diagnosis and management of common sleep disorders

8/3/2019 Diagnosis and Management of Common Sleep Disorders

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a report by

Emmanuel Mignot1 and Robson Capasso 2

1. Howard Hughes Medical Institute Investigator; 2. Post-doctoral Fellow, Sleep Medicine, Stanford Sleep Disorders Center

Sleep is the golden chain that ties health and our bodies together.

Thomas Dekker

Untreated sleep disorders such as sleep apnoea, restless legs syndrome

(RLS) and narcolepsy are common and often undiagnosed. They have

significant effects on quality of life and can even lead to death, for example

in the context of an accident caused by tiredness while driving.

Furthermore, these disorders can cause symptoms that may be confusedwith neuropsychiatric conditions such as depression or schizophrenia or

that can contribute to treatment resistance. A number of studies have

shown associations between sleep and genuine neuropsychiatric disorders.

The Basic Neurobiology of Sleep

Sleep is not a passive state. The neural substrates underlying sleep states

include sleep- and wake-on neuronal networks. Wake-on-promoting

systems are typically brainstem and hypothalamic systems that project to

the cortex and or the thalamus, which then activates the cortex. These

include cholinergic ascending systems (pedunculopontine and laterodorsal

tegmental areas and basal forebrain), adrenergic locus coeruleus,

serotonergic raphe nuclei, hypocretin-containing lateral hypothalamicsystems and histamine-containing tuberomammillary hypothalamic nuclei.

General brain activation ensues, with high glutamate release and

electroencephalography (EEG) desynchronisation and consciousness.

Wakefulness is the co-ordinated expression of many behaviours that are

constantly changing in response to variations in the external and internal

milieu. Most likely, each arousal system is particularly active under specific

circumstances, and there is an intense interaction among them.1,2

Dopaminergic cell groups of the substantia nigra (SN) and ventral

tegmental area (VTA), for example, do not seem to significantly increase

overall neuronal activity in wakefulness, but are certainly activated by

specific behaviours in wakefulness and are involved in the wake-

promoting effects of most stimulants, such as amphetamines,

methylphenidate and modafinil.

A smaller number of systems are sleep-active in the brain: during non-

rapid eye movement (NREM) sleep, most of the brain activity is decreasedand the EEG is desynchronised, characterised by the appearance of slow

wave activity. Major sleep-promoting centres include a group of anterior

gamma-aminobutyric acid (GABA)-ergic hypothalamic and basal

forebrain sleep-on networks, including the ventrolateral preoptic (VLPO)

and median preoptic (MnPO) nucleus of the hypothalamus.3 These

systems strongly inhibit the wake-active systems mentioned above. Of

final interest is REM sleep, a paradox as the brain is generally active (most

notably the cortex, with a wave-like desynchronised EEG and associated

dreaming) while REM and muscle paralysis (atonia) occur. In REM sleep,

cholinergic systems and many sleep-on systems are active, but

monoaminergic systems are turned off.46 Most antidepressants are

strong REM sleep suppressants. Sleep and wake tendencies can be seenas the sum of two processes: homeostatic and circadian. The homeostatic

process is a reflection of the sleep debt. It reflects the fact that the longer

we are awake, the more sleepy we become. It has been claimed that

adenosine (AD), an inhibitory neuro-transmitter, accumulates in the basal

forebrain with wakefulness and plays a role in the integration of sleep

pressure, inhibiting wake-on systems.2,46 Caffeine is a very popular wake-

promoting agent, and its main mechanism of action is through AD

receptor antagonism. This homeostatic factor interacts with the circadian

process, which has evolved as an adaptation to the solar cycle of light and

dark and is present in almost all mammals.

Independently of sleep debt, the circadian clock sends a wake-promotingsignal that peaks in the afternoon (best tracked by body temperature

fluctuations without sleep) so that it opposes the mounting sleep debt that

results from having been awake since the morning, maintaining alertness

during the day. An opposite interaction occurs during the night so that the

tendency to sleep is at its peak in the early hours of the morning, allowing

us to sleep longer once the sleep debt has been reduced by the previous

sleep cycles. The suprachiasmatic nucleus (SCN) in the hypothalamus

functions as the main circadian pacemaker, controlling the timing of the

sleepwake cycle, and is mostly influenced by light and, to a lesser extent,

by melatonin, a hormone produced in the night by the pineal gland. 7 This

process may be disrupted in shift workers and when we cross time zones.

This is commonly known as jet-lag, and causes a broad constellation of

symptoms including fatigue, disorientation, irritability (worse in the early

morning of the original time zone) and impaired sleep (worse in the early

evening of the original time zone, sometimes called the forbidden zone).

Diagnosis and Management of Common Sleep Disorders

An Overview for the Psychiatrist

T O U C H B R I E F I N G S 2 0 0 8

Insomnia

44

Emmanuel Mignot is a Howard Hughes Medical Institute

Investigator, a Professor of Psychiatry and Behavioral Sciences

and Director of the Center for Narcolepsy at Stanford

University. He is internationally recognised as having

discovered the cause of narcolepsy. Dr Mignot has received

numerous grants and honours, including National Sleep

Foundation (NSF) awards and the Jacobaeus prize. He is the

co-author of over 100 original scientific publications and serves

on the Editorial Board of several sleep disorder journals.

E: [email protected]

Robson Capasso completed medical school and further

surgical training at the Universidade Federal do Parana in

Curitiba, Brazil. After completion of psychiatry training at

the University of Miami, he is now pursuing a

postdoctoral fellowship in Sleep Medicine at the Stanford

Sleep Disorders Center.


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45E U R O P E A N P S Y C H I A T R I C R E V I E W

Diagnosis and Management of Common Sleep Disorders An Overview for the Psychiatrist

Insomnia

Insomnia refers to a complaint of difficulty falling asleep, frequent and/or

prolonged awakenings, early-morning awakenings or non-restorative,

poor-quality sleep in an individual who has adequate opportunity for

sleep. Insomnia is not defined by sleep laboratory measures or any specific

sleep duration. Chronic, serious insomnia affects 10% of the population,

with a higher predisposition among females.8 As insomnia occurs only

when there is adequate opportunity for sleep, it must be distinguished from

sleep deprivation, in which the individuals short sleep duration results from

inadequate opportunity.

The most common daytime impairments associated with insomnia include

complaints of fatigue, mood disturbance and impaired cognitive function.

Actual daytime sleepiness is not common among individuals with

insomnia.9 Medical conditions, most importantly those associated with pain

and almost all psychiatric disorders, are also linked to insomnia. A thorough

medication history is essential, including prescription drugs (antidepressants

or antihypertensives commonly cause insomnia), over-the-counter

medications, substances such as caffeine and alcohol and illicit drugs.Insomnia is commonly described as being secondary to other conditions,

associated with other sleep disorders (sometimes due to sleep apnoea) or

primary (when no other aetiology can be identified). Secondary insomnia

refers to the insomnia syndrome when it is thought to be due to a medical

or psychiatric disorder, or to the effects of a substance or medication.

However, recently a consensus conference has rejected this simple

dichotomy due to insufficient evidence, especially in the neuropsychiatric

context.9 Why some depression cases are associated with insomnia or

excess sleep is unknown, and a causal relationship from depression to

insomnia or hypersomnia is not established. Interestingly, several studies

have shown that the presence of insomnia predicts the development of

depression years later, suggesting that insomnia could participate in thedevelopment of depression.10 Poor sleep quality is reported in up to 90%

of patients with depression.10 Fava and colleagues demonstrated that

patients with co-morbid insomnia and depression experience a faster, more

effective antidepressant response when treated with a sleep agent and

antidepressant combination than when treated with either a sleep agent or

an antidepressant alone.11 Generalised anxiety disorder patients complain

of trouble sleeping in 6070% of cases, and there is an overlap between

interventions that target insomnia and those that are used in treating

anxiety disorders, including medications and cognitive strategies that target

worry, tension and maladaptive cognitions.12

Behavioural Treatments of Insomnia

The treatment of insomnia has recently evolved, as insomnia has been

shown to often benefit greatly from non-pharmacological interventions.

Psychological and behavioural therapies have consistently been shown to

improve primary insomnia or insomnia associated with medical or psychiatric

disorders, both objectively and subjectively. Studies have found that

improvements may be achieved more quickly with drug treatment, but are

more sustained with cogitive behavioural therapy (CBT).13 One limitation of

behavioural therapies is not a lack of efficacy, but the need for repeated

follow-up and coaching of patients for several weeks to ensure compliance

and stable behavioural changes, a difficult endeavour in countries wherecare is rationed. The components of behavioural treatments for insomnia are

summarised below.13,14

Sleep Restriction

This involves limiting time in bed to that spent actually sleeping, creating

a mild sleep deprivation and increasing homeostatic pressure for sleep;

this reduces poor sleep and enhances regularity of sleep/wake. Quality

first, than quantity is the motto of sleep restriction therapy. This

component may be the most essential. In extreme cases, the fear of not

sleeping is so intense that patients may stay in bed for 10 hours trying to

sleep more, thereby producing sleep disruption and insomnia.

Cognitive Therapy

Based on Becks model, this psychotherapeutic approach seeks to modify

sleep-related dysfunctional beliefs and thoughts and the maladaptive

cognitive processes involved in the exacerbation and perpetuation of

insomnia. One example is the belief that one may need eight to nine

hours of sleep based on what family and friends report, while in fact

there is great individual variability in the required number of hours for a

restful night of sleep.

Sleep Hygiene

Sleep hygiene therapy aims to provide patients with education about

how to improve their sleeping habits. One example would be to avoidcaffeine or alcohol consumption for four to six hours before bedtime.

Another piece of advice is to have a dark bedroom and to avoid bright

light exposure when going to the bathroom in the middle of the night,

as this may disrupt circadian rhythms (a dimmer switch is recommended).

Stimulus Control

Stimulus control therapy is based on the principles of conditioning. It aims

to re-establish the bed and bedroom as stimuli for sleep, creating a

consistent sleep/wake schedule. Therapists advise: If you are unable to fall

asleep in 1520 minutes, get out of bed and engage in a quiet, non-striving

activity. Only return to bed when you are sleepy again.

Relaxation and Sleep Management

Sleep management therapy aims to reduce the cognitive and emotional

hyperarousal that is incompatible with sleep.

The most common daytime impairments

associated with insomnia include

complaints of fatigue, mood disturbance

and impaired cognitive function.

Studies have found that improvements

may be achieved more quickly with drug

treatment, but are more sustained with

cognitive behavioural therapy.


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46 E U R O P E A N P S Y C H I A T R I C R E V I E W

Insomnia

Light Therapy

In some cases, although patients experience difficulty sleeping during the

night, maintaining sleep until the late morning is not a problem. This is

often seen in adolescents, and is known as delayed sleep phase syndrome,

a circadian clock disorder. Advanced sleep phase syndrome, another

circadian clock disorder, is also sometimes seen in the elderly when living

indoors permenantly. In these cases, consistent, daily light therapy can be

very helpful in re-training the circadian cycle (morning when delayed,

evening when advanced).15 Light therapy may also have antidepressant

effects.16 Regular exercise at scheduled times may also help. Melatonin can

also be used (particularly in completely blind subjects), and in these cases

low physiological doses (0.3mg) should be used.17 However, importantly,

melatonin is less effective at re-setting circadian rhythms than bright

daylight or light-box exposure at an intensity of 10,000 lux. Behavioural

therapies are educational to the patient and can provide insomnia patients

with a set of tools to apply in times of stress and insomnia relapses.

Evaluation with a sleep log is needed first to determine in which phase of

sleep problems occur (e.g. difficulties falling asleep, falling asleep too early

or too late) and usual daily sleep amounts (generally underestimated by the

insomnia patients). In sleep restriction, usual daily sleep amounts are then

decreased by 30 minutes to one hour, and the patient is asked to wake at

the same time each day. After a few weeks the subject feels more sleepy

at bedtime and sleeps more consistently. Feedback and monitoring on a

weekly basis are needed to titrate sleep deprivation and timing and to

provide cognitive therapy advice.

Pharmacological Treatment of Insomnia

Insomnia may be treated with CBT and instruction in sleep hygiene, either

alone or in association with hypnotic medications.18,19 As taking many of

these drugs can become a habit, it is usually best to use pharmaceutical

agents for a maximum of three days in a row (this is enough in the context

of jet lag), although in some cases pharmacological treatment is more

appropriate than behavioural therapies (psychiatric context, failure of

behavioural therapy). Almost all US Food and Drug Administration(FDA)-approved options for the treatment of insomnia (see Table 1)1820 are

GABAergic modulators acting on the benzodiazepine-binding site of the

GABAA receptor, a complex chloride channel composed of a large number

of possible subunits. A typical benzodiazepine drug has anticonvulsant,

anxiolitic, hypnotic, myorelaxant and amnesic properties, although different

compounds can have slightly different effects on the various symptoms

depending on the dose. A meta-analysis of benzodiazepine use in the

treatment of insomnia showed that sleep latency for patients receiving a

benzodiazepine was 4.2 minutes shorter, and that patients slept for an

average of 61.8 minutes longer than those in the placebo group.20

The older compounds, of benzodiazepine structure have a broad effect onmany GABAA receptor subtypes, whereas some of the more

recent compounds that do not have a benzodiazepine structure

(zolpidem, eszopiclone, zaleplon) have a more specialised effect. This last

property is likely to increase receptor subtype specificity,21 and these

non-benzodiazepine GABAA benzodiazepine receptor-binding compounds

may have more hypnotic than myorelaxant, anticonvulsant and antianxiety

effects, although this is clearly dose-dependent. At high doses, these

compounds are similar to classic benzodiazepines. Less dependence/

tolerance has been suggested for these new compounds at a constant dose,

and many patients can take these compounds daily for decades without

significant problems. The potential abuse of hypnotic medications remains a

concern for some physicians. This may lead them to avoid or limit the use of

pharmacological treatment for their insomnia patients; however, abuse of

benzodiazepine and benzodiazepine-like hypnotics is rare among insomnia

patients. The use of hypnotics should be carefully evaluated in patients with

a previous history of substance abuse or dependence, and it is good clinical

practice to monitor prescriptions and regularly assess the patients

Table 1: US Food and Drug Administration-approvedAgents for the Treatment of Insomnia

Medication Class Duration of Half-life Use Side Effects

Action (hours)

Estazolam BZP Intermediate 1024 Mainly Drowsiness,

for SMI dizziness,

unco-ordinationand amnesia

Temazepam BZP Intermediate 3.518.4 Mainly Drowsiness,

for SMI dizziness,

unco-ordination

and amnesia

Triazolam BZP Short 1.55.5 Mainly Drowsiness,

for SOI dizziness,

unco-ordination,

amnesia and

rebound

insomnia upon

cessation

Flurazepam BZP Long 2.3100 # Drowsiness,

dizziness,

unco-ordination

and amnesia

Quazepam BZP Long 3973 # Drowsiness,

dizziness,

unco-ordination

and amnesia

Zaleplon N-BZP Short 1 Mainly Drowsiness

BZP for SOI

agonist

Eszopiclone N-BZP Intermediate 6 SOI and Drowsiness,

BZP SMI dizziness and

agonist unpleasant taste

Zolpidema N-BZP Short 1.44.5 SOI Drowsiness,

BZP dizziness

agonist

Ramelteon Melatonin Short 25 SOI Drowsiness,

receptor dizziness

(MT1/MT2)

agonist

SMI = sleep maintenance insomnia; SOI = sleep-onset insomnia; BZP = benzylpiperazine;

N-BZP = non-benzylpiperazine; GABA = gamma-aminobutyric acid.

# Usually not recommended due to a long half-life and high likelihood of daytime sedation.

Alprazolam, lorazepam, clonazepam, siazepam and midazolam are not FDA-approved for

treatment of insomnia; however, they are very commonly prescribed as hypnotics.

a: Zolpidem has a controlled-release formulation with a dual-layered tablet: one layer releases

zolpidem immediately and a second layer provides a slower release of additional zolpidem for

maintenance of plasma zolpidem concentrations, and may be used for SOI and SMI. In some cases, although patients

experience difficulty sleeping during the

night, maintaining sleep until the late

morning is not a problem.


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medication use.19 The major property to consider for prescription is half-life

and duration of action. Zaleplon, for example, acts for only two to three

hours, and may be useful for sleep-initiating difficulties or early-morning

insomnia in jet-lag. Zolpidem and zolpidem CR or eszopiclone are effective

for five to six hours and six to seven hours, respectively.19,20

Ramelteon, a selective melatonin receptor agonist, was recently approved

for the treatment of insomnia. This compound has more of an effect on

sleep onset than sleep maintenance22 and thus may be less effective in

the overall treatment of insomnia, but also has less potential for

dependence and thus may be more appropriate for patients with a

history of substance abuse. Antihistaminics and sedating antidepressants

(mirtazapine, trazodone) lack objective evidence for their use as

hypnotics, but are commonly used.8 The mode of action of these drugs is

the blocking of the H1 receptors or of the 5-HT2 receptor. A problem with

these compounds is that they have not been designed for hypnotic use,

and often have a long duration of action, leading to daytime sleepiness

and morning grogginess.

Restless Legs Syndrome and Periodic

Limb Movements of SleepDespite being different clinical entities, RLS and periodic limb

movements of sleep (PLMs) are usually discussed together due to the

high chance of co-existence, a similar genetic predisposition and

the use of similar treatments. They generally present with insomnia,

restless sleep and/or excessive daytime sleepiness, and they may be

present in as many as 25% of patients who have sleep disorders. RLS

is common and is severe in 34% of the population. 23,24 It is more

common in females (especially during pregnancy), is often familial and

is exacerbated by neuroleptics. All patients with a sleep problem should

be evaluated for RLS.

RLS is a sensorimotor disorder characterised by a nearly irresistible urgeto move the legs. It is often accompanied by other dysesthesias or

paresthesias occurring primarily at rest and at night, and is alleviated

by movement. RLS is frequently associated with PLMs,25 which are

repetitive movements that affect one or both legs and usually occur

during NREM sleep. PLMs is sometimes associated with awakening. The

typical movement found in PLMs is a flexing of the ankle, knee and hip

with an extension of the toes. PLMs is found in 80% of RLS patients

undergoing polysomnogram.23

According to the Standards of Practice Committee of the American

Academy of Sleep Medicine (AASM), The Practice Parameters for the

Dopaminergic Treatment of Restless Legs Syndrome and Periodic Limb

Movement Disorder24 states that: levodopa with decarboxylase

inhibitor, and the dopaminergic agonists pergolide, pramipexole and

ropinirole are effective in the treatment of RLS and PLMs. Other

dopamine agonists (talipexole, cabergoline, piribidel and alpha-

dihydroergocryptine) and the dopaminergic agents amantadine and

selegiline may be effective in the treatment of RLS and PLMD, but the

level of effectiveness of these medications is not currently established.

Lastly, no specific recommendations can be made regarding

dopaminergic treatment of children or pregnant women with RLS or

PLMD. The use of dopamine agonists is generally thought to be

preferable to that of L-DOPA on a chronic basis. Opioids and

benzodiazepines are commonly used for the treatment of these

conditions as a second intention; however, the risk of drug dependence

must be considered.

Importantly, RLS can be secondary to medical disorders, including

iron deficiency, neuropathies and renal disease. Ferritin levels should

be investigated in these patients: if below 4560mg/ml, iron

supplementation should be considered.

Hypersomnia/Excessive Daytime Sleepiness

Disease and SymptomsThe International Classification of Sleep Disorders (ICSD) defines excessive

daytime sleepiness (EDS) as the inability to stay awake and alert during the

major waking episodes of the day, resulting in unintended lapses into

drowsiness or sleep.25 Several factors may cause hypersomnia,

including medical and neurological conditions (e.g. rheumatological

disorders, congestive heart failure, cancer, hypothyroidism, anaemia,

neurodegenerative disorders such as Parkinsons and Alzheimers disease,

head trauma and encephalitis), primary sleep disorders (sleep-disordered

breathing [SDB], PLMs, idiopathic hypersomnia, narcolepsy) and medication

use or withdrawal (opioids, anticonvulsants, antidepressants, illicit drugs). In

a population-based study, hypersomnia was associated with psychiatric

disorders in 46.5% of cases.26

It is important to bear in mind that althoughmedical, neurological or psychiatric illness or medication side effects can be

a cause of sleepiness, insufficient sleep is the most common cause of EDS in

the general population.

The atypical features specific to a mood disorder episode include

hypersomnia as a diagnostic feature in the diagnostic criteria from the

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text

Revision (DSM-IV-TR).27 An association between hypersomnia and a mood

episode is reported in 1620% of patients;28 however, there is a paucity

of objective findings documented. Nofzinger et al.29 performed a multiple

sleep latency test (MSLT) to objectively evaluate daytime sleep latency in

depressed patients, and the results did not show abnormalities, suggesting

that the hypersomnia in such patients is a subjective complaint. As a result,

hypersomnia in a psychiatric context is difficult to evaluate and treat. A

misdiagnosis may result in gross mismanagement (e.g. the use of

Insomnia may be treated with cognitive

behavioural therapy and instruction in

sleep hygiene, either alone or in

association with hypnotic medications.

Despite being different clinical

entities, restless legs syndrome and

periodic limb movements of sleep are

usually discussed together due to the

high chance of co-existence, a similargenetic predisposition and the use

of similar treatments.


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Insomnia

antidepressants in SDB patients complaining of hypersomnolence who are

misdiagnosed with depression). In contrast, a number of patients with

conversion disorder or depression can be misdiagnosed as having

hypersomnia or narcolepsy, with negative consequences. Finally, as will be

discussed later, it is not uncommon for patients with a hypersomnia

complaint to have a combination of problems that all contribute to the

symptoms they are experiencing (typically mood and anxiety disorder, mild

sleep apnoea, disturbed sleep at night and poor sleep hygiene).

Sleep-related Breathing Disorders

The disorders of this subgroup are characterised by disordered breathing

during sleep (SDB). Chief among them is obstructive sleep apnoea (OSA),

which causes fragmented sleep and sleepiness due to arousals secondary to

episodes of complete (apnoeas) or partial (hypopnoeas) upper airway

obstruction occurring during sleep with oxygen desaturations. Sleep apnoea

is more frequent in males, the obese or those with a small jaw, but should

not be excluded in children or even in an underweight female. In addition

to EDS, patients may complain of insomnia, fatigue and decreased energy

levels (symptoms that are mistakenly attributed to depression), and theirpartners often report loud snoring or breathing interruptions.30 The

estimated prevalence of SDB, defined as an apnoeahypopnoea index (AHI)

(an index known to be associated with and to predict an increased risk of

high blood pressure and various cardiovascular complications) of 5 or

higher, is 9% for women and 24% for men.31

A milder form of SDB, called upper airway resistance syndrome,32 has

also been described. In these cases, frank apnoea is not present, but

the airway narrows during sleep, forcing the sleeper to increase

respiratory effort (fighting to breathe), leading to arousal and

disturbing sleep without frank obstruction and oxygen desaturations.

These milder events, called respiratory-effort-related arousals (RERAs),are best observed with the use of an oesophageal manometer during

the polysomnogram. Problematically, there is only a weak correlation

between the presence of sleep apnoea and daytime symptoms such as

sleepiness. Consequently, some patients may have severe sleep apnoea,

sleep fragmentation and desaturation with a higher risk of

cardiovascular complications, but no memory of bad sleep or no

complaint of daytime sleepiness.

The gold standard diagnostic test is a polysomnogram performed in a

sleep laboratory. The AHI is usually determined, as well as lowest and

mean oxygen desaturations two important severity factors. An AHI

score of >30 and desaturation during sleep of below 80% is severe.

Continuous positive airway pressure (CPAP) is still considered to be first-

line therapy for treatment of SDB. In CPAP, a nasal or nasaloral mask is

provided and continuous positive pressure applied to the upper airway

during sleep. By stabilising the airway walls, CPAP alleviates the tendency

for the upper airway to collapse, ameliorating breathing disturbances and

allowing sleep with less interruption. Studies have shown that CPAP

therapy significantly improves subjective and objective measures of

daytime sleepiness in patients with OSA.33,34 CPAP is safe, but often not

tolerated or used regularly, mainly due to a lack of care by providers, who

do not help the patients to tolerate and become accustomed to the

machine by finding the right pressure device, mask and accessories and

coaching them during the first month of prescription. As a result,

although some patients find it effective immediately, many patients are

discouraged and do not use the device for long enough to see benefits.Alternatives to CPAP for the treatment of OSA include a variety of

pharyngeal soft tissue and maxillarymandibular surgical interventions.

These procedures address the various points of obstruction in the upper

airway or any anatomical variants that predispose an individual to an

SBD.35,36 Mandibular advancing dental devices are a treatment option for

mild-to-moderate OSA in patients intolerant of CPAP who are not

candidates for surgery.36 Surgical therapies for SDB, although liberating

when effective (no need for constant use of CPAP), should be carefully

considered, as many procedures are ineffective and painful. Similarly,

reducing nasal obstruction can ameliorate sleep apnoea by reducing airway

resistance and collapse, but is rarely curative. Finally, weight loss can be

effective in reducing SDB, although it is difficult to maintain. Any changein body mass index (BMI) of more than 10% should prompt clinicians to

reconsider SDB severity.

Narcolepsy

Narcolepsy is a serious sleep disorder characterised by excessive daytime

sleepiness and abnormal REM sleep manifestations, including cataplexy

(sudden loss of muscle tone triggered by strong emotions), sleep paralysis,

hypnagogic (at sleep onset) and hypnopompic (at wake-up time)

hallucinations and sleep-onset REM periods.25 The main finding in these

patients is a decrease in hypocretin/orexin concentrations in the

cerebrospinal fluid (CSF)37 and in the number of hypocretin neurons in

post mortem brain tissue.38 EDS is usually the first symptom to appear, andis exacerbated when the patient is physically inactive. It is often irresistible,

despite the individual making desperate efforts to fight the urge to sleep,

and is frequently associated with dreaming.39 Despite the EDS, narcoleptic

patients generally have disrupted nocturnal sleep, falling asleep as soon as

they get into bed but waking up several times during the night. Cataplexy

is the best diagnostic marker of the disease. It is characterised by a sudden

drop of muscle tone triggered by emotional factors, usually by positive

emotions such as laughing, or by anger, but almost never by stress, fear or

physical effort. It is sometimes limited to facial muscles or to the arms

or legs, with dysarthria, jaw tremor, head or jaw dropping, dropping of

objects or unlocking of the knees.3941

Other symptoms of dissociated REM sleep in patients with narcolepsy

include sleep-related hallucinations and sleep paralysis (an inability to

move the limbs or the head or to speak or breathe normally, either at

Restless legs syndrome can be

secondary to medical disorders,including iron deficiency,

neuropathies and renal disease.

Sleep apnoea is more frequent in males,

the obese or those with a small jaw, but

should not be excluded in children or

even in an underweight female.


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sleep onset or upon awakening, mainly from REM sleep, despite being

mentally awake, and usually lasting just a few seconds).41 Sleep paralysis

and sleep-related hallucinations are present in only 50% of people with

narcolepsy and can be present in another conditions, so cannot be used

in diagnosis; however, they should be carefully evaluated as occasionally

patients may be misdiagnosed as schizophrenic.42 Onset is usually during

adolescence, although cases have been seen in those who are only a few

years old and in those above 70 years of age.

The negative social impact of narcolepsy has been extensively described. It

can impair driving ability, cause car or machine accidents and reduce

professional performance (leading to people becoming unemployed,

changing jobs frequently or retiring early).43,44 Depression has also been

reported in 1837% of cases.45 A patient with suspected narcolepsy should

undergo a polysomnogram followed by a daytime MSLT, a test that consists

of a series of naps. It is used to see how quickly the patient falls asleep in

quiet situations during the day. The MSLT is the standard way of measuring

the level of daytime sleepiness. The aim of the polysomnogram is to

eliminate other causes of daytime sleepiness (mainly sleep apnoea) andto assess whether the patient has had enough sleep (at least six hours)

before the MSLT. Additionally, the polysomnogram might show a shortened

REM sleep latency. The MSLT mean daytime sleep latency is eight minutes

or shorter, with two or more sleep onsets in REM periods (SOREMPs). The

time from sleep onset to REM sleep should be less than 15 minutes in at

least two naps. An additional diagnostic tool for the identification of

narcolepsy with cataplexy is the association with a specific human leukocyte

antigen (HLA) allele, the DQB1*0602, identified in 8595% of patients with

narcolepsycataplexy. However, in the US 12% of Asian people, 25% of

white people and 38% of African-Americans in the general population have

this allele, but obviously only a small fraction of these have

narcolepsy. Additionally, HLA is positive in only 4060% of patientswith narcolepsy without cataplexy, and in 75% of familial cases of

narcolepsy.46,47 However, importantly, sleep paralysis and dream-like

hallucinations also occur in isolation in normal people, often in association

with sleep deprivation, anxiety and depression.

Measuring CSF-hypocretin-1, obtained through lumbar puncture, is

often useful in making the diagnosis of narcolepsy. CSF hypocretin 1

concentrations lower than 110ng/l, or 30% of local normal

values, are highly indicative of narcolepsy. Low CSF hypocretin

concentrations are highly specific (99%) and sensitive (8789%) for

patients with clear-cut cataplexy, and specific (99%) but not sensitive

(16%) for those with mild, atypical or absent cataplexy, and for

patients with familial or HLA-negative narcolepsy.37,42

Current treatments for narcolepsy are aimed at specific symptoms and

are not directed against the disease as a whole. Treatment includes

stimulants (modafinil, methylphenidate, amphetamines) for daytime

sleepiness and sleep attacks,4851 low-dose antidepressants (typically

venlafaxine) that are well-known for their REM suppressant capacity

for cataplexy and other REM-associated symptoms52,53 and hypnotics for

disturbed night-time sleep. Sodium oxybate (-hydroxybutyrate [GHB])

acts as a neurotransmitter via its own receptors and via the stimulation of

GABAB receptors, and shows efficacy in managing REM-related

symptoms including cataplexy, hypnagogic hallucinations and sleep

paralysis. It is also effective against sleepiness.5456 Narcolepsy/hypocretin

deficiency can be associated with schizophrenia, depression, anxiety,

obsessive compulsive disorder and any other psychiatric conditions. In

these cases, the clinical picture is often more difficult to recognise, and

treatment is more difficult.

Hypersomnia

In contrast to narcolepsycataplexy, a disorder with a clear

pathophysiology (HLA-associated hypocretin deficiency), a number ofpatients present with sleepiness, some of the narcolepsy symptoms and/or

diagnostic results (positive sleep test with short REM latency and/or short

sleep latency; HLA positivity) but not low CSF hypocretin. Some of these

patients experience severe sleepiness, excessive sleep (more than 10 hours

of daytime sleep every day) and documented abnormal MSLT. In these

unusual cases, neurological work-up is important. More commonly,

patients may present with mildly abnormal nocturnal sleep (mild insomnia,

short sleep), excessive napping, a borderline positive MSLT (with or

without SOREMPs) and significant subjective complaints of daytime

fatigue and sleepiness. In these cases, it is not uncommon to have a

combination of problems, such as mild SDB, insufficient nocturnal sleep,

depression/anxiety and/or some element of conversion disorder. In thesecases, the clinician should treat one condition after the other, using (in

order) behavioural and light therapy to consolidate nocturnal sleep, mild

non-amphetamine stimulants (atomoxetine, modafinil) to treat a possible

central nervous system (CNS) hypersomnia, CPAP to treat mild sleep

apnoea and antidepressants and psychotherapy if depression or anxiety

disorders are present. Stronger treatments using amphetamine stimulants

may be needed, but are best limited, as it is not uncommon for patients

to develop a rapid tolerance.

The special case of Kleine-Levin Syndrome (KLS), which is probably less

rare than commonly thought, should be mentioned, as it is commonly

misdiagnosed as a psychiatric condition. The disorder affects

adolescents (often males) and is characterised by dramatic and sudden

episodes of sleepiness (sleeping for more than 14 hours per day) with a

general feeling of fogginess and confusion. Episodes are self-limiting in

Narcolepsy is a serious sleep disordercharacterised by excessive daytime

sleepiness and abnormal rapid eye

movement (REM) sleep manifestations,

including cataplexy sleep paralysis,

hypnagogic and hypnopompic

hallucinations and sleep-onset

REM periods.

A patient with suspected narcolepsy

should undergo a polysomnogram

followed by a daytime multiple sleep

latency test, a test that consists of a

series of naps.


7/7


Insomnia

one to three weeks. Aggressiveness when awake, hyperphagia and

hypersexuality often occur during the episodes. Most importantly,

patients are completely normal between episodes, which re-occur with

no pattern for several years to several decades (median 12 years), and

finally decrease in intensity and frequency until they stop altogether.

Unfortunately, there is no treatment for KLS. The most important

recommendation is to leave the patient in a familiar environment (at

home) if not in danger during episodes. Stimulants are typically

unhelpful if the episodes are intense, as confusion and aggressiveness

may result instead of excess sleep. When episodes are frequent,

thymoregulators such as lithium or carbamazepine have been

suggested to reduce episode frequency.57

Sleepwalking, Night Terrors and Parasomnias

Many patients complain of abnormal activity during sleep. REM

behaviour disorder affects older males. The patient acts out during

dreaming, often hurting himself or the person he shares a bed with. It is

typically a precursor of Parkinsons disease or Lewy body dementia.58

Sleepwalking and night terrors occur during slow-wave sleep, which isusually one hour after sleep onset, and are often associated with stress

and anxiety. Similarly, in adults, some patients may wake up partially and

go to eat during the night. A variation of consciousness is often present

in these disorders, where the patients is half asleep and half awake. In

some cases, these conditions can be difficult to distinguish from

nocturnal seizures, although in these cases movements and behaviour

are usually more consistent. Behavioural and pharmacotherapy can be

helpful in parasomnias.

Conclusion

A thorough evaluation of sleep disturbances in neuropsychiatric

patients is needed. Once identified, problems such as sleep apnea,

hypersomnia or insomnia should be aggressively treated, as they may

well be causal or participatory to the clinical picture and its impact.

Unfortunately, however, expertise in sleep medicine is often not easily

available and waiting lists for access to sleep centres are long. Co-

ordinated action by a psychiatrist and a sleep medicine specialist is

often needed in these cases, or, even better, psychiatrists should be

encouraged to learn the required skills to take advantage of this new

discipline and make their patients better. We hope this review willencourage clinicians to enter this new area.

1. Espaa RA, Scammell TE, Sleep neurobiology for the clinician,

Sleep, 2004;27(4):81120.

2. Saper CB, Chou TC, Scammell TE, The sleep switch: hypothalamic

control of sleep and wakefulness, Trends Neurosci, 2001;24:72631.

3. Uschakov A, Gong H, McGinty D, Szymusiak R, Neuroscience,

2007;150(1):10420.

4. Lu J, Greco MA, Sleep circuitry and the hypnotic mechanism of

GABAA drugs, J Clin Sleep Medicine, 2006;2(2):S1926.

5. Borbely AA, Achermann P, Concepts and models of sleep

regulation: an overview,J Sleep Res, 1992;1:6379.

6. Wurts SW, Edgar DM, Circadian and homeostatic control of REM

sleep: promotion of REM tendency by the supra-chiasmatic

nucleus, Neuroscience, 2000;20:430010.7. Moore RY, Suprachiasmatic nucleus in sleepwake regulation,

Sleep Med, 2007;8(Suppl. 3):2733.

8. Buysse DJ, Definition, Diagnosis, Classification and Etiology of

Chronic Insomnia,J Clin Sleep Medicine, 2005;1(4)4523.

9. NIH State-of-the-Science Conference Statement on

Manifestations and Management of Chronic Insomnia in Adults,

NIH State-of-the-Science Conference Statement, 2005.

10. Tsuno N, Besset A, Ritchie K, Sleep and depression, J Clin Psychiatry,

2005;66(10):125469.

11. Fava M, McCall WV, Krystal A, et al., Eszopiclone co-administered

with fluoxetine in patients with insomnia co-existing with major

depressive disorder, Biol Psychiatry, 2006;59(11):105260.

12. Papadimitriou GN, Linkowski P, Sleep disturbance in anxiety

disorders, Int Rev Psychiatry, 2005;17(4):22936.

13. Morin CM, Combined therapeutics for insomnia: should our first

approach be behavioral or pharmacological?, Sleep Med,

2006;7(Suppl. 1):S1519.

14. Morin CM, Cognitive-Behavioral Approaches to the Treatment of

Insomnia, J Clin Psychiatry, 2004;65(Suppl. 16):3340.

15. Sack RL, Auckley D, Auger RR, et al., American Academy of Sleep

Medicine. Circadian rhythm sleep disorders, Sleep, 2007;30(11):

14841501.

16. Westrin A, Lam RW, Seasonal affective disorder: a clinical update,

Ann Clin Psychiatry, 2007;19(4):23946.

17. Lewy AJ, Emens JS, Lefler BJ, et al., Melatonin entrains

free-running blind people according to a physiological

doseresponse curve, Chronobiol Int, 2005;22(6):10931106.

18. Silber M, Chronic Insomnia, New Eng J Med, 2005;353:80310.

19. Neubauer DN, Pharmacologic approaches for the treatment of

chronic insomnia, Clin Cornerstone, 2003;5:1619.

20. Neubauer DN, PDR Clinical Handbook: Insomnia with Clinical Strategies,

New York: Thompson, 2004.

21. Holbrook AM, Crowther R, Lotter A, et al., Canadian MedicalAssociation Journal, 2000;162(2):22533.

22. Devi V, Shankar PK, Ramelteon: A melatonin receptor agonist for

insomnia, J Postgrad Med, 2008;54(1):458.

23. Karatas M, Restless legs syndrome and periodic limb movements

during sleep, Neurologist, 2007;13(5):294301.

24. Littner MR, Kushida C, Anderson WM, et al., Practice Parameters

for the Dopaminergic Treatment of Restless Legs Syndrome and

Periodic Limb Movement Disorder, An American Academy of Sleep

Medicine Report, Sleep, 2004;27(3):5579.

25. International Classification of Sleep Disorders, Diagnostic and coding manual,

2nd edn, American Sleep Disorders Association, Westchester, 2006.

26. Ford DE, Kamerow DB, Epidemiological study of sleep

disturbances and psychiatric disorders: An opportunity for

prevention?, JAMA, 1989;262:147984.

27. Amercian Psychiatric Association, Diagnostic Criteria from Diagnostic

and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision

(DSM-IV-TR), Washington DC, 2000.28. Tsuno N, Besset A, Ritchie K, Sleep and Depression, J Clin Psychiatry,

2005;66(10):125469.

29. Nofzinger EA, Thase ME, Reynolds CF, et al., Hypersomnia in

bipolar depression,Am J Psychiatry, 1991;148(9):117781.

30. Guilleminault C, Tilkian A, Dement WC, The sleep apnea

syndromes, Annu Rev Med, 1976;27:46584.

31. Young T, Palta M, Dempsey J, et al., The occurrence of

sleep-disordered breathing among middle-aged adults, N Engl J

Med, 1993;328:123035.

32. Guilleminault C, Kirisoglu C, Poyares D, et al., Upper airway

resistance syndrome: a long-term outcome study, J Psychiatr Res,

2006;40(3):2739.

33. Patel SR, White DP, Malhotra A, et al., Continuous positive airway

pressure therapy for treating sleepiness in a diverse population

with obstructive sleep apnea: results of a meta-analysis,Arch Intern

Med, 2003;163:56571.

34. Morisson F, Decary A, Petit D, et al., Daytime sleepiness and EEG

spectral analysis in apneic patients before and after treatment

with continuous positive airway pressure, Chest, 2001;119:4552.

35. Riley RW, Powell NB, Guilleminault C, Otolaryngol Head Neck Surg.

1993;108(2):11725.

36. Leibowitz SM, Brooks SN, Black JE, Excessive Daytime Sleepiness:

Considerations for the Psychiatrist Psychiatric Clinics of North America,

2006;29:92145.

37. Mignot E, Lammers GJ, Ripley B, et al., The role of cerebrospinal

fluid hypocretin measurement in the diagnosis of narcolepsy and

other hypersomnias,Arch Neurol, 2002;59:155362.

38. Peyron C, Faraco J, Rogers W, A mutation in a case of early onset

narcolepsy and a generalized absence of hypocretin peptides in

human narcoleptic brains, Nat Med, 2000;6:9917.

39. Overeem S, Mignot E, van Dijk JG, et al., clinical features, new

pathophysiologic insights and future perspectives, J Clin Neurophysiol,

2001;18:78105.40. Scammell TE, The neurobiology, diagnosis and treatment of

narcolepsy, Ann Neurol, 2003;53:15466.

41. Anic-Labat S, Guilleminault C, Kraemer HC, et al., Validation of a

cataplexy questionnaire in 983 sleep-disorder patients, Sleep,

1999;22:7787.

42. Dauvilliers Y, Arnulf I, Mignot E, Narcolepsy with cataplexy Lancet,

2007;369:499511.

43. Broughton R, Ghanem Q, Hishikawa Y, et al., Life effects of

narcolepsy in 180 patients from North America, Asia and Europe

compared with matched controls, Can J Neurol Sci, 1981;8:299304.

44. Beusterien KM, Rogers AE, Walsleben JA, Health-related quality

of life effects of modafinil for treatment of narcolepsy, Sleep,

1999;22:75765.

45. Roth B, Nevsimalova S, Depression in narcolepsy and

hypersommia, Arch Neurol Neurochir Psychiatr, 1975;116:

291300.

46. Mignot E, Lin L, Rogers W, et al., Complex HLA-DR and -DQinteractions confer risk of narcolepsy-cataplexy in three ethnic

groups,Am J Hum Genet, 2001;68:68699.

47. Siebold, Hansen BE, Wyer JR, et al., Crystal structure of HLA-

DQ0602 that protects against type 1 diabetes and confers strong

susceptibility to narcolepsy, Proc Natl Acad Sci U S A, 2004;10.

48. Billiard M, Modafinil: pharmacology and therapeutic perspectives,

Rev Neurol, 2003;159:1225.

49. Mignot E, Nishino S, Guilleminault C, Dement WC, Modafinil

binds to the dopamine uptake carrier site with low affinity, Sleep,

1994;17:4367.

50. Mitler MM, Shafor R, Hajdukovich R, et al., Treatment of

narcolepsy: objective studies on methylphenidate, pemoline and

protriptyline, Sleep, 1986;9:26064.

51. Auger RR, Goodman SH, Silber MH, et al., Risks of high-dose

stimulants in the treatment of disorders of excessive somnolence,

Sleep, 2005;28:66772.

52. N Langdon, J Shindler, JD Parkes, Bandak S, Fluoxetine in the

treatment of cataplexy, Sleep, 1986;9:3713.

53. M Smith, J Parkes, Dahlitz M, Venlafaxine in the treatment of the

narcoleptic syndrome,J Sleep Res, 1996;5:217.

54. TE Scammell, The neurobiology, diagnosis and treatment of

narcolepsy, Ann Neurol, 2003;53:15466.

55. J Black, Houghton W, Xyrem International Study Group, Sodium

oxybate improves excessive daytime sleepiness in narcolepsy, Sleep,

2006;29:93946.

56. US Xyrem Multicenter Study group, A randomized, double blind,

placebo-controlled multicenter trial comparing the effects of three

doses of orally administered sodium oxybate with placebo for the

treatment of narcolepsy, Sleep, 2002;25:429.

57. Arnulf I, Zeitzer JM, File J, et al., Kleine-Levin syndrome: a

systematic review of 186 cases in the literature, Brain,

2005;128:276376.

58. Iranzo A, Molinuevo JL, Santamara J, et al., REM sleep behaviordisorder as an early marker for a neurodegenerative disorder: a

descriptive study, Lancet Neurol, 2006;5(7):5727.

diagnosis and management of common sleep disorders

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