Neurology in Practice
THE BARE ESSENTIALS
Sleep disorders in neurology
Paul J Reading
Correspondence to INTRODUCTION
Dr P J Reading, Consultant Sleep medicine is relevant in both neurology
Neurologist, The James
Cook University Hospital, and general medicine. A disordered sleepwake
Middlesbrough TS4 3BW, UK; cycle can have major effects on many common
Paul.Reading@stees.nhs.uk neurological complaints such as headache and
epilepsy, and it may also directly affect impor-
tant general health issues, such as blood pres-
sure. Furthermore, sleep related disorders such as
parasomnias, particularly with agitation, can be
hazardous to patients and bed partners while also
being diagnostic clues in some neurodegenerative
diseases.
SLEEP PHYSIOLOGY
The traditional view that sleep is simply the
absence of wakefulness has been increasingly
re ned over the past 50 years or so. Rather, it is a
precisely orchestrated and complex state with dis-
tinct and mutually exclusive phases: non-rapid eye
movement (stages 14) and rapid eye movement
sleep (non-REM and REM sleep, respectively),
de ned largely by the surface EEG. In a typical
night, there are 45 cycles of non-REM and REM
sleep (gure 1). In REM sleep, the cortical EEG is
highly activated in common with wakefulness,
usually corresponding to the vivid dreaming that
accompanies REM sleep. REM sleep periods pre-
dominate towards the end of the nocturnal sleep
period whereas the deepest stages of non-REM
sleep (stages 3 and 4) tend to occur within an hour
of sleep onset.
NORMAL VERSUS ABNORMAL
Given the normal variation in sleep patterns and
habits between people, distinguishing whether
or not a sleep related symptom suggests a formal
disorder can be difcult. It is a salutary fact that
normal ageing is associated with deteriorating
and poorly consolidated nocturnal sleep.
At least six EEG arousals per night, shown by
intrusions of rhythm on the surface EEG,
associated body movements and heart rate
variability, are commonplace after middle age;
early changes in the quality of deep, slow-
wave (ie, non-REM) sleep can be detected
even in young adults.
Periodic limb movements, usually of little
clinical signicance, are extremely prevalent
with increasing age and occur in a third of the
elderly population.
300
At the other end of the age scale, confusional
arousals or benign behaviours arising suddenly
from deep sleep are so common in young chil-
dren as to be considered normal.
Occasional sleep starts or other disturbing sen-
sory phenomena at sleep onset also occur in
younger people, especially if sleep deprived.
Furthermore, there is variation in apparent sleep
needs and people may be classied as long or
short sleepers. And the preferred timing of sleep
can differ quite dramatically between night owls
and morning larks. Age itself also has a signi-
cant effect on inherent circadian rhythms; most
people advance their natural time of sleep onset
by roughly 30 min every decade.
Determining whether sleepwake problems
are secondary to behavioural, environmental or
psychological factors can be very difcult. If there
is signicant diagnostic uncertainty from the his-
tory alone, sleep investigations tend not to be
particularly helpful. As with most neurology, a
detailed clinical history (where possible corrobo-
rated by any bed partner or parent) remains key
to diagnosis.
HYPERSOMNIAS
Excessive daytime sleepinessand so reduced
levels of alertnessoccurs to a troubling extent
in about 5% of the population (ie, falling asleep
inappropriately during the day, not simply tired,
fatigued or lethargic). Assuming there is sufcient
opportunity and time for overnight sleep, the
commonest cause is poor quality or fragmented
nocturnal sleep secondary to a chronic disorder
such as obstructive sleep apnoea (table 1).
Sleep apnoea
Obstructive sleep apnoea is common and usually
easy to recognise if there is a history of severe
snoring interspersed by long gaps in the breathing
pattern, terminated by large gasps. Although pre-
dominantly affecting overweight males, particu-
larly with central obesity, it can also affect thin
individuals with a narrowed palate due to a reced-
ing chin, for example. The absence of a bed part-
ner can lead to diagnostic uncertainty although
the diagnosis should always be considered if a
person wakes after an apparently normal length
of sleep feeling unrefreshed with a dry mouth and
hangover-like headache.
2010;10:300309. doi:10.1136/jnnp.2010.224097

Central sleep apnoea, often in association with
a CheyneStokes breathing pattern, also causes
daytime somnolence and is con rmed by noctur-
nal oxygen desaturations in the absence of respi-
ratory effort. Severe obstructive sleep apnoea
patients may have a mixed picture with varying
degrees of central sleep apnoea too. If central sleep
apnoea predominates, there are usually other fac-
tors, such as signicant heart failure or a brain-
stem lesion.
Narcolepsy
The prevalence in the white populations is
around 1 in 2000.
Most patients date symptom onset to ado-
lescence although signicant delays in diag-
nosis, especially in less severe cases, are
commonplace.
A second peak of onset probably occurs in
early middle age.
There is loss of hypothalamic neurons con-
taining the neuropeptide hypocretin (orexin)
but the reasons are unknown.
Narcoleptics struggle to effectively maintain
wakefulness, and even sleep for more than a
few hours. The nature of the excessive sleepi-
ness is not particularly unique although severely
affected patients also have sleep attacks in
which they awake from short sleep episodes with
no recall of the prior imperative to sleep. As well
A B
Awake
Awake
Stage 1
Stage 1
Stage 2 Stage 2
Stage 3
Stage 3
Stage 4
Stage 4
1 2 3 4 5 6
Time (h)
Figure 1 (A) EEG waveforms that define wake and non-rapid eye movement (non-
REM) sleep stages. (B) An idealised hypnogram summarising the distribution of the
sleep stages through a typical night. Black bars refer to REM sleep during which the EEG
pattern returns to that seen in wakefulness.
Table 1 Some causes of excessive daytime sleepiness
Secondary causes due to poor quality overnight sleep
Common Obstructive sleep apnoea
Restless legs syndrome and periodic limb movements of sleep
Nocturnal painfor example, diabetic neuropathy or arthritis
Neurodegenerative diseasefor example, parkinsonism
Medication (includes hypnotic misuse)
Environmental factors such as noise
Anxiety
Rare Oesophageal acid reflux
Severe bruxism
Primary causes
Narcolepsy
Idiopathic hypersomnolence
Post-traumatic brain injury
2010;10:300309. doi:10.1136/jnnp.2010.224097
Neurology in Practice
as a tendency to nap if bored or unoccupied, most
narcoleptics also fall asleep in unusual situations
such as in public. More common are brief lapses of
awareness or assumed micro-sleeps in which the
patient performs automatic and often inappropri-
ate behaviours (eg, placing bizarre objects in the
fridge or writing nonsense syllables down a page
during a lecture). Losing objects around the house
is a frequent complaint.
REM sleep is particularly dysregulated such
that elements of it, including paralysis and visual
imagery, often intrude into the wakeful state.
However, although sleep paralysis and hallucina-
tory experiences around sleepwake transition
are important symptoms, they are not specic to
narcolepsy and may occur in isolation, particu-
larly in young sleep deprived individuals.
Cataplexy is the most specic symptom of nar-
colepsy although it only occurs in around two-
thirds of patients.
Variable degrees of weakness are reported in
the context of emotion or its anticipation (pos-
itive rather than negative emotions are more
frequent precipitants, especially in relaxed
situations with family or friends).
Surprise, sporting success and frustration are
other common triggers.
It can be subtle and require direct questioning
to be picked up; for example, stuttering dys-
arthria as a punch line is attempted or slight
neck exion, sometimes with facial twitching,
or head bobbing when emotional.
Full blown attacks of cataplexy rarely cause
injury because most people learn to anticipate
their collapses and have a few seconds to pre-
pare themselves.
There is a wide spectrum of severity with
some patients having many episodes every
day.
In general, cataplexy is worse when the patient
is particularly drowsy.
Feeling generally weak at the knees in the con-
7 text of intense emotion, including anger, can be
normal and should be interpreted with caution if
mild or subtle. Furthermore, sudden drop attacks,
with or without an emotional trigger, are occa-
sionally functional (if there is the opportunity to
test deep tendon reexes during an attack, they
may well be preserved).
Mild or atypical cases of narcolepsy are often
misdiagnosed or overlooked, especially since
investigations tend not to improve diagnostic
certainty and may even be misleading; although
considered key to diagnosis, the multiple sleep
latency test has a high proportion of false posi-
tive and, more commonly, false negative results
(see below). A reliable history is the mainstay of a
condent diagnosis (table 2).
With increasing awareness of narcolepsy and
access to medical information, some people may
feign symptoms to gain access to stimulants or
benets. Although this is probably rare, it should
be considered when the stories appear textbook
301
 Neurology in Practice
perfect, especially if investigations are not sup-
portive. Urine testing for stimulants has been
advocated but some genuine patients almost cer-
tainly self medicate secretly with illegal stimu-
lant drugs.
Management
In decreasing order of importance, the main
areas that may need medical treatment are
daytime sleepiness, cataplexy and fragmented
nocturnal sleep (table 3).
Planned naps and avoidance of large carbohy-
drate rich meals can be useful strategies.
Narcoleptics are at risk of other sleep disorders
that may contribute adversely to their clinical
picture and need treating. For example, the
Table 2 Relevant areas of the sleep history to explore in possible narcolepsy
Questions/probes for diagnosis Comments and caveats
Are there episodes of transient weakness Typical cataplexy is virtually diagnostic for narcolepsy;
when emotional (or anticipating emotion) weakness can be subtle, ask about speech, mouth or
with no loss of awareness? neck symptoms
Feeling slightly weak at the knees when extremely
angry is usually not cataplexy
Beware that very sudden attacks or prolonged episodes
may have a non-organic basis
Some patients may feign cataplexy to gain stimulants
A range of emotions may act as triggers with
amusement or pleasant surprise as the commonest
Attacks nearly always occur in relaxed company and
are therefore rare to witness in clinic
Is overnight sleep disturbed? Most narcoleptics have fragmented nocturnal sleep
often with intrusive vivid dreams or hallucinations
Counterintuitively, frank sleep onset insomnia at a
conventional hour is reported by some narcoleptics
Most forms of parasomnia, including sleep walking and
periodic limb movements, are commoner in narcoleptics
Children, in particular, may become phobic of sleep and
may insist on sleeping with the bedroom lights on, for
example
What is the nature of daytime naps? Narcoleptics may be unable to fight the need to sleep
and naps are usually reported in public or inappropriate
places
Naps are often short (less than 15 min) and restorative
with a refractory period of relative alertness that may
last a few hours
Dream-like phenomena during naps are very suggestive
of narcolepsy
Dreams, in general, may be difficult to distinguish from
reality and many narcoleptics report embarrassing
situations or conversations that arise from this
confusion
Is there evidence for automatic behaviours? Presumed micro-sleeps or lapses causing impaired
vigilance frequently result in bizarre behavioursfor
example, placing objects in inappropriate places or
writing nonsense prose while in a state between sleep
and wake
Are there REM sleep related phenomena? Visual hallucinations or sleep paralysis around sleep
wake transitions are not specific to narcolepsy but
should be assessed
Narcoleptics also report hallucinations in other
modalities (auditory, tactile) and often have paralysis at
sleep onset rather than offset
Are there other general health issues? Appetite dysregulation with food cravings, particularly
overnight for sweet items, appears common in
narcolepsy
Obesity is common and does not arise simply through
relative inactivity
REM, rapid eye movement.
302
metabolic consequences of the syndrome can
produce signicant obesity and subsequent
obstructive sleep apnoea. Restless legs syn-
drome, periodic limb movement disorder and
REM sleep behaviour disorder are also fre-
quently seen.
Many narcoleptics respond only partially to
optimum medical treatments and remain sig-
nicantly disabled, often unable to hold down
employment or enjoy a normal social life.
Secondary mood disorders should, therefore,
not be overlooked.
Idiopathic hypersomnia
This is a poorly understood clinical entity that
often mimics or is mistaken for narcolepsy (but it
is around 10 times rarer) (table 4). In practice, the
distinction may not be crucial given the similar
pharmacological treatment strategies to narco-
lepsy. A common disabling symptom is inability
to wake up effectively at a conventional hour,
particularly if the patient lives alone and relies on
an alarm clock. The symptoms are particularly
troublesome in winter.
KleineLevin syndrome
This is an extremely rare disorder in which the
key symptom is intermittent severe drowsiness
which typically lasts for a continuous period of
several days, every few weeks or so, sometimes
resembling a recurrent encephalopathy. For a con-
dent diagnosis, aside from excessive sleepiness,
there also needs to be a change in cognition, per-
sonality or behaviour when drowsy, with return
to normality between episodes. These changes
can vary from subtle increased irritability to
frank compulsions involving hypersexuality or
dramatic binge eating.
Treatment remains empirical and often disap-
pointing. Wake promoting medication may be of
limited efcacy during symptomatic spells. If a
prophylactic approach is warranted, a variety of
agents such as carbamazepine, valproate and lam-
otrigine have been tried. Lithium may be helpful
in severe cases.
There is usually spontaneous improvement
with time but there is little known about long
term prognosis.
PARASOMNIAS
By their nature, events arising from sleep, espe-
cially if frequent and associated with agitation,
can cause considerable concern to the subjects and
alarm to their bed partners. It is usually possible
to be condent of their nature, provided a good
corroborative history is available.
Sometimes, epileptic seizures, usually arising
from the frontal lobes, can be very difcult to dis-
tinguish from certain parasomnias, particularly
those agitated arousal disorders arising from deep
non-REM sleep. EEG and video monitoring may
be needed overnight. The latter is usually of more
2010;10:300309. doi:10.1136/jnnp.2010.224097
 Neurology in Practice

Table 3 Drug treatments for narcolepsy

Drug Dose Comments

Wake promotion
Cataplexy
Disrupted overnight sleep
REM, rapid eye movement.
Modafinil 100400 mg daily, usually in two doses (oral) Typically taken early morning and around lunchtime
A flexible regimen usually recommended and higher doses
are almost certainly safe
Occasionally adverse effects of headaches and gastric upset
may limit use
An enzyme inducer, so care needed with contraceptive pill,
for example
Dexamfetamine 1060 mg daily, taken through the day in 5 or Now a secondline treatment but often useful as an add-on to
10 mg doses (oral) modafinil in low dose
Agitation and blood pressure may need monitoring
Abuse potential appears low in narcoleptics
Methylphenidate 2050 mg daily, taken through the day in Similar pharmacological profile to dexamfetamine although
10 mg doses (oral) slightly longer lasting
Selegiline 1040 mg daily, usually in two doses (oral) Metabolised to amphetamine
Can be useful as a mild stimulant, usually at doses higher
than for Parkinsons disease
Mazindol 24 mg daily, usually in two doses (oral) An agent with wake promoting properties introduced as an
appetite suppressant over 20 years ago
Recently reintroduced as an unlicensed drug for narcolepsy
and may be effective if more conventional approaches are
unsuccessful
Venlafaxine 75225 mg daily, usually in one dose of the Most antidepressants suppress REM sleep and raise the
long acting preparation (oral) threshold for cataplexy
Clomipramine 2075 mg daily, in one or two doses (oral) Often effective but adverse effects may limit usefulness
Sodium oxybate 4.59 g nightly, taken before bed and typically Good trial data suggest it may reduce attacks by up to 90%
at 02:00, if awake (oral) Short half-life, so taken before bed and during the night
Fear of misuse and expense limit practical use
Clonazepam or other hypnotic Standard doses Benzodiazepines may improve sleep continuity but often
resulting sleep is unrefreshing
Care needed if sleep apnoea a possibility
Sodium oxybate 4.59 g nightly (oral) Usually improves sleep quality and helps daytime
somnolence as a result
Avoid with alcohol as respiratory depression a risk

Table 4 Distinguishing features of idiopathic hypersomnia Non-REM sleep parasomnias

Symptom Comment
Daytime napping unavoidable Naps tend to be unrefreshing and prolonged but otherwise
unremarkable (usually no REM sleep-related phenomena)
Automatic behaviours common Patients are generally inattentive through the day and full
levels of alertness rarely achieved
Overnight sleep prolonged Sleep quality and quantity both appear normal or even
better than average, even if formally measured by a
polysomnogram
Waking in morning difficult Often the most disabling symptom
People usually confused or drunken if forcibly awoken
Mood disorders are common Usually a consequence rather than a cause of excessive
sleepiness
Average sleep latency on multiple sleep Deep non-REM sleep often achieved in a 20 min nap
latency test typically less than 5 min opportunity but not REM (by definition)
REM, rapid eye movement.
diagnostic assistance, allowing behavioural analy-
sis of the disturbances. In general, seizures should
be seriously considered if:
events recur frequently through the night and
are strikingly stereotyped;
there is dystonic posturing or repetitive,
seemingly bizarre motor behaviours such as
cycling;
quick recovery to full arousal from events also
strongly favours seizures;
as does previous lack of sleep walking, sleep talk-
ing or other common childhood parasomnias.
The spectrum of night terrors, confusional arous-
als and sleep walking reects sudden and abnor-
mal partial arousals from the deepest stages of
non-REM sleep, usually within an hour or two
of sleep onset. Although particularly common
in young children, this may persist in over 1% of
adults when the nocturnal behaviours typically
become more complex, goal seeking and not infre-
quently associated with adverse consequences
(eg, violent or sexual assaults). Memory for any
nocturnal events or behaviours is vague, at best,
even though subjects may appear to interact and
respond verbally to bed partners and successfully
negotiate complex environments while symptom-
atic. These parasomnias can be strongly familial.
Increasing the depth of slow wave sleep, typi-
cally by sleep deprivation, together with internal
or external factors causing partial arousals from
sleep are often triggers in predisposed subjects.
It is therefore appropriate to give advice on sleep
hygiene or even investigate for secondary sleep dis-
orders such as sleep apnoea or periodic leg move-
ments in adults with troublesome parasomnias.
In some individuals there are triggers such as
alcohol or sleeping in an unfamiliar environment.
In others, stress and anxiety are recognised pre-
cipitants and event frequency improves if these
can be reduced.

2010;10:300309. doi:10.1136/jnnp.2010.224097 303

 Neurology in Practice

Long term drug treatment is rarely justied: particularly to REM periods when snoring is
Low dose clonazepam in short courses of a usually most prevalent.
week or two is probably an effective strategy REM sleep behaviour disorder also occurs in the
to cover particularly symptomatic spells in context of narcolepsy, usually with relatively
most adults, but this can worsen snoring. benign motor activity in dreams that are not par-
Antidepressants have been successful in indi- ticularly aggressive, and in people with additional
vidual case reports. non-REM sleep parasomnias (considered to have
an overlap parasomnia).
REM sleep parasomnias If drug treatment is considered:
Although only recently described in humans, the clonazepam is the agent of choice: 0.252 mg
phenomenon of dream enactment in which the orally before bed;
normal mechanism of REM sleep atonia fails, is melatonin can also be used, possibly in combi-
increasingly recognised to be important. Most nation with clonazepam: 25 mg orally.
likely arising from damage to a small area ventral
to the locus coeruleus, this disorder is frequently
associated with a variety of neurodegenerative Nocturnal jerks
diseases, sometimes acting as an early diagnostic Sudden nocturnal movements that may or may
non-motor marker. not have a recognisable rhythmical nature can be
Most often seen in parkinsonian syndromes, troublesome, particularly to bed partners.
it has a striking male preponderance and may If the legs are predominantly involved and the
lead to signicant physical injury. movements occur in light sleep in the rst half of
It can usually be recognised from the history the night, periodic limb movements are most likely,
alone although it may sometimes be con- particularly if there is also a history of restless
fused with agitated non-REM parasomnias in legs syndrome. Severe periodic leg movements
younger people (table 5). often cause partial arousals and, if the initial
Do not confuse it with agitated or violent movements are not analysed in detail from video,
arousals secondary to hypoxia caused by the subject appears simply to dget through the
obstructive sleep apnoea which may be linked night. If sleep is signicantly disturbed or day-
time sleepiness troublesome, an empirical trial
of a dopaminergic agonist is often justied and
Table 5 Some distinguishing features between non-REM parasomnias and REM sleep sometimes rewarding, especially if the move-
behaviour disorder. Note that some (younger) people may have both types of parasomnia ments produce autonomic or EEG signs of arousal
(overlap parasomnia) during overnight recordings.
Differentiating feature Non-REM parasomnia or arousal REM sleep behaviour disorder Various potentially disturbing motor and sen-
disorder
sory phenomena can occur at the precise point
Sex prevalence Equal Striking male predominance, of sleep onset and cause sleep onset insomnia.
especially if onset after middle age Benign hypnic jerks are common and usually trivial
Age Common in children, persists in Increases with age but can be associated with explosive sensations
12% of adults
in the head or other colourful misperceptions.
Frequency through night Usually single event within 1.5 h Often recurs and becomes more
of sleep onset; episode may last vigorous as night proceeds, These sleepwake transition disorders are non-
several minutes corresponding to REM periods epileptic although their underlying mechanism is
Brief episodes with vocalisation are unknown. They are generally benign, respond to
typical, rarely lasting up to a minute reassurance and usually to a short acting hypnotic
Confusion Amnesia for event and confusion on If awoken during event, memory such as zopiclone if necessary.
apparent arousal the norm;visual for narrative dream experience In propriospinal myoclonus there appears to be a
hallucinations may be recalled but common, usually a quick and full
no true dream narrative return to normal alertness spinal focus that causes repetitive exing of the
Ambulation Leaving the bed and even bedroom Very rare to leave bed unless they trunk, specically when the subject is drowsy,
not uncommon fall out usually in the supine position. Occasionally, a
Eyes Eyes usually open and person Eyes usually shut, unable to navigate discrete spinal lesion can be identied with imag-
appears at least partially or use objects in purposeful manner ing. Short acting hypnotics such as zopiclone are
responsive to external environment
often successful.
Violence May be directed, especially if bed Any victims are generally
partner tries to interact with or bystanders Head banging in early childhood is fairly com-
calm the person Enacted dreams are generally mon and can persist into adolescence or even
aggressive, defensive or have a adulthood. The movements generally start in
sporting theme severe drowsiness or at the sleepwake transition
Sexual behaviours Intimate behaviour may arise from Amorous or intimate behaviours
but, with increasing age, often change in nature
deep sleep as a parasomnia with no seem extremely rare
subsequent recollection. and persist through sleep, even affecting the REM
Investigations Polysomnogram may reveal sudden Polysomnogram usually shows lack sleep stage.
arousals from deep non-REM of normal atonia in REM sleep even if Body rocking and repetitive lateral head move-
sleep, with or without confusion; frank movements are subtle ments are typical manifestations of this so-called
disorders causing secondary
arousals such as severe snoring rhythmical movement disorder of sleep. The
may need addressing patient is often oblivious to the movements or
REM, rapid eye movement. even appears to gain some level of comfort.

304 2010;10:300309. doi:10.1136/jnnp.2010.224097


INSOMNIA
Chronic insomnia affects sleep onset, sleep
maintenance or both, and has a loose de nition
of inadequate sleep for at least 3 months despite
the opportunity and desire to do so. Despite
extremely poor nocturnal sleep, most insomniacs
are unable to nap during the day. Daytime symp-
toms of irritability, low mood and poor concen-
tration are almost universal.
Idiopathic insomnia starts in early childhood and
is poorly understood, presumably reecting a con-
stitutional tendency for poor sleep.
Psychophysiological insomnia is the commonest
form of chronic insomnia. It most often follows
a stressful life event that initially triggers poor
sleep. The disturbed sleep persists and often
worsens over subsequent years.
Paradoxical insomnia describes people who say
they spend hours lying awake at night, even
though, to others, they appear to be asleep. They
tend to overestimate the time it takes them to fall
asleep and underestimate their total sleep time.
Structural brain lesions are a rare cause of insom-
nia. Bilateral thalamic infarcts have been associ-
ated with severe symptoms as have most prion
diseases, occasionally in the preclinical stages, par-
ticularly the aptly named fatal familial insomnia.
Limbic encephalitis in association with antibodies
to voltage gated potassium channels can produce
severe insomnia, agitation and hallucinations.
Management
Long term hypnotic drugs are generally not effec-
tive or appropriate. Indeed, there is an increas-
ing reluctance to prescribe hypnotics in primary
care, largely through fear of dependence.
Cognitivebehavioural therapy tailored for
sleep related problems is the best treatment,
possibly in combination with a hypnotic.
If severe insomnia is associated with de nite
increased daytime sleepiness, serious consid-
eration should be given to possible secondary
underlying causes that may be fuelling the poor
sleepfor example, unrecognised yet potentially
treatable restless legs syndrome. Also, abnormali-
ties of circadian rhythm (see below) may mimic
sleep onset insomnia when there is signicant
delay of the sleep phase.
CIRCADIAN MISALIGNMENT
Most normal people have a profound nadir of
alertness at around 04:00 and, less so, at 15:00,
independent of previous activities and wakeful-
ness, ultimately governed by the suprachiasmatic
nucleus in the hypothalamus. Signicant prob-
lems with either staying awake or getting to sleep
can arise from an abnormal clock mechanism or
when external factors con ict with a persons
inherent circadian rhythm.
Extrinsic circadian disorders
Jet lag is generally more troublesome travelling
eastwards than westwards because it is usually
2010;10:300309. doi:10.1136/jnnp.2010.224097
Neurology in Practice
more difcult for people to advance their internal
clocks. Some are more prone to symptoms than
others. Melatonin can be used although success
depends crucially on a correct dose and precise
timing which may vary between individuals. In
general a low dose of 0.5 mg 2 h before intended
sleep is appropriate. Anecdotally, fasting for the
duration of travel is said to quicken adaptation
to the new time zone. Furthermore, on arrival,
avoiding bright lights, or darkness, for a few hours
having travelled westwards, or eastwards, respec-
tively, may help.
Chronic shift work sleep disorder is an underesti-
mated problem. Staying awake for monotonous
tasks during a night shift becomes more difcult
with age and sometimes merits formal wake pro-
moting medication such as moda nil. Inability
to sleep effectively during the day compounds
the increased sleep drive during the night shift.
Hypnotics during the day may help but rarely pro-
vide restorative sleep.
Intrinsic circadian disorders
There are several disorders of the internal timing
mechanism.
Delayed sleep phase syndrome is the common-
est and exists in a mild form in many teenagers.
An inability to sleep easily before around 01:00
or later is not always due to behavioural or social
factors and can reect an inherent circadian dys-
rhythmia. The main problem is inability to arise
for work or study at a conventional hour. In some
cases, melatonin, at low dose (0.5 mg) around
21:00, together with exposure to blue light from a
light box just before the desired waking time can
help to entrain the clock mechanism.
Advanced sleep phase syndrome is rarer and causes
the opposite problem of extremely early nights
and subsequent awakenings. This is often famil-
ial and there are mutations in a key gene involved
in the molecular machinery controlling circadian
rhythmicity.
Blind from birth people frequently struggle to
conform to a strict 24 h sleepwake schedule
because most humans have a natural tendency for
a 24.5 h daily cycle that is entrained precisely to
24 h by light stimuli and social cues. Judicial use
of melatonin can be very successful. Rarely, the
same problem occurs in sighted individuals.
Brain disorders due to severe autism, advanced
Huntingtons or Alzheimers disease and possibly
schizophrenia, can sometimes produce a totally
chaotic sleepwake cycle with little discern-
ible rhythmicity. The disruptive effects on daily
functioning, and associated distress to carers are
often considerable and very difcult to manage
effectively.
SLEEP DISORDERS AND PATTERNS IN
NEUROLOGICAL DISEASE
A sleep history is relevant to any condition which
might be adversely affected by a disrupted sleep
wake cycle, for example:
305
 Neurology in Practice
propensity to generalised seizures after sleep
deprivation or poor quality sleep in idiopathic
generalised epilepsy;
worsening migraine headaches in the context
of insomnia.
Moreover, treating disorders such as obstructive
sleep apnoea can sometimes cure cluster head-
aches and signicantly improve seizure control in
patients with epilepsy.
Since the recognition that most cases of pri-
mary narcolepsy are due to specic loss of hypo-
cretin neurons in the hypothalamus, numerous
cases of excessive daytime sleepiness, sometimes
with REM sleep related phenomena such as cata-
plexy, have been reported. Most reect hypotha-
lamic pathology with tumours or in ammatory
changes in the hypothalamus itself, or around
the third ventricle (gure 2). A narcolepsy pheno-
type is also recognised in various rare disorders:
PraderWilli syndrome, Norries disease, Moebius
syndrome and Niemann Pick type C disease.
Parkinsonism
Parkinsons disease and other parkinsonian syn-
dromes may be associated with sleep related
symptoms although it can be difcult to differen-
tiate between the effects of the neurodegenerative
disease itself and the consequences of nocturnal
motor disturbances and drug therapy.
Excessive daytime sleepiness is very common in
Parkinsons disease, especially in the advanced
stages, affecting at least 30% of patients. It can be
caused by the following.
Poor quality nocturnal sleep due to hypokine-
sia and inability to turn in bed, pain, dystonia
or even tremor. Increasing overnight dopamin-
ergic medication with a long acting agonist
may help daytime somnolence but this can
produce worsening nightmares or related phe-
nomena. Non-specic hypnotics such as low
dose clonazepam rather than dopaminergic
drugs may improve sleep continuity and subse-
quent daytime alertness. In those who remain
sleepy despite attempts to improve overnight
sleep, moda nil is safe and can be effective.
Selegiline is metabolised to amphetamine and
so may be used as a wake promoting strategy.
Signicant sleep apnoea should always be con-
sidered; have a low threshold for investigating
and treating obstructive sleep apnoea.
Dopaminergic therapies can sometimes
worsen daytime drowsiness; low doses of dop-
amine agonists occasionally lead to striking
daytime sleepiness and frank sleep attacks
which resolve on discontinuation.
In advanced parkinsonism, a narcolepsy phe-
notype is fairly common with sleepwake dys-
regulation over the 24 h cycle. Unlike primary
narcolepsy, CSF hypocretin levels are normal
and there is no cataplexy or sleep paralysis.
REM sleep behaviour disorder is increasingly recogn-
ised in both premotor and/or advanced Parkinsons
306
disease although symptoms may be subtle and
drug treatment unnecessary. Clonazepam is often
successful although the dose may need to be
titrated from 0.25 mg up to 2 mg or more. If tol-
erance is an issue or if clonazepam is ineffective,
long acting melatonin (2 mg) is a useful alterna-
tive. Most antidepressants exacerbate REM sleep
behaviour disorder and should be discontinued if
practicable.
Impulse control disorders are an adverse effect of
dopamine agonists potentially leading to behav-
iours disrupting sleep such as internet gambling.
Troublesome nocturnal confusion and hallucinations
in advanced parkinsonism are difcult to treat;
quetiapine or cholinesterase inhibitors such as
rivastigmine, even in the absence of frank demen-
tia, may improve overnight sleep quality and day-
time performance.
Multiple system atrophy is particularly associ-
ated with abnormal nocturnal sleep. REM sleep
behaviour disorder is extremely common and
sleep disordered breathing often needs treating
(this can be complex, involving both obstructive
and central elements, and stridor during sleep is a
life threatening complication).
Multiple sclerosis
Sleep is frequently disrupted by pain, muscle
spasms and urinary urgency which all contribute
to daytime somnolence. Restless legs syndrome,
presumably secondary to spinal cord pathol-
ogy, also seems very common and may respond
to standard dopaminergic therapy. Aside from
fatigue as an almost universal feature of estab-
lished multiple sclerosis, a subgroup also appear
extremely and excessively sleepy, occasionally
with cataplexy. Possibly this is more common in
the related condition of neuromyelitis optica; con-
vincing MR changes are sometimes seen within
and around the hypothalamus where there is
dense aquaporin antibody binding (gure 2).
Traumatic brain injury
The heterogeneity of head injuries, in terms of
severity and site, together with the lack of pro-
spective data make it difcult to estimate the
prevalence and nature of the resulting sleep
wake disturbances which can be a signicant
problem. It is not possible to correlate specic
sleep related symptoms with the nature or
degree of cerebral injury. Severe sleepiness gen-
erally subsides with time. Insomnia is also com-
mon although pain, psychological factors and
post-traumatic stress disorder may all exacer-
bate the situation.
Neuromuscular disease
Treating nocturnal hypoventilation when severe
neuromuscular disease causes respiratory mus-
cle compromise can improve quality of life.
Overnight oximetry or monitoring of carbon
dioxide levels can be useful in con rming inad-
equate ventilation, most apparent when patients
2010;10:300309. doi:10.1136/jnnp.2010.224097

Figure 2 MRI revealing oedema and likely inflammatory change in the brain and spinal
cord of a patient with neuromyelitis optica. Bilateral hypothalamic changes in (A) and (B)
(arrowed on fluid attenuation inversion recovery (FLAIR) sequence) most likely explain
the severe sleepiness, resembling narcolepsy. The long inflammatory spinal lesion is
arrowed in (C) (T2 weighted image). I am grateful to Professor David Bates for these
images.
are lying at and in deep sleep, particularly the
REM stage. Symptoms may be relatively subtle
and mimic obstructive sleep apnoea with unre-
freshing nocturnal sleep, morning headaches and
severe daytime lethargy. Even in terminal con-
ditions such as advanced motor neuron disease,
non-invasive ventilation in appropriate patients is
rewarding and should be considered. Other more
benign diagnoses include acid maltase deciency
when preferential involvement of the diaphragm
may produce severe nocturnal problems with gas
exchange.
Myotonic dystrophy is particularly associated
with daytime somnolence. Aside from poten-
tial breathing related problems overnight, there
appears to be a central cause for the commonly
seen profound somnolence. Stimulants such as
moda nil can be effective.
THE USE (AND ABUSE) OF INVESTIGATIONS
Subjective scales and diaries
The commonest and most convenient way of
assessing excessive daytime sleepiness or a dis-
turbed sleepwake cycle is for people to com-
plete a subjective questionnaire such as the
Epworth scale (box 1) and/or ll out a sleep diary
over a fortnight or so. Although such scales may
be a useful screen, and occasionally for assess-
ing treatment, they are of little use diagnosti-
cally and are prone to misinterpretation or bias.
Depending on the situation, symptoms can
clearly be exaggerated (eg, paradoxical insomnia)
2010;10:300309. doi:10.1136/jnnp.2010.224097
Neurology in Practice
or underplayed (eg, a driver wishing to retain a
licence).
Oximetry
Overnight oximetry is a simple technique to
assess sleep disordered breathing and should be
considered if severe snoring, witnessed nocturnal
apnoeas or simply unrefreshing overnight sleep
is reported and there are daytime consequences,
especially in overweight individuals.
A nger probe monitors nocturnal oxygen
desaturations and may demonstrate the typi-
cal cyclical pattern of dips in sleep apnoea.
Heart rate variability is also measured and can
be a useful indication of generally disturbed
sleep even if breathing parameters are normal.
False positive and negative results are not
uncommon and caution should be taken if
they are discordant with the clinical impres-
sion. Increasingly, home monitoring is being
extended to include chest leads, nasal ow
monitors and limb movement detectors which
give much more information as to the nature of
any apnoeas, obstructive or central, and other
causes of arousals such as limb restlessness.
Polysomnography
Several parameters are monitored simultane-
ously in a dedicated environment for assessing
the quality, quantity and efciency of sleep:
sleep staging with EEG monitoring; extended
oximetry with nasal airow, chest expansion,
snoring and body position monitoring; limb
movement detectors; and video analysis.
A summary of the data is displayed as a hyp-
nogram, demonstrating the distribution of
sleep stages and awakenings through the night
(gure 3).
The quality of any information obtained
depends critically on trained technologist
input. Although sleep staging is often auto-
mated using sophisticated software, the results
still need to be veried by visual inspection.
Ideally, a trained technician should be present
during recordings.
Two nights of recording allow acclimatisation
to the sleep laboratory setting with more use-
ful and valid information.
A patients drug history is important as a potential
confounding factor in sleep analysis. For example,
the vast majority of antidepressants suppress REM
sleep and some exacerbate nocturnal limb move-
ments such that interpretation of any underlying
primary sleep disorder can then be difcult.
Aside from breathing related sleep disorders, it
is arguable how often a full polysomnogram will
help with diagnosis and management in cases
where the clinical picture is unclear despite a
detailed history. However, it can be useful in:
con rming a tendency for non-REM sleep
parasomnias (gure 4);
307
 Neurology in Practice
Box 1 Subjective tests: The Epworth Sleepiness Scale
Rate the likelihood of dozing in the following situations:
Sitting and reading
Watching TV
Sitting inactive in a public place (eg, theatre or meeting)
Sitting as a passenger in a car for an hour without a break
Lying down to rest in the afternoon when circumstances permit
Sitting and talking to someone
Sitting quietly after lunch without alcohol
Sitting in a car while stopped for a few minutes in traffic
Patient rates each item as 0 (would never doze) to 3 (high chance of dozing).
Epworth Sleepiness Scale score is total score: 024; higher score=more
sleepiness.
Figure 3 A hypnogram showing good sleep through the night. The distribution of non-
rapid eye movement (non-REM) and REM sleep is normal and there are no significant
arousals. M indicates movements. W refers to wake periods. Numbers 14 indicate the
depth of non-REM sleep (1 and 2 are light sleep, 3 and 4 are deep slow wave sleep). The
red bars correspond to REM sleep periods.
demonstrating muscular tone or movements
during REM sleep in REM sleep behaviour
disorder;
evaluating periodic limb movements and their
potential for causing arousals;
identifying other causes of secondary insom-
nia such as unsuspected periodic limb move-
ments or severe bruxism;
the disturbed or preserved sleep architec-
ture in narcolepsy and idiopathic hypersom-
nia, respectively, can be a useful diagnostic
marker.
Ideally, a polysomnogram should be performed to
monitor quality and quantity of sleep before day-
time tests of wakefulness or sleepiness such as the
multiple sleep latency test (below).
Multiple sleep latency test
This is the standard investigation for assess-
ing daytime sleepiness objectively. Ideally after
monitoring the amount and quality of the pre-
vious nights sleep, a the patient is given four or
ve nap opportunities at 2 hourly intervals in a
suitable sleep inducing environment. He or she is
asked to lie on a bed fully clothed and encouraged
to sleep. The average latency from lying down to
stage 1 sleep is an objective indication of sleep
propensity. If REM sleep is reached within 15 min
in at least two of the naps, this ful ls the criteria
308
for narcolepsy, assuming the mean sleep latency
across the naps is 8 min or less. Most narcoleptics
achieve sleep well within 5 min.
A standard and rigid protocol is crucial as the
investigation is extremely sensitive to proce-
dural deviations. For example, if the patient is
allowed to walk around between naps, the sleep
latency can increase dramatically and give a false
negative result in an excessively sleepy patient.
Frequently, in non-specialist centres, the envi-
ronment is not conducive for inducing sleep,
again giving a false impression or underestimate
of sleepiness levels.
Sleep latencies tend to rise with age even
though the elderly are generally considered as
more sleepy. There is a wide normal range, how-
ever, with mean latencies less than 10 min gener-
ally considered potentially abnormal.
People who are simply sleep deprived due to
insufcient sleep can pose a diagnostic challenge;
monitoring the sleepwake cycle for a fortnight
prior to sleep latency testing with a sleep diary
or actigraphy (see below) can provide useful
information.
CSF hypocretin
The discovery that classical narcolepsy with cata-
plexy is nearly always associated with deciency
of the neuropeptide, hypocretin, which could be
measured in CSF, fuelled optimism for a reliable
diagnostic test. Unfortunately, very low levels
(<110 pg/ml) are generally only seen in cases
where there is little diagnostic doubt clinically,
particularly when there is clear cut cataplexy.
However, it is worth measuring CSF hypocretin
when:
likely narcolepsy with comorbid sleep disor-
ders such as obstructive sleep apnoea;
subjects are unwilling to discontinue medi-
cation already started because of a previous
positive response;
assessing narcolepsy in children too young for
a multiple sleep latency test;
a multiple sleep latency test is not diagnostic
but suspicion for narcolepsy remains high.
Tests of wakefulness and vigilance
For excessively sleepy patients, rather than assess-
ing their ability to sleep easily with a multiple sleep
latency test, the more important safety question
for work and driving is whether they can stay alert
and avoid naps, lapses and so-called micro-sleeps.
The latter tend to last around 3 s and can some-
times occur with the eyes open. Unfortunately,
practical tests of wakefulness and vigilance are
underdeveloped with little normative data.
The maintenance of wakefulness test instructs
subjects to stay awake, usually in four 40 min
sessions, in a monotonous isolated environment
while monitored for drowsiness and sleep onset.
This has been used mostly in trials for wake pro-
moting drugs. It will miss minor lapses which are
2010;10:300309. doi:10.1136/jnnp.2010.224097

Figure 4 A hypnogram of a 28 year-old-man with a significant tendency for agitated
non-rapid eye movement (non-REM) sleep parasomnias. At 02.00 and 05.00, he appears
to quickly arouse from deep sleep to wakefulness (this feature is often a marker for
non-REM sleep parasomnias and he exhibited a confusional arousal in his initial brief
apparent awakening). Of further interest, the proportion of light (stage 2) non-REM sleep
is abnormally high (around 65% of total sleep), potentially explaining why he found
nocturnal sleep unrefreshing. Although he was unaware of leg movements, he was
extremely restless as revealed by the periodic leg movements (PLM) and leg movement
(LM) traces. This limb activity may have been increasing his parasomnia by causing
some sleep deprivation and also partially arousing him from deep sleep.
Further reading
Baumann CR, Werth E, Stocker R, et al. Sleepwake disturbances 6 months
after traumatic brain injury: a prospective study. Brain 2007;130
(Pt 7):187383. (The first prospective study assessing sleepwake
disturbances after head injury and the possible relation of reduced hypocretin
levels to sleepiness.)
Billiard M, Bassetti C, Dauvilliers Y, et al. EFNS guidelines on management
of narcolepsy. Eur J Neurol 2006;13:103548.
Derry CP, Harvey AS, Walker MC, et al. NREM arousal parasomnias and
their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis.
Sleep 2009;32:163744. (A final paper in a series from this group that
examines the semiology of arousal disorders and nocturnal seizures. A
useful and simple clinical algorithm is provided.)
American Academy of Sleep Medicine. International classification of
sleep disorders, diagnostic and coding manual, 2nd edn. Westchester, IL:
American Academy of Sleep Medicine, 2005. (A surprisingly readable and
useful guide to the diagnosis and classification of all known sleep disorders.)
Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine,
5th edn. Philadelphia: Saunders, 2010. (The standard text on sleep medicine
in its fifth edition. A large, comprehensive tome with a largely American bias.)
Overeem S, Reading PJ. Sleep disorders in neurology: a practical approach.
Chichester: Wiley-Blackwell, 2010. (A new textbook on sleep medicine from
a neurological perspective aimed at the non-specialist.)
Postuma RB, Gagnon JF, Vendette M, et al. Markers of neurodegeneration
in idiopathic rapid eye movement sleep behaviour disorder and Parkinsons
disease. Brain 2009;132(Pt 12):3298307.
Silber MH, Krahn LE, Morgenthaler TI. Sleep medicine in clinical practice.
London: Taylor and Francis, 2004.
Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs
syndrome: an evidence-based review and implications for clinical practice.
Mov Disord 2008;23:2267302.
2010;10:300309. doi:10.1136/jnnp.2010.224097
Neurology in Practice
crucial for safe driving and other tasks requiring
constant vigilance.
Specic tests of vigilance include the psychomo-
tor vigilance test and the Oxford Sleep Resistance
Test. These require a subject to monitor and respond
to briey presented visual stimuli over a prolonged
monotonous session. Results are very sensitive to
even relatively minor sleep deprivation. It can be
difcult to distinguish normality from pathologi-
cal or dangerous levels of drowsiness.
Actigraphy
This is a technique for monitoring relatively small
movements, usually of the upper limb, over long
periods, often weeks. Lack of movement is taken as
a surrogate for sleep. The technology has advanced
considerably and the wristbands used to measure
movements can now also record light levels, noise
(eg, snoring), heart rate and other potentially
important parameters. The technique is inexpen-
sive, naturalistic and generates vast amounts of
data. Meaningful results, though, depend crucially
on the precise questions being asked. It is mostly
used as a research tool or, clinically, for con rming
sleep diaries and demonstrating abnormal sched-
ules such as in circadian rhythm disorders.
CONCLUSIONS
Sleep medicine merits a higher pro le when
assessing specic sleep related symptoms and
when managing many common neurological
conditions.
A working knowledge of the nature and range
of the commoner sleep disorders is usually
enough to form a condent diagnosis from
the history alone, provided a reliable witness
account is available.
Specialised investigations are indicated in
some cases although they have limitations
and a relatively high frequency of false posi-
tive and negative results.
Although drug treatment is limited, most drugs
to improve wakefulness and/or nocturnal sleep
are relatively safe and often effective.
In many neurological disorders, it is surpris-
ing how often a poor sleepwake cycle causes
worsening symptoms.
Acknowledgements This article was reviewed by Matthew
Walker, London, UK.
Competing interests None.
Provenance and peer review Commissioned; externally peer
reviewed.
309