CMJ1103-CME_Quinnell.qxd 5/15/11 12:47 AM Page 282 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 fac- tors 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 282 © Royal College of Physicians, 2011. All rights reserved. CMJ1103-CME_Quinnell.qxd 5/15/11 12:47 AM Page 283 CME Sleep disorders 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 nar- colepsy 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 nar- colepsy 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 asso- ciation 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 © Royal College of Physicians, 2011. All rights reserved. 283 CMJ1103-CME_Quinnell.qxd 5/15/11 12:47 AM Page 284 CME Sleep disorders 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