Narcolepsy, Idiopathic Hypersomnolence and Related Conditions

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CME Sleep disorders Clinical Medicine 2011, Vol 11, No 3: 282–6

coma or malingering. The weakness of Narcolepsy, idiopathic hypersomnolence cataplexy is typically bilateral and can involve the legs (‘weak at the knees’), and related conditions hands, face, neck or shoulder girdle. Frequency can range from rarely to sev- naps; if these are not possible, they can eral times a day. Ptosis may give the Timothy G Quinnell, consultant respiratory impression of unconsciousness and dis- physician; Ian E Smith, consultant have irresistible sleep episodes (‘sleep tract from the correct diagnosis but, physician and director attacks’). The identification of other factors such as sleep disordered breathing apart from occasional evolution into Respiratory Support and Sleep Centre, (SDB) contributing to sleepiness should sleep, awareness is preserved. Papworth Hospital, Cambridge not discourage the pursuit of a diagnosis The differential diagnosis of cataplexy of narcolepsy if features are compelling includes periodic paralysis, myasthenia because sleep disorders can coexist.9 gravis, atonic seizures and vertebrobasilar Narcolepsy with cataplexy is primarily a insufficiency.10 The absence of cataplexy disorder of excessive daytime sleepiness can represent disease-in-evolution or so- (EDS) and episodic collapse. Despite a Cataplexy called ‘monosymptomatic narcolepsy’9 quality of life impact similar to Cataplexy is emotionally triggered but other diagnoses should be considered. Parkinson’s disease (PD)1 and significant muscle weakness and, with EDS, is individual and societal costs2 it is often essential to the diagnosis of classical Other narcoleptic symptoms overlooked. A UK survey found median narcolepsy.9–11 Symptoms usually time from first symptom to diagnosis to develop months or years after EDS but, The other symptoms of the ‘narcoleptic be 10.5 years.3 The delay in diagnosis because sleepiness can be overlooked, tetrad’ involve different facets of rapid may be because it is uncommon cataplexy is sometimes the presenting eye movement (REM) sleep invading (European prevalence 0.047%4), but is complaint. It should be considered wakefulness: no doubt exacerbated by a paucity of when patients present with apparent sleep paralysis (persistent motor sleep medicine training (median 5 min • absence episodes, unexplained collapse atonia) in UK medical undergraduate or episodic clumsiness. Prolonged or hypnogogic/hypnopompic halluci- curricula5). Narcolepsy has a variety of • intractable episodes (status cata- nations (dream-like experiences presentations which may be wrongly plecticus) may be mistaken for seizures, during sleep-wake transitions). attributed to more familiar disorders or lifestyle and there is an overlap with nor- mality. EDS is reported by up to 10% of Table 1. Causes of excessive daytime sleepiness. the general population6 and objective Insufficient sleep Time measures of sleepiness do not reliably • Quality (alcohol, caffeine) differentiate narcoleptics and normal • Both (noise, temperature) subjects.7 It is important for the acute • Other disorder Pain care physician to be aware of the features • Nocturia of, and means for, diagnosing narcolepsy • Dyspnoea so that opportunities to treat this dis- • Cough abling condition are not missed. • Medications • Daytime sedation • Nocturnal sleep disruption (diuretics, steroids, statins) Diagnosis Anxiety/depression Anyone reporting EDS warrants a Circadian rhythm disorder • Advanced sleep phase syndrome detailed sleep history. It is important to • Delayed sleep phase syndrome tease out an increased propensity to fall • Shift work disorder asleep from other symptoms reported as • Jet lag tiredness, particularly physical and emo- Sleep-disordered breathing • Obstructive sleep apnoea tional fatigue. The Epworth Sleepiness • Central sleep apnoea Scale can be a useful measure.8 • Hypoventilation Explanations for perceived sleepiness, Narcolepsy including lifestyle, mood disorders, other Restless legs syndrome/periodic limb movement during sleep medical conditions and medication, Idiopathic hypersomnia should be explored (Table 1). People with Recurrent hypersomnia narcolepsy typically need brief, refreshing

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Automatism, poor nocturnal sleep and autoimmune condition triggered by Subjects undergo PSG-monitored nap dream enactment (REM sleep behaviour infection.19,20 opportunities at two-hourly intervals.7 disorder) can also occur.9–11 Mean sleep latency is usually less than Although not inevitable in, or exclu- Investigation eight minutes in narcolepsy (most nar- sive to, narcolepsy, when accompanying coleptics fall asleep within 5 min)7 and cataplexy and sleep attacks, it is under- Nocturnal polysomnography multiple REM sleep episodes occur standable how lack of familiarity with (Fig 3). International guidelines man- The investigation of choice for unex- these features can result in narcolepsy date a combination of these two criteria plained EDS is nocturnal polysomnog- being mistaken for seizures, psychiatric but sensitivity is only around 80% in raphy (PSG). Electroencephalogram, disorders or malingering. classical cases and they are not entirely chin electromyogram and electro-oculo- specific.9,21,22 gram enable the staging of wakefulness, Physical examination REM and non-REM sleep. Respiratory and leg monitoring allow screening for The physical examination is usually Other investigations SDB and periodic limb movement. normal. Cataplexy has characteristic Features suggestive of narcolepsy include HLA testing has only limited utility as it features, including areflexia and facial rapid sleep onset and premature entry is positive in up to 38% of non-narcolep- twitching, but episodes usually occur 18 into REM sleep (Fig 2). tics. A negative test with a classical his- only in relaxed, intimate settings and so tory may cause pause for thought. CSF 11 are rarely seen in clinic. Unless the orexin assay may be useful when PSG Multiple sleep latency test diagnosis can be confidently made and MSLT are unavailable, but the test is on clinical features alone, suspected Diurnal sleep drive is measured by the invasive and less discriminatory in cases narcolepsy and other unexplained cases multiple sleep latency test (MSLT). without cataplexy.9,14 of EDS should undergo specific investigation.9 Thalamus Pathophysiology Magnocellular basal forebrain Ventral tegmental area The discovery of the neurotransmitter (Acetylcholine) and subtana nigra orexin (hypocretin) has refined the (Dopamine) pathophysiological description of narcolepsy as a condition of sleep-wake instability.12 Orexin stabilises wake and sleep states through widespread subcor- tical neuronal projections from the lat- eral hypothalamus (Fig 1). Cerebrospinal fluid (CSF) and brain studies have established that most people with narcolepsy and cataplexy have orexin deficiency.14–16 Up to 2% of narcoleptics have symp- Perifornical area tomatic first-degree relatives but most (Hypocren) 17 Raphe nuclei cases are sporadic. Global research has (Serotonin) yielded only one case of human narcolepsy caused by a prepro-orexin gene Tuberomammillary nucleus mutation15 but wider genetic studies (Histamine) continue. There is a strong human Locus coeruleus leukocyte antigen (HLA) association. Pedunculoponne and (Noradrenaline) The DQB1*0602 haplotype is found in laterodorsal tegmental nuclei 88–98% of patients with non-familial (Acetylcholine) cataplexy.18 The newly discovered association of narcolepsy with a T cell Fig 1. Hypocretin (orexin) system. The sleep-wake cycle is governed by a complex, multilevel receptor polymorphism and demonstra- neuronal system in the brainstem, thalamus, hypothalamus and basal forebrain. Hypocretin- producing neurons in the hypothalamus stabilise the activity of other key neuronal groups tion of elevated antistreptococcal anti- involved in the control of sleep and waking. These nuclei and their principal bodies in recent-onset cases support the neurotransmitters are shown here in highly schematic fashion. Reproduced with permission hypothesis of a genetically determined from BMJ Publishing Group Ltd.13

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Fig 2. Polysomnogram summary (hypnogram) from patient with narcolepsy. There is rapid sleep onset (blue arrow) and early rapid eye movement (REM) sleep (red arrow). There are clinically insignificant numbers of apnoeas (purple marks) and periodic limb movements (bottom trace in blue) which do not explain sleepiness in this case.

Secondary narcolepsy and other weeks to years. Cognitive and behav- aetiology or diagnostic test, these are hypersomnias ioural abnormalities, classically binge- arbitrary. There is typically difficulty eating and hypersexuality, are variably waking up in the morning (sleep inertia) Rarely, other medical disorders present associated. A prolonged 24-hour sleep and EDS. Naps are more prolonged than with narcoleptic features. Those fea- time may be demonstrated if PSG is in narcolepsy and usually unrefreshing. If turing cataplexy include: achieved during an episode.9 Lithium nocturnal sleep duration allows time for • hypothalamic lesions may be useful, but evidence for its the performance of MSLT after PSG, the • paraneoplastic encephalitis effectiveness is limited.23 mean sleep latency should be under eight • Niemann-Pick type C disease In patients with unexplained EDS, minutes without associated multiple • Coffin-Lowry syndrome. idiopathic central nervous system hyper- REM sleep episodes.9 somnolence (ICNSH) should be consid- In the absence of abnormalities on ered. This diagnosis has been Management neurological examination there is no jus- 24 inconsistently described and ascribed. Lifestyle tification for neurological imaging. The new International Classification of Narcolepsy-like sleepiness has been Sleep Disorders has attempted to address Optimal sleep hygiene is important for reported in: this inconsistency with diagnostic cri- any disorder with EDS. Nocturnal sleep • head trauma teria9 but, in the absence of any known should be sufficient and regular and the • myotonic dystrophy • Prader-Willi syndrome 20 • PD Sleep latency REM latency • multisystem atrophy. To fulfil diagnostic criteria, patients should have the characteristic MSLT features with SDB excluded or 9 controlled. (min) Latency Recurrent hypersomnias are rare and little understood. Kleine-Levin syn- 0 drome is the best characterised, with 1234 recurrent episodes of hypersomno- NAP # lence, often first in adolescence, which Fig 3. Characteristic narcoleptic multiple sleep latency test result showing evolution of latencies. may last several days and be inter- The subject slept on each of four opportunities offered through the day. The mean sleep latency is spersed with asymptomatic intervals of only 1.5 min and rapid eye movement (REM) sleep is seen in three of the naps.

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environment conducive to sleep. Alcohol Anticataplectics and timely diagnosis should be the and caffeine intake should be moderated. norm. Symptoms can be disabling and Brief naps are often useful in narcolepsy If cataplexy requires treatment, the REM costly but effective treatment is available. but rarely in ICNSH. Patients should be sleep-suppressing tricylic antidepres- sants and selective serotonin reuptake advised of the need to report their diag- Conflict of interests nosis to the driving authorities and not inhibitors have an established but poorly to drive until EDS is controlled. evidenced role. They can also be useful in TQ has received sponsorship from UCB sleep paralysis and hallucinations. Pharma Ltd and a travel bursary from Alternatives include venlafaxine and Cephalon UK to attend sleep medical confer- Wakefulness-promoting therapy reboxetine.23 Rebound cataplexy can ences. IES has received a speaker’s fee from Cephalon UK and sponsorship from UCB Drug treatment for hypersomnolence is occur with drug withdrawal. Pharma Ltd to attend a sleep medical similar for narcolepsy and ICNSH, conference. although the evidence base is stronger for Sodium oxybate narcolepsy. References Modafinil is recommended as first-line Sodium oxybate is effective in narcolepsy treatment for narcolepsy.23 Tolerance and and cataplexy23 although its mode of 1 Beusterien KM, Rogers AE, Walsleben JA dependency are not reported. Side effects action is not clear. It is a profound seda- et al. Health-related quality of life effects of are usually mild and rarely lead to discon- tive, promoting deep non-REM (slow modafinil for treatment of narcolepsy. wave) sleep. Its rapid onset of action and Sleep 1999;22:757–65. tinuation. Modafinil is used in ICNSH, 2 Dodel R, Peter H, Walbert T et al.The although it may not be as effective as in short half-life require it to be taken at socioeconomic impact of narcolepsy. Sleep narcolepsy; this use is not licensed in the night in divided doses. These are titrated 2004;27:1123–8. UK.23,25 It may be an option in hyper- up over several weeks until symptoms are 3 Morrish E, King MA, Smith IE, Shneerson somnia associated with PD and myotonic controlled, maximum dose reached JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 23 (9 g) or side effects preclude further dystrophy. 2004;5:37–41. increase. Full benefit takes longer to 4 Ohayon MM, Priest RG, Zulley J, Smirne S, Dexamfetamine. Dexamfetamine (5–60 manifest. There is no tolerance, depen- Paiva T. Prevalence of narcolepsy sympto- mg/day), methylphenidate (5–100 dency or withdrawal syndrome. Often matology and diagnosis in the European mg/day) and other stimulants have long used first-line in the USA, its expense general population. Neurology means it is reserved for refractory cases 2002;58:1826–33. been used to treat narcolepsy and 5 Stores G, Crawford C. Medical student ICNSH. They can be very effective, in the UK where funding requires indi- education in sleep and its disorders. J R although there is potential for toler vidual case approval. Coll Physicians Lond 1998;32:149–53. ance and dependency. Sympathomimetic 6 Breslau N, Roth T, Rosenthal L, Andreski P. side effects are recognised and higher Daytime sleepiness: an epidemiological Conclusions study of young adults. Am J Pub Health doses have been associated with 1997;87:1649–53. psychosis.24 Risk-benefit data are scanty It is important to consider the possibility 7 Littner MR, Kushida C, Wise M et al. and these drugs are usually second-line of narcolepsy and other non-respiratory Practice parameters for clinical use of the therapy.23 disorders in patients with EDS. Accurate multiple sleep latency test and the mainte- nance of wakefulness test. Sleep 2005;28:113–21. 8 Johns MW. A new method for measuring Key points daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–5. Narcolepsy is under-recognised and should be considered in cases of unexplained daytime 9 American Academy of Sleep Medicine. sleepiness or collapse Diagnostic and coding manual. International classification of sleep Narcolepsy has significant adverse effects on quality of life and socioeconomic disorders, 2nd edn. Westchester, IL: impacts AASM, 2005. 10 Aldrich M. Narcolepsy and related disor- Accurate diagnosis requires careful consideration of clinical and electrophysiological ders. In: Aldrich M, Sleep medicine.New features York: Oxford University Press, 1999:152–74. Effective drug treatments are available 11 Parkes JD, Chen SY, Clift SJ, Dahlitz MJ, Dunn G. The clinical diagnosis of the nar- Exclusion of classical narcolepsy should prompt the consideration of coleptic syndrome. J Sleep Res monosymptomatic or secondary narcolepsy, and idiopathic hypersomnolence because 1998;7:41–52. treatment can still be effective 12 Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol KEY WORDS: cataplexy, collapse, excessive sleepiness, idiopathic hypersomnolence, 2003;53:154–66. narcolepsy

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13 Zeman A, Britton T, Douglas N et al. Narcolepsy and excessive daytime sleepi- Obstructive sleep apnoea: relevance ness. BMJ 2004;329:724–8. 14 Mignot E, Lammers GJ, Ripley B et al.The to non-sleep clinicians role of cerebrospinal fluid hypocretin mea- surement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol Ian E Smith, consultant respiratory This article reviews areas of overlap 2002;59:1553–62. 15 Peyron C, Faraco J, Rogers W et al.A physician and director; Timothy G with non-cardiological specialties. An mutation in a case of early onset nar- Quinnell, consultant respiratory physician accompanying article discusses colepsy and a generalized absence of the cardiovascular associations of sleep hypocretin peptides in human narcoleptic Respiratory Support and Sleep Centre, apnoea syndromes. (pp 275–8). brains. Nat Med 2000;6:991–7. Papworth Hospital, Cambridge 16 Thannickal TC, Moore RY, Nienhuis R et al. Reduced number of hypocretin neurons in Symptoms human narcolepsy. Neuron 2000;27:469–74. Obstructive sleep apnoea (OSA) is a 17 Mignot E. Genetic and familial aspects of common condition which greatly Most people with OSA are males in mid- narcolepsy. Neurology 1998;50(2 Suppl 1): impacts on quality of life and is associ- life and around 70% are obese. It is, how- S16–22. ated with reduced life expectancy. Most ever, important not to assume all 18 Lin L, Hungs M, Mignot E. Narcolepsy and diagnosed cases are managed by respira- the HLA region. J Neuroimmunol patients fit this stereotype. A more com- 2001;117:9–20. tory physicians. There is established, plete risk profile is given in Table 1.2 The 19 Hallmayer J, Faraco J, Lin L et al. well-evidenced guidance on treatment, most frequently reported symptoms are Narcolepsy is strongly associated with the especially with continuous positive daytime sleepiness and unrefreshing T-cell receptor alpha locus. Nat Genet airway pressure (CPAP).1 However, given sleep with poor concentration. Low 2009;41:708–11. an incidence of at least 2% in the adult 20 Aran A, Lin L, Nevsimalova S et al. mood and marital disharmony are also Elevated anti-streptococcal antibodies in population, it is inevitable that clinicians commonly present.3 These symptoms patients with recent narcolepsy onset. Sleep from a range of specialties will see reduce quality of life but may be misin- 2009;32:979–83. patients with OSA of whom up to 80% terpreted as due to fatigue or depression. 21 Aldrich MS, Chervin RD, Malow BA. Value will be undiagnosed. Such patients may In women in particular the primary of the multiple sleep latency test (MSLT) present in extremis in the emergency for the diagnosis of narcolepsy. Sleep complaint may be one of feeling tired all 1997;20:620–9. room or as outpatients with symptoms the time with no energy, rather than 22 Mignot E, Lin L, Finn L et al. Correlates that mimic those of another disorder or falling asleep uncontrollably in the day- of sleep-onset REM periods during the with a comorbid condition that predis- time. Headache especially on waking has Multiple Sleep Latency Test in poses to OSA. It is also important to have been thought to be a symptom of OSA community adults. Brain an understanding of prescribing for 2006;129:1609–23. and may be present when severe OSA patients with OSA, including the risks of 23 Morgenthaler TI, Kapur VK, Brown T et al. leads to ventilatory failure with CO2 Practice parameters for the treatment of sedation. retention, but headache alone is not narcolepsy and other hypersomnias of central origin. Sleep 2007;30:1705–11. 24 Ali M, Auger RR, Slocumb NL, Table 1. The STOP BANG scoring system. This validated score can be used as a quick screen for Morgenthaler TI. Idiopathic hypersomnia: obstructive sleep apnoea (OSA) risk, particularly in judging presurgical risk and the need to refer 2 clinical features and response to treatment. for diagnostic respiratory studies. Reproduced with permission from Wolters Kluwer. J Clin Sleep Med 2009;5:562–8. Symptom Question 25 Mitler M, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with S Snoring Do you snore loudly (louder than talking or loud stimulants. ASDA standards of practice. enough to be heard through closed doors)? Sleep 1994;17:352–71. T Tiredness Do you often feel tired, fatigued or sleepy during the daytime? O Observed apnoea Has anyone observed you stop breathing during your sleep? Address for correspondence: Dr TG P Pressure Do you have or are you being treated for high blood Quinnell, Respiratory Support and pressure? Sleep Centre, Papworth Hospital, B BMI Ͼ35 kg/m2 Papworth Everard, Cambridgeshire A Age Ͼ50 years CB23 3RE. N Neck circumference Ͼ40 cm E-mail: [email protected] G Male gender

High risk of OSA: у3 questions answered yes. Low risk of OSA Ͻ3 questions answered yes. BMI ϭ body mass index.