking narcolepsy and OSAHS are unknown. It is possible that a lack of hypocretin predisposes this population to obesity, which also occurs with significantly greater frequency among patients with narcolepsy. These patients are at risk of further weight gain even after treatment is initiated,72 which means that OSA is more likely to occur over time. In addition to concurrent obesity, it has been proposed that there may be neural dysfunction in an area where respiratory and sleep-waking systems are closely interconnected, such as the nucleus tractus solitarius and ponto-medullary recticular formation, as implied by the parallel impairment of central control of breathing and manifested by respiratory dysrhythmia during sleep and sleep–wake patterns in patients with narcolepsy.15
Narcolepsy and respiratory regulation in animals
The hypothalamus, where hypocretin neurons are exclusively located, has long been recognized as being involved in the modulation of ventilation.73 Recent studies demonstrated that this effect is partially mediated by the hypocretin system. First, hypocretin neurons may be involved in matching ventilation to changes in states of consciousness. Anatomically, they send projections both ‘upwards’ to arousal-regulating regions such as the thalamus and cortex, and ‘downwards’ to brainstem central respiratory nuclei, such as the raphe nuclei, nucleus tractus solitarius, the rostral ventrolateral medulla and the phrenic and hypoglossal nuclei.10,73 Both OX1R and OX2R are expressed in the breathing centre, and OX2R messenger RNA was detected in hypoglossal motoneurons. Hypothalamic hypocretin cells also act as acid and CO2 sensors10,13 and receive afferent signals from the amygdala and the bed nucleus of the stria terminalis, which may be important for regulation of breathing during emotional stimuli.10 Second, activation of hypocretin receptors at various sites of the brainstem and spinal cord influences breathing rate and depth, and coordination between upper airway and thoracic pump muscles. Microperfusion of hypocretin either to sites in the pre-Bötzinger region or phrenic nucleus produces a dose-dependent, significant increase in diaphragm electromyographic activity.13 Injection of exogenous hypocretin into the hypoglossal motor nucleus increases genioglossus muscle activity. In addition, administration of hypocretin-2 in the pontine respiratory group prolongs the pre-inspiratory activity of the hypoglossal nerve, which is essential for the maintenance of upper airway patency.12
Further evidence linking the hypocretin system and breathing comes from mice with genetic deletion of the gene encoding prepro-orexin. Kuwaki and colleagues demonstrated that hypocretin participates importantly in central chemoreception in a vigilance state and diurnal cycle-dependent manner.2,13 An increase in respiratory activity elicited by electrical impulses from the lateral hypothalamus diminished in knockout mice lacking the hypocretin gene.12 Attenuation of respiratory excitation during fight-or-flight responses was noticed in these animals. Further measurements revealed a decreased CO2 response while awake but not during sleep, which is consistent with the notion that the activity of orexinergic neurons is higher during waking than sleep periods. Supplementation with orexin-A or -B partially restored the attenuated hypercapnic response in orexin knockout mice, while blockage of OX1R and/or OX2R by antagonist induced a reduction in the CO2 response in wild-type mice, predominantly in wakefulness. Orexin-B induced greater stimulation of ventilation than orexin-A, whereas orexin-A had a more profound effect on sleep, indicating that the respiratory effect of hypocretin is independent of sleep to some degree. Hypocretins may also be involved in the stabilization of breathing. Respiratory long-term facilitation, a physiological feature that is presumed to stabilize the respiratory control system and reduce sleep apnoea, was absent in hypocretin knockout mice, which is consistent with the finding that these mice had more frequent apnoea during sleep.
However, hypocretin knockout mice did not respond differently from wild-type mice in regard to the response to hypoxia. Therefore, hypocretins are possibly not involved in the ventilatory hypoxic response in animals.
Narcolepsy and respiratory regulation in humans
Human narcolepsy–cataplexy with deficits in the endogenous hypocretin system is also associated with the genetic marker, HLADQB1*06:02. In addition to the possible influence of hypocretin per se, there is evidence suggesting an impaired chemo-responsiveness in patients with narcolepsy–cataplexy. Narcolepsy is associated with a higher incidence of sleep apnoea,14,16 which has been considered a disorder of respiratory control.74 Long-term nocturnal sleep disturbance in narcoleptic patients may alter chemo-responsiveness and mimic the changes in sleep deprivation. Fragmented sleep and hypoxia due to a high incidence of sleep apnoea may further impair the ventilatory responsiveness of these patients.75 In contrast to findings in gene knockout mice, significantly depressed hypoxic responsiveness, but not hypercapnic response, was observed in a large sample of human narcolepsy–cataplexy subjects.14 Further analysis revealed that depressed hypoxic response in human subjects with narcolepsy–cataplexy was independent of body mass index, age, gender and the severity of narcoleptic symptoms such as sleepiness and cataplexy, and had no relationship with hypocretin deficiency. An unexpected finding was that the mechanism for differences in hypoxic responsiveness between narcolepsy–cataplexy patients and control subjects could relate to HLADQB1*06:02 rather than disease. Healthy unaffected subjects with the HLADQB1*06:02 marker (22% of the Chinese population) had the same reduced hypoxic response as patients who were almost 100% HLADQB1*06:02 positive. It is possible, therefore, that there is a novel effect of HLA or an adjacent gene polymorphism on the well-known inter-individual variation in hypoxic responsiveness. Recent developments in narcolepsy research support the hypothesis that narcolepsy is an immune-mediated disease;70 a close association between the hypoxic response and HLADQB1*06:02 implies the possibility of immune-mediated destruction of type I glomus cells in the carotid bodies, the peripheral chemoreceptor for detection of hypoxia. The different findings from animal and human studies cannot be fully explained by the fact that the orexin knockout mouse is an inaccurate pathophysiological model of human narcolepsy, as depressed hypoxic responses were not observed when hypocretin/ataxin-3 transgenic mice were used—these animals having an aetiology and course of disease similar to human narcolepsy (Han et al., unpubl. data, 2010). One animal study has shown that orexin-B has a stronger effect than orexin-A in increasing spontaneous ventilation.12 This is a question worth investigating further, when a specific method for measuring CSF orexin-B levels in humans is available.14
Understanding the link between OSAHS and narcolepsy–cataplexy is of high clinical relevance. A diagnosis of narcolepsy may be overlooked or confounded by coexisting OSAHS, especially when cataplexy is underrecognized. More than one sleep-onset REM periods during an MSLT, a diagnostic hallmark of narcolepsy, may occasionally occur in untreated patients with OSAHS,76–78 and OSA patients may also have moderately diminished CSF hypocretin-1 levels, but which are not lower than the suggested cut-off value for narcolepsy. Suspected narcolepsy should always be actively investigated and further tests considered in OSA patients with residual EDS, despite the correct use of continuous positive airway pressure (CPAP) therapy and in those with onset of sleepiness at a young age and a frank contrast between major sleepiness and mild to moderate OSA. In OSA patients in whom it is not clear if there is coexisting atypical narcolepsy–cataplexy, initial use of CPAP for several weeks to eliminate the possibility of SDB, followed by re-evaluation of daytime sleep by questionnaire or MSLT may help in making the diagnosis of narcolepsy, as unlike patients with OSA only, EDS generally does not improve significantly in those with overlapping narcolepsy. On the other hand, it is difficulty to make the diagnosis of OSAHS in narcoleptic patients. The Epworth Sleepiness Scale (ESS) cannot be used as a measure of symptomatic severity (EDS) of OSAHS in patients with coexistent narcolepsy.17 OSA may be easily ignored in patients using modafinil, due to amelioration of the symptom of sleepiness.
In narcolepsy, nocturnal sleep is often further disrupted by coexistent OSA. There is evidence to support the routine use of CPAP as an additional non-pharmacological therapy for moderate to severe OSAHS in narcoleptic patients.16 However, CPAP treatment alone may benefit hypoxaemia and sleep fragmentation but will not reduce daytime sleepiness, and because long-term adherence with CPAP therapy is poor in patients with narcolepsy–cataplexy, more supportive interventions are needed.16 For patients who remain sleepy during the daytime, despite adequate CPAP therapy, stimulant medications such as modafinil are recommended as a useful adjunct treatment for the management of residual daytime sleepiness. Sodium oxybate is a potential alternative for a patient with narcolepsy–cataplexy; however, recent reports have implicated sodium oxybate in several cases of worsening sleep-related breathing disturbances and accidental death.79 Patients with narcolepsy and moderate to severe OSAHS who are using sodium oxybate should comply fully with CPAP therapy, and their respiratory status should be periodically evaluated by nocturnal oximetry, as worsening Epworth Sleepiness Scale scores alone should not be used as an indication of the development or worsening of OSA in these patients.16
Narcolepsy–cataplexy is most commonly caused by a loss of hypocretin-producing cells in the hypothalamus. The disorder is tightly associated with HLADQB1*06:02, suggesting that in most patients, the cause may be autoimmune destruction of these cells. Low CSF hypocretin-1 levels can be used to confirm the diagnosis. Current treatments are based on symptoms. Findings from animal models show promise for use of emerging therapies that act downstream of the hypocretin abnormality. There are multiple implications for respiratory medicine of advances in narcolepsy–cataplexy research including: a need for all respiratory physicians managing SDB to also recognize sleepiness and narcolepsy–cataplexy; the potential for an immune process triggered by upper airway infections to explain the link between the HLA association and hypocretin deficiency; and a high incidence of SDB among narcoleptic patients being related to impairment of control of central breathing function in both animals and humans. All of these findings are highly relevant to patient care.
This work was supported by research grants from the National Science Foundation of China (81070069), the Sino-German Center for Research Promotion (GZ538) and Beijing Municipal Science and Technology Commission (D1011000050010029) to F.H.