Non-apnoeic hypersomnia and narcolepsy

Transcription

1 How to Treat PULL-OUT SECTION Complete How to Treat quizzes online /cpd to earn CPD or PDP points. INSIDE Common causes Assessment of Management of Idiopathic hypersomnolence Other hypersomnias the author Non-apnoeic hypersomnia and Institute of Fine Arts, Detroit Dr Anup Desai senior staff specialist, department of respiratory and sleep medicine, Prince of Wales Hospital, Randwick; consultant physician in private practice, Camperdown (BMC) and Randwick; and clinical senior lecturer, faculty of medicine, University of Sydney and University of NSW. Background EXCESSIVE daytime sleepiness is a common symptom in general practice. Patients may describe daytime fatigue or tiredness, waking up feeling unrefreshed, or daytime lethargy as alternative symptoms to excessive daytime sleepiness. The cause and management of these symptoms needs to be considered in every patient who presents in this way. Obstructive sleep apnoea is a significant and common cause of excessive daytime sleepiness and had been covered in a previous How To Treat article (20 August 2010). However, there are many common and significant non-apnoeic conditions that also cause excessive daytime sleepiness. The common causes that need to be addressed include sleep deprivation, insomnia, effect of medication and underlying medical conditions. Further assessment of excessive daytime sleepiness should consider, idiopathic hypersomnia and other primary brain disorders. cont d next page Copyright 2014 Australian Doctor All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means without the prior written permission of the publisher. For permission requests, howtotreat@cirrusmedia.com.au 2014 australiandoctor.com.au/seminars EARLY BIRD discount now available Seminar for GPs Earn CPD Points DIGESTIVE HEALTH VISIT /seminars PHONE Sydney - 14 June 2014 Melbourne - 28 June 2014 Sponsor 4 April 2014 Australian Doctor 23

2 How To Treat Non-apnoeic hypersomnia and Common causes Sleep deprivation SLEEP is a basic homeostatic process, which means it is essential for normal organ function and life. As an individual deprives themselves of sleep, there is an increase in the drive or pressure for sleep. Sleep drive is similar to other homeostatic processes, such as hunger or thirst. If a person does not eat they become progressively more hungry. A similar pattern of function relates to sleep, so sleep deprivation or a lack of adequate sleep time has important physiological consequences, including daytime tiredness and sleepiness. Sleep loss or deprivation can be of a short duration, for example, staying up late on a weekend night. More commonly, however, sleep loss occurs on a chronic partial basis in many people who shorten their sleep hours to less than eight hours a day because of lifestyle, work or family commitments. Chronic restriction of sleep hours is very common in our society and needs to be considered as a cause of fatigue and excessive sleepiness in all patients. A practical example of the importance of obtaining adequate sleep each night and how sleep loss can adversely affect people was provided by Dawson and Reid, who equated the performance impairment caused by sleep deprivation with that due to alcohol intoxication. 1 They compared the performance on a computer-administered test of hand-eye co-ordination between subjects kept awake for 28 hours and subjects who consumed 10-15g of alcohol at 30-minute intervals until their mean blood alcohol concentration reached 0.10%. They showed that after 17 hours of sustained wakefulness, performance impairment had decreased to a level equivalent to that observed at a blood alcohol concentration of 0.05%. Further, after 24 hours without sleep, performance decreased to a level equivalent to that observed at a blood alcohol concentration of roughly 0.10%. Insomnia Insomnia is a distressing difficulty involving delayed sleep onset, disturbed sleep maintenance and/or early morning waking, so that the individual s sleep is insufficient for their needs. As a consequence of poor sleep, patients with insomnia experience daytime fatigue, tiredness and sleepiness. A detailed sleep history will readily identify symptoms of nocturnal insomnia (such as difficulty going to sleep, fragmented sleep, difficulty getting back to sleep in the middle of the night if woken, and/or early morning waking) and hence provide the clue that their daytime fatigue or sleepiness may be due to insomnia. Addressing psychological comorbidities If insomnia symptoms are identified, they should be treated with CBT +/- hypnotic agents. Comorbid medical and psychiatric disorders also need to be identified and treated separately. A recent classification change (DSM-5) has stressed the importance of treating insomnia separately to comorbid conditions (eg, major depression) rather than considering the cause of the insomnia to be the major depression and focusing management on this condition only. Management General treatment approaches to insomnia are: Improving sleep hygiene, such as avoiding caffeine and alcohol before bed. Behavioural approaches to treat conditioned elements, such as stimulus control measures that reduce learnt wakefulness in bed, and to optimise the circadian regulation of sleep. Cognitive approaches to address unrealistic expectations about sleep and anxiety over sleeplessness. Treating comorbid sleep disorders (eg, obstructive sleep apnoea or restless legs syndrome). Treating comorbid psychiatric or adjustment disorders. Treating comorbid medical conditions (eg, chronic pain, nocturnal cough, hot flushes) or medications/drugs that may be contributing to the insomnia symptoms. The topic of insomnia in general practice was covered in detail previously in a separate How to Treat article (19 July 2012). 2 Readers are encouraged to read this for more information on this topic. Medications Various drugs can cause excessive daytime sleepiness. Common examples include CNS depressants, second-generation antiepileptics, histamine H1 receptor antagonists, some antihypertensives and dopaminergic agonists. CNS depressant drugs Most CNS depressant drugs act as agonists at the GABA A receptor complex. Benzodiazepines, especially the long-acting agents, are frequently used to induce sleep at night-time, but they can also lead to residual sleepiness the next day, particularly in the morning. Second-generation antiepileptic drugs Second-generation antiepileptic drugs can enhance GABA activity through various mechanisms that directly or indirectly involve the GABA A receptor. These drugs Common medical disorders that can cause excessive daytime sleepiness include cancer, fibromyalgia, chronic fatigue syndrome, nocturnal pain conditions, neurological disorders and psychiatric disorders. include gabapentin, tiagabine, vigabatrin and pregabalin. Some evidence indicates these drugs have sedative activity. Histamine H 1 receptor antagonists Antagonists acting at the histamine H 1 receptor have sedating effects. One of the most commonly reported side effects associated with the use of H 1 antihistamines is daytime sleepiness. Antihypertensives Antihypertensives, particularly beta blockers, are reported to produce sedation during the daytime. These CNS effects are thought to be related to the differential liposolubility of the various compounds. Dopaminergic agonists Dopaminergic agonists used to treat Parkinson s disease can cause daytime sleepiness. This has been reported as an adverse event in clinical trials and in case reports as sleep attacks while driving. It is now clear these sleep attacks are not attacks per se but are the expression of excessive sleepiness. Medical and psychiatric conditions Drug abuse and some medical disorders are associated with daytime sleepiness that is independent of the presence of other sleep disorders. Common medical disorders that can cause excessive daytime sleepiness include cancer, fibromyalgia, chronic fatigue syndrome, nocturnal pain conditions, neurological disorders (eg, Parkinson s disease) and psychiatric disorders (eg, depression). Restless legs syndrome Sleep-disrupting disorders are important causes of excessive daytime sleepiness. These include obstructive sleep apnoea (see How To Treat Sleep Apnoea, 20 August 2010) and restless legs syndrome. Restless legs syndrome is characterised by an urge to move, usually associated with paraesthesia, that occurs or worsens at rest and is relieved by activity. Symptoms are typically worse in the evening and during the night. The symptoms of restless legs syndrome can have a major impact on nocturnal sleep and daytime functioning. Some patients report difficulty falling asleep or waking up shortly after sleep onset with unpleasant leg sensations. They can also often experience excessive daytime fatigue and somnolence, probably as a consequence of disrupted nocturnal sleep. As mentioned previously, the condition needs to be considered in all patients with insomnia as a potential cause of their sleep disruption. Periodic limb movements Most patients with restless legs syndrome experience stereotyped repetitive movements once asleep, a condition known as periodic limb movements during sleep. These are best described as rhythmic extensions of the big toe and dorsiflexions of the ankle with occasional flexions of the knee and hip. Periodic limb movements during sleep are also reported in people without any sleep complaint. Although they are rare in young individuals, they are relatively common in the older adult. When periodic limb movements during sleep are seen in patients who complain of sleep-onset or sleepmaintenance insomnia or of primary hypersomnia, it is called periodic limb movement disorder. The basic assumption is that the movements are responsible for the non-restorative sleep and daytime somnolence reported by these patients. Although some studies have suggested that periodic limb movements during sleep may be associated with sleep wake complaints, many authors have concluded that they have little impact on nocturnal sleep or daytime vigilance. This is an ongoing controversial area. Dopamine agonist therapy is effective in controlling periodic limb movements during sleep and may be useful as a therapeutic trial in some patients with hypersomnia without other causes and severe limb movements on sleep study testing. 24 Australian Doctor 4 April 2014

3 Assessment of NARCOLEPSY is a disabling sleep disorder of CNS origin associated with excessive daytime sleepiness and other sleep phenomena that occur during the day when the patient should usually be awake. It should be considered in patients with a long history of daytime sleepiness, particularly if their sleepiness is disabling. Narcolepsy is also an important diagnosis to consider in patients who do not improve with the management of other sleep disorders such as those with obstructive sleep apnoea who remain sleepy despite adequate CPAP therapy. Epidemiology and inheritance patterns Narcolepsy was first described more than 100 years ago by Westphal and Gelineau. Varying prevalence rates have been reported in international studies. A high prevalence rate of 0.15% was reported in a Japanese population while a low 0.002% prevalence rate was reported in an Israeli Jewish population. 3,4 The difference in prevalence rates may be partly explained by differences in how the condition is defined and by the fact that in some suspected cases a definite diagnosis is not possible. Both genders are affected equally. The age of onset ranges from early childhood to those in their 50s. It has a bimodal incidence, with the largest peak at about age 15 and another peak at about age 36. Family members are at increased risk of developing this condition if another family member is affected. The risk of a first-degree relative developing -cataplexy is 1-2%, which is a 10- to 40-fold increased risk compared with the general population. However, with only 1-2% of first-degree relatives affected, most cases present sporadically to doctors, with a clear-cut family history being unusual. Clinical features Narcolepsy is characterised by four typical symptoms: excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic or hypnopompic hallucinations. These four symptoms are known as the tetrad. In addition, patients with commonly report disturbed nocturnal sleep and symptoms suggestive of automatic behaviour. Most of the clinical features of can be considered as intrusions of REM sleep into wakefulness. REM sleep is normally an actively dreaming state of sleep in which all muscles are paralysed, except for some respiratory muscles. People with experience REM phenomena (eg, dreaming and paralysis) while awake, causing typical symptoms (eg, hypnogogic hallucinations and sleep paralysis). People with often describe fragmented or disturbed nocturnal sleep. This is partly due to the underlying pathophysiology of the condition, in which sleep states are less stable, as well as to the increased prevalence of Table 1: Diagnostic criteria for with and without cataplexy Narcolepsy with cataplexy Narcolepsy without cataplexy; or thought to be secondary to a known medical condition EDS almost daily for at least three months EDS almost daily for at least three months Definite history of cataplexy, defined as sudden and transient episodes of loss of muscle tone triggered by emotions No other disorder accounts for the symptoms Diagnosis should be confirmed whenever possible with: polysomnography/mslt or CSF hypocretin-1 concentration <110pg/mL EDS = Excessive daytime sleepiness In people with, hypnagogic or hypnopompic hallucinations may occur at the same time as sleep paralysis. Typical cataplexy absent, but doubtful or atypical cataplexy may be present No other disorder accounts for the symptoms Supportive evidence is required with polysomnography/mslt MSLT = multiple sleep latency test: positive if sleep latency 8 minutes and two sleeponset REM periods CSF = cerebrospinal fluid other sleep disorders in this group. Nightmares, obstructive sleep apnoea, periodic limb movements during sleep, REM behaviour disorder and sleepwalking are all described as being more frequent in people with. Excessive daytime sleepiness Excessive daytime sleepiness is usually the first symptom to develop while other symptoms of such as cataplexy may not appear for years. People with have a general background feeling of sleepiness and also describe a strong urge to sleep recurring throughout the day. This urge to sleep is heightened by monotony and can be characteristically inappropriate (eg, falling asleep in conversation). The history of excessive daytime sleepiness often goes back several years before the patient s presentation. At times patients may have been diagnosed with conditions such as depression or chronic fatigue syndrome in the past, with those diagnoses warranting review if a diagnosis of is subsequently established. Automatic behaviour Up to 40% of patients with can manifest automatic behaviour. This involves the performance of routine activities (eg, emptying the dishwasher or hanging clothes on the line) with reduced awareness. The patient is usually unaware or amnestic of the activity, performing the activity as they fluctuate between sleep and wakefulness. If they perform an activity for which skill is required, frequent mistakes are made, for example, their writing may be meaningless or illegible. Cataplexy Cataplexy is an important and very specific symptom for. However, it may take years to appear. It is a sudden bilateral loss of muscle tone that typically lasts seconds to minutes. It reflects the appearance of normal REM sleep atonia, experienced pathologically in the waking state. Common examples of cataplexy include buckling of the knees, drooping of the head, sagging of the jaw or slurring of speech. At times, cataplexy can be more subtle, such as facial grimacing or twitching of other facial muscles. Cataplexy is provoked by strong emotion, especially laughter. Other emotive precipitants include anger, exhilaration, athletic activity, surprise and sexual activity. During a cataplectic attack, there is no loss of consciousness. If tested, patients are areflexic. Cataplectic attacks start abruptly, but take several seconds to peak. Injury is therefore uncommon because people can sit down or find support if needed. An excessively sleepy individual with clear-cut cataplexy has in the absence of other explanations for their daytime sleepiness. Sleep paralysis Sleep paralysis can occur in normal people as well as those with. It occurs as individuals go off to sleep or wake from sleep. During an episode, the person feels paralysed (they cannot move their limbs, speak or breathe deeply). However, they are fully aware and can recall the event. Hypnagogic or hypnopompic hallucinations In people with, hypnagogic or hypnopompic hallucinations may occur at the same time as sleep paralysis. Hypnagogic hallucinations occur as they fall asleep and hypnopompic hallucinations occur as they wake from sleep. These hallucinations are vivid auditory or visual phenomena occurring during the transition between sleep and awakening. They are often bizarre and frightening, and rarely pleasant. When associated with sleep paralysis, the whole experience may be quite frightening. Pathophysiology Narcolepsy research has been facilitated by canine and mice models for the condition. Mignot, from Stanford University, has been able to use his colony of narcoleptic dogs to identify the gene responsible for canine. 5 His research group determined that the dogs carry a mutation in the receptor for a neurotransmitter variously called hypocretin or orexin. 6 At about the same time, a group working with mice determined that the absence of a functional version of the hypocretin gene in these mice was associated with the appearance of REM sleep at sleep onset (murine ). 7 Human has been found to be associated with low levels of hypocretin in the CSF, implicating the hypocretin system in human. However, human appears to be associated with loss of hypocretin neurons in the hypothalamus, rather than abnormalities in the gene responsible for hypocretin production. Hypocretin-1 levels in the CSF have been found to be low, particularly in patients with who also have cataplexy and specific human leukocyte antigen (HLA) subtype DQB1* This has led to speculation that an HLA-related autoimmune response of unknown origin may trigger damage to those hypocretin-secreting cells, leading to the development of. Narcolepsy is now thought to be due to a single neurotransmitter disorder (a disorder of hippocampal hypocretin), in the same way that Parkinson s disease is a disorder of nigrostriatal dopamine, and Alzheimer s disease a disorder of hippocampal acetylcholine. Diagnosis The International Classification of Sleep Disorders outlines the diagnostic criteria for. 9 These criteria generally require a patient to have symptoms of and specific results on sleep study testing. Table 1 sets out the criteria that differentiate patients with clear-cut cataplexy from those in whom the history of cataplexy is not typical or in whom is thought to be secondary to a known medical condition (eg, a CNS lesion). In the presence of clear-cut cataplexy, the diagnosis can be made without sleep study testing, although in many cases it is still performed. In cases where typical cataplexy is absent, sleep study testing is required for a formal diagnosis. Narcolepsy due to a known medical condition is uncommon. It has been described mainly in patients with lesions or disease affecting the hypothalamus (eg, tumours, multiple sclerosis or sarcoidosis of the hypothalamus). These patients are excessively sleepy and either have definite cataplexy or positive sleep studies for. Their excessive sleepiness cannot be explained by another sleep disorder, a mental disorder or drugs. Multiple sleep latency test The main sleep study test used to assist in the diagnosis of is the multiple sleep latency test (MSLT). This is a daytime test that measures sleepiness. It is performed in a sleep laboratory after a full (eight-hour) night-time sleep study. To ensure accurate interpretation of the MSLT, patients should have no psychotropic medication (including stimulants, antidepres- cont d page 28 4 April 2014 Australian Doctor 25

4 How To Treat Non-apnoeic hypersomnia and from page 25 sants, benzodiazepines, anti-epileptic agents) for two weeks before the test. A urine drug screen is performed on the day of the MSLT to exclude drugs that may affect the results. The night-time sleep study is performed first. This ensures that the MSLT data are not contaminated by the effects of sleep deprivation, and that other sleep disorders that could cause excessive sleepiness are not present. The night study itself may suggest if there is an early REM period or a very fragmented sleep pattern. The MSLT consists of polysomnographic monitoring of sleep parameters for 20 minutes in a quiet, dark and comfortable bedroom. Polysomnographic monitoring in a MSLT refers to a sleep study set-up with the recording leads focusing on brain activity (EEG) to detect sleep. The first test is usually performed about two hours after the patient has woken after a standard overnight diagnostic sleep study. The patient is asked to try to sleep ST LUKES HOSPITAL SLEEP STUDY REPORT Multiple Sleep Latency Test (MSLT) Patient Name: XXXX XXXX Date of Birth: 01/01/1989 Body Mass Index: 20.7 (kg/m 2 ) Date of Study: 24/11/2011 Date Reported: 01/12/2011 Sleep Latency (min) REM latency (min) Test Mean Sleep Latency: Mean REM Latency: Urine Drug Screen on day of testing: Comments Test Test on four or five occasions ( nap opportunities ) at two-hour intervals throughout the day. Test minutes 5 minutes negative The patient slept in four of the four testing periods, and four REM onsets were seen. Conclusion: Mean sleep latency is severely reduced; low sleep latency and four REM onsets is consistent with ; clinical review is recommended Figure 1: MSLT showing a typical positive result for. Interpretation The time to sleep onset and the presence of a sleep-onset REM period are documented. The latter is defined as REM sleep that occurs within 15 minutes of sleep onset. A mean sleep latency of less than or equal to eight minutes and the presence of REM sleep in at least two naps are needed to establish a diagnosis of without cataplexy (figure 1). It is important to note that while a sleep-onset REM period in a multiple sleep latency test is supportive of a diagnosis of, it is not pathognomonic. Other causes include sleep deprivation, withdrawal of REM-suppressant drugs (especially antidepressants) and obstructive sleep apnoea. The results of MSLT need to be considered in the overall clinical context of the patient. Other laboratory tests HLA DQB1*602 gene testing The HLA DQB1*0602 gene can be identified in laboratory testing. The presence of this is supportive of the diagnosis of, but again not pathognomonic. This test is far less useful than the MSLT and does not have a role in the diagnosis of currently. This is largely because the antigen has a 18-35% prevalence in the general population and of those who have the antigen more than 99% do not have. There are also patients with who are HLA negative. CSF hypocretin Although a CSF hypocretin measurement <110pg/mL is listed in International Classification of Sleep Disorders criteria, this test is not used in Australia as far as we are aware. Part of the reason may be the low sensitivity of the test (about 16%) in patients who may have without cataplexy, which is the group of patients that requires additional tests for diagnosis. 10 CSF hypocretin measurements may be considered in patients with suspected with cataplexy when the MSLT is difficult to interpret (eg, in those taking medications that influence the MSLT), or those with other disorders that influence the MSLT (eg, severe insomnia), or in cases of insufficient sleep. Management of Non-pharmacological treatment THE aim of treatment is symptom control. The non-pharmacological approach involves putting in place a regular napping schedule, addressing contributing factors and managing the risks posed by narcoleptic attacks. Strategies are listed in the box, right. Non-pharmacological approach to the treatment of One or two well-timed 20-minute naps, which can improve sleepiness for 1-3 hours Avoiding drugs that can produce daytime sleepiness or insomnia Smoking cessation, as nicotine can worsen and cataplexy Discouraging intake of caffeine and alcohol, especially in the late afternoon and early evening, to help consolidate night-time sleep Encouraging a regular and adequate sleep schedule Caution about potential dangers associated with driving or operating equipment when drowsy Pharmacotherapy for excessive daytime sleepiness Modafinil Modafinil, a non-amphetamine wakefulness-promoting agent, is the first-line medication for treatment of excessive daytime sleepiness due to. The recommended dosage is 200mg mane, although a splitdose strategy (eg, mane and early afternoon) can be beneficial and should be considered for patients who remain sleepy in the second part of the day despite a morning dose. Modafinil is safe and welltolerated. Side effects are uncommon but include headache, nausea, dry mouth, anorexia and diarrhoea. Co-administration with drugs metabolised by the hepatic cytochrome P450-3A system (eg, diazepam, phenytoin and propranolol) may increase their circulating levels. Women using ethinyloestradiol should be advised to use alternative methods of contraception, as peak plasma concentration of the drug may be decreased by modafinil. Unfortunately modafinil is not PBS-subsidised as first-line therapy for in Australia but it may be prescribed first-line as a private script. To be subsidised by PBS, modafinil must be initiated by a qualified sleep medicine practitioner or qualified neurologist and only if dexamphetamine poses an unacceptable medical risk to the patient or if significant intolerance to dexamphetamine develops. The specialist needs to apply to Medicare Australia with evidence that sleep or EEG studies support the diagnosis of. Sympathomimetics Sympathomimetic stimulants such as dexamphetamine and methylphenidate (Ritalin) have a long history of effective use in clinical practice for the treatment of. Most clinical studies show improvements in excessive daytime sleepiness in 65-85% of subjects. Dexamphetamine has the added advantage of a mild anti-cataplectic effect. Dexamphetamine and methylphenidate should generally be initiated by a sleep specialist after a definite diagnosis is made and the need for stimulants is established. Ongoing prescription can be given by the GP with application to and approval from the state department of health to be the patient s registered prescriber for these medications. Dexamphetamine, the more common sympathomimetic stimulant to treat, is usually initiated at a dose of 10-15mg per day, although the ultimate treating dose could be much higher, depending on the degree of improvement in excessive daytime sleepiness and any side effects of treatment. Frequent side effects of sympathomimetic stimulants include irritability, sweating, anorexia and tremors (see box, right). Tolerance may develop in up to one-third of patients and there is potential risk of abuse. There is data to support the effectiveness of sodium oxybate, the sodium salt of the CNS depressant gamma-hydroxybutyrate (GHB), for the treatment of cataplexy, excessive daytime sleepiness, and disrupted sleep due to. However, as far as we are aware, this drug is not used in Australia for the treatment of because of concerns regarding side effects and abuse. The main potential problem of sodium oxybate is the potential for abuse. Other adverse effects include headache, nausea, dizziness and a metallic taste. A rare but serious side effect is an acute confusional state that appears to resolve soon after discontinuation of treatment. Selegiline, an irreversible inhibitor of monoamine oxidase type B, improves excessive daytime sleepiness and has an anti-cataplectic effect at doses of 10-40mg/day. The use of this drug is limited by potential drug interactions and diet-induced interactions. Pharmacotherapy for cataplexy Tricyclic antidepressants Tricyclic antidepressants, especially clomipramine and imipramine, have long been used to treat cataplexy. These drugs also reduce the severity of sleep paralysis and Frequent side effects of sympathomimetic stimulants Irritability Sweating Anorexia Weight loss Tremor Palpitations Mood changes Aggressiveness Insomnia hypnagogic hallucinations. They can be associated with significant anticholinergic side effects, which include dry mouth, constipation, weight gain, glaucoma and urinary retention. Men may experience decreased libido, impotency and delayed ejaculation. These agents can also lower the seizure threshold. A rare adverse event occurring on abrupt discontinuation is rebound cataplexy, which can lead to status cataplecticus. SSRIs and SNRIs SSRIs (eg, fluvoxamine, paroxetine, fluoxetine) have been used in the treatment of cataplexy. These drugs have a lesser degree of anticholinergic and sedative effects than tricyclic antidepressants. Status cataplecticus has been reported with use of this class of agents. Venlafaxine, an atypical antidepressant that increases serotonin and noradrenaline uptake, may also reduce cataplexy. Side effects can be relatively mild. However, randomised, double-blind, placebo-controlled studies testing its efficacy are still pending. Future treatments Further research includes work on hypocretin-based therapy, novel monoamine re-uptake inhibitors and possibly immunotherapy as other treatments for. 28 Australian Doctor 4 April 2014

5 Idiopathic hypersomnolence ANOTHER central cause of excessive daytime somnolence is idiopathic hypersomnolence. This can present similarly to without cataplexy, although REM phenomena are absent. The condition is diagnosed in patients with excessive daytime sleepiness despite adequate sleep and after exclusion of other causes of excessive daytime sleepiness. Patients commonly have marked daytime sleepiness, often with prolonged, uninterrupted and nonrefreshing deep nocturnal sleep. Difficulties in waking are often observed as sleep drunkenness. Sleep drunkenness refers to a condition of prolonged transition from sleep to waking, with partial alertness, mild disorientation, drowsiness or mental fogginess. Unlike, naps are not Other hypersomnias Kleine Levin syndrome THIS uncommon disorder is a form of recurrent hypersomnia that occurs primarily in adolescents. There is a male preponderance. It is characterised by episodes of excessive daytime somnolence, usually, but not invariably, accompanied by hyperphagia, aggressiveness, and hypersexuality, lasting days to weeks, and separated by asymptomatic periods of weeks or months. During symptomatic periods, individuals sleep up to 18 hours a day and are usually drowsy (often to the degree of stupor), confused, and irritable the remainder of the time. Polysomnographic studies Table 2: Diagnostic criteria for idiopathic hypersomnia Idiopathic hypersomnia with long sleep time Nocturnal sleep time >10 hours MSLT: sleep latency <8 minutes (6.2 ± 3.0) Fewer than two sleep-onset REM periods MSLT = multiple sleep latency test Some cases of menstrual-related hypersomnia have responded to blocking ovulation with oestrogen and progesterone. Idiopathic hypersomnia without long sleep time Nocturnal sleep time 6-10 hours MSLT: sleep latency <8 minutes (6.2 ± 3.0) Fewer than two sleep-onset REM periods show long total sleep time with high sleep efficiency and decreased slow-wave sleep. MSLT studies demonstrate short sleep latencies and sleep-onset REM periods. The aetiology of this syndrome remains obscure. Symptomatic cases of Kleine Levin syndrome associated with structural brain lesions have been reported, but most cases are idiopathic. Treatment with stimulant medication is usually only partially effective. Effects of treatment with lithium, valproic acid or carbamazepine have been variable but generally unsatisfactory. Fortunately, in most cases episodes become less frequent over time refreshing. Patients often describe an insidious onset before age 30. The condition usually persists for life. The International Classification of Sleep Disorders diagnostic criteria for idiopathic hypersomnia are listed in Table 2. 9 Patients with idiopathic hypersomnia lack cataplexy and have fewer than two sleep-onset REM periods on the MSLT. The disorder is divided into two groups, depending on whether nocturnal sleep is prolonged (>10 hours) or not. Treatment consists of psychostimulant therapy to improve excessive daytime sleepiness. The same drugs are used as for the treatment of excessive daytime sleepiness due to. Naps and behavioural interventions may not be as beneficial. and eventually subside. Menstrual-related hypersomnia Another form of recurrent hypersomnia is menstrual-related periodic hypersomnia, in which excessive daytime sleepiness occurs during the days preceding menstruation. The prevalence of this syndrome has not been well characterised. Likewise, the aetiology is not known but presumably the symptoms are related to hormonal changes. Some cases of menstrual-related hypersomnia have responded to blocking ovulation with oestrogen and progesterone (eg, with contraceptive pills). References 1. Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature 1997; 388: Desai AV, Bartlett D. How to Treat Insomnia. Australian Doctor, 20 July Honda Y. Census of, cataplexy and sleep life among teenagers in Fujisawa city. Sleep Research 1979; 8: Lavie P, Peled R. Narcolepsy is a rare disease in Israel. Sleep 1987; 10: Mignot E. Genetic and familial aspects of. Neurology 1998; 50:S Lin L, et al. The sleep disorder canine is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: Chemelli RM, et al. Polysomnographic characterization of orexin-2 receptor knockout mice. Sleep 2005; 23:A Chabas D, et al. The genetics of. Annual Review of Genomics and Human Genetics 2003; 4: American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd edn. AASM, Westchester (IL), Mignot E, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of and other hypersomnias. Archives of Neurology 2002; 59: Case study A 30-YEAR-old woman presented with persistent tiredness and sleepiness that had been occurring since age 15. She had been previously diagnosed with seasonal affective disorder and depression and had trialled different antidepressants without any benefit. Other medical history included mild intermittent asthma, a deviated nasal septum and hay fever. Her regular medications at the time of initial assessment were salmeterol-fluticasone and salbutamol inhalers. She described a history of disabling tiredness and sleepiness for many years. She recalled being very drowsy during lectures when she was at university, often missing the content of the lectures. About 10 years before, when living overseas, she was referred for sleep studies but moved to Australia before her testing could be done. More recently, she had started falling asleep at work while at her desk and on occasions she had had to go to the bathroom to refresh herself so she could function. She described a ready ability to fall asleep while reading or watching television. While on holidays, she could easily sleep about 16 hours at a time. She did not drive because she did not feel that it was safe to do so in view of her sleepiness. Further history revealed mildly fragmented sleep. On occasions one or both legs had given way, though there was not always an emotive precipitant. She also experienced vivid dreams and had had at least one hypnagogic hallucination. There was also a strong family history of on her maternal side. Examination revealed a BMI of 23kg/m 2, within the normal range. Her oropharynx was normal. General physical examination was unremarkable. Sleep study testing A diagnostic sleep study was ordered, which did not reveal any obstructive sleep apnoea. The next day the patient had MSLT, which showed severe hypersomnolence (mean sleep latency 3.7 minutes) with one sleep-onset REM period. Assessment The longstanding sleepiness, functional limitation from sleepiness, MSLT results, and family history of all suggested a clinical diagnosis of. Therapy Modafinil was started as initial therapy. Despite a moderate improvement in her symptoms, she experienced nausea and headaches with this medication and was then switched to dexamphetamine at a total daily dose of 15mg. With dexamphetamine, she became more functional and alert with no further cataplectic attacks. cont d next page 4 April 2014 Australian Doctor 29

6 How To Treat Non-apnoeic hypersomnia and Conclusion EXCESSIVE daytime sleepiness is common and has many causes. This article has outlined many of the causes of excessive daytime sleepiness that need to be considered in the differential diagnosis when evaluating patients for this symptom. Obstructive sleep apnoea is being increasingly recognised and diagnosed in general practice. However, knowledge and assessment for these other causes of daytime sleepiness is very important, particularly in those cases where obstructive sleep apnoea is not diagnosed and the patient remains excessively sleepy, or when the clinical picture is not typical for obstructive sleep apnoea. Conditions such as insomnia, restless legs syndrome,, and idiopathic hypersomnia require their own specific treatments to improve the patient s daytime sleepiness. Further reading Bhat A, El Solh AA. Management of. Expert Opinion in Pharmacotherapy 2008; 9: Biliard M, et al. Family studies in. Sleep 1994; 17:S54-S59. Browman C, et al. Tobacco use by narcoleptics and daytime sleep tendency. Drug and Alcohol Dependence 1984; 14: Dauvilliers Y, et al. Clinical aspects and pathophysiology of. Clinical Neurophysiology 2003; 114: Dauvilliers Y, et al. Age at onset of in two large populations of patients in France and Quebec. Neurology 2001; 57: Dyken ME, Yamada T. Narcolepsy and disorders of excessive somnolence. Primary Care: Clinics in Office Practice 2005; 32: Honda Y. Census of, cataplexy and sleep life among teenagers in Fujisawa city. Journal of Sleep Research 1979; 8:191. Hublin C, et al. Epidemiology of. Sleep 1964; 17:S7-S12. Lavie P, Peled R. Narcolepsy is a rare disease in Israel. Sleep 1987; 10, Mullington J, Broughton R. Scheduled naps in the management of daytime sleepiness in -cataplexy. Sleep 1993; 16: Schindler J, et al. Amphetamine, mazindol, and fencamfamin in. British Medical Journal (Clinical Research Edition) 2005; 290: Schwartz JR, et al. Dose effects of modafinil in sustaining wakefulness in patients with residual evening sleepiness. Journal of Neuropsychiatry and Clinical Neuroscience 2005; 17: Online resources Australasian Sleep Association How to Treat Quiz Non-apnoeic hypersomnia and 4 April 2014 Instructions Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. GO ONLINE TO COMPLETE THE QUIZ /education/how-to-treat 1. Which TWO statements are correct regarding the epidemiology of? a) Prevalence rates of vary from 0.002% to 0.15% b) Narcolepsy is more common in males c) Narcolepsy has a peak incidence in people aged d) The risk of a first-degree relative developing -cataplexy is 1-2% 2. Which TWO statements are correct regarding the pathophysiology of? a) Narcolepsy is associated with low levels of hypocretin in the cerebrospinal fluid b) The underlying pathology is thought to be a genetic defect in hypocretin production c) There is an association between and human leukocyte antigen (HLA) subtype DQB1*0602 d) Narcolepsy is most likely due to multiple neurotransmitter defects 3. Which TWO statements are correct regarding the clinical features of? a) Narcolepsy is associated with REM sleep phenomena during wakefulness b) Narcolepsy is characterised by a tetrad of symptoms that include cataplexy and sleep paralysis c) Cataplexy is a prolonged dramatic loss of tone in all muscles of the body d) Almost all patients with manifest automatic behaviour 4. Which TWO statements are correct regarding the diagnosis of? a) Under the International Classification of Sleep Disorders, a diagnosis of only requires a positive CSF hypocretin-1 level b) In patients with clear-cut cataplexy, the diagnosis of may be made without sleep study testing c) Excessive daytime sleepiness almost daily for three weeks is necessary for diagnosis of d) Narcolepsy may result from a tumour of the hypothalamus 5. Which TWO statements are correct regarding investigations for? a) The multiple sleep latency test monitors how frequently the patient wakes at night b) Patients should have no psychotropic medication for two weeks before the multiple sleep latency test c) A positive HLA DQB1*0602 gene test is pathognomonic for d) The CSF hypocretin test has a poor sensitivity for without cataplexy 6. Which THREE strategies are part of the nonpharmacological treatment of? a) Smoking cessation counselling b) Avoiding napping during the day c) Avoiding drugs that can produce daytime sleepiness or insomnia d) Caution about potential dangers associated with driving 7. Which TWO statements are correct regarding the pharmacological treatment of? a) Modafinil is a non-amphetamine wakefulness-promoting agent for the treatment of excessive daytime sleepiness due to b) Dexamphetamine should not be used for c) Selegiline is a safe first-line choice for treating cataplexy d) Tricyclic antidepressants may be used to treat cataplexy 8. Which THREE classes of medications may cause day time sleepiness? a) Second-generation antiepileptic drugs such as gabapentin b) Corticosteroids such as prednisolone c) Dopaminergic agonists such as pramipexole d) Beta-blockers such as atenolol 9. Kitty is a 17-year-old Year 12 student who presents complaining of excessive daytime sleepiness for the past three months. Which TWO statements are correct regarding the initial approach to her presentation? a) Kitty s lifestyle and study commitments should be specifically reviewed b) If Kitty has depression she will suffer from insomnia, not daytime sleepiness c) Kitty is too young to have idiopathic hypersomnia d) A menstrual history is an important part of her initial assessment 10. Kitty was diagnosed as suffering from insomnia as well as depression. Which THREE strategies are correct in managing her insomnia? a) Kitty should be advised of stimulus-control measures b) Kitty s insomnia symptoms and depression should be recognised and treated as the same condition c) Cognitive approaches should be adopted to address unhelpful thoughts and anxiety d) A full medical history should be taken so comorbidities may be treated CPD QUIZ UPDATE The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the triennium. You can complete this online along with the quiz at. Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. how to treat Editor: Dr Steve Liang steve.liang@cirrusmedia.com.au Next week A disorder of pigmentation is a common presentation. They can occasionally be associated with an underlying systemic disorder, so it is important to recognise their causes in order to achieve the best treatment outcome. Over the next two weeks, How to Treat discusses pigmentary disorders in general and then looks at individual hyperpigmentary and hypopigmentary conditions in more detail. The authors are Dr Deepani Rathnayake, consultant dermatologist, Base Hospital Dambulla, Sri Lanka; and Professor Rod Sinclair, director, head, dermatology, Epworth Hospital, Melbourne, Victoria. 30 Australian Doctor 4 April 2014