Sleep Movement Disorders andNeurologic MovementDisorders

Carl D. Boethel, MD, FCCP*, Shirley F. Jones, MD, FCCP,James A. Barker, MD, CPE, FCCP

KEYWORDS

� Movement disorders � Neurologic injury � Epilepsy � Rhythmic movement body disorder� Somnambulism � Somniloquy

KEY POINTS

� This article will discuss common sleep movement disorders and neurologic movement disorders.

� Neurologic injury, such as stroke or traumatic brain injury, often markedly alters sleep.

� Sleep movement disorders, including frontal lobe epilepsy, somnambulism, somniloquy, rhythmicmovement body disorder, REM behavior disorder, and restless leg syndrome, are discussed.

INTRODUCTION

In this article we discuss 2 types of movementdisorders. First, we briefly discuss common sleepmovement disorders and, second, we discussneurologic movement disorders. Neurologic injury,such as stroke or traumatic brain injury, oftenmarkedly alters sleep, and we cover much of thatin detail as well.

There are a variety of “things that go bump in thenight.” These could be roughly lumped into thecategory of sleep movement disorders. To beginwith, epilepsy often arises from sleep and is morecommon in sleep than in wake. Frontal lobeepilepsy can be difficult to diagnose becausestereotypic behaviors can be seen, and, thus, theepilepsy can be mistaken for a parasomnia oreven conversion disorder.

Somnambulism, or sleep walking, and somnilo-quy, or sleep talking, are common events. Theseare the most common parasomnias. They ariseprimarily out of stage 3 or slow-wave sleep(SWS). This is extremely common in childhoodbut still may occur in adulthood.

Division of Pulmonary, Critical Care, and Sleep Medicine,Science Center-College of Medicine, Scott & White Health* Corresponding author.E-mail address: CBOETHEL@sw.org

Sleep Med Clin 7 (2012) 631–642http://dx.doi.org/10.1016/j.jsmc.2012.10.0041556-407X/12/$ – see front matter � 2012 Elsevier Inc. Al

Rhythmic movement body disorder or bed rock-ing is an idiopathic disorder that is common inchildhood but does occasionally persist in adult-hood. A persistent rocking motion or head hittingpillow motion may occur at the beginning of sleepor even throughout the night. Multiple medicationattempts have generally been unsuccessful. Theuse of a water bed may actually be the most effec-tive therapy. Hypnosis has also been tried.Rhythmic movement disorder can be a frontallobe seizure, so investigation is indicated beforeassigning this diagnosis.

Restless legs syndrome (RLS) is a commondisorder. There are 2 groups of patients. One isan autosomal dominant inherited group, usuallywith onset early in life such as teenage years. Thesepatients have a creepy, crawly feeling, usually onthe legs or sometimes on arms. All 4 extremitiescan be involved. There is an urge to move, and itis actually quite difficult for these patients to holdstill for an entire hour. The second form is associ-ated with iron deficiency. It can also be known tooccur after beginning certain medications such as

Department of Internal Medicine, Texas A&M Healthcare, 2401 South 31st Street, Temple, TX 76508, USA

l rights reserved. sleep.theclinics.com

Boethel et al632

tricyclic antidepressants. Parkinson’s medicationsare used to treat this disorder but paradoxically cansometimes make it worse. There is a clinical corre-late during sleep that is called periodic limb move-ment disorder. Periodic limb movement disordercan be associated with a number of other sleepdisorders, in particular obstructive sleep apnea(OSA). The association with sleep apnea is notwell understood. The periodic limb movementdisorder is typically in the first third of the nightwithmuscle contractions lasting 0.5 to 5.0 secondsat regular intervals of 40 to 90 seconds. Periodiclimb movements are not generally seen duringrapid eye movement (REM) sleep. Most expertsthink that periodic limb movements need to showevidence of an accompanying arousal to beconsidered clinically significant. In fact, periodiclimb movements cannot be staged or counted ifthey occur within anOSAbecause there is an asso-ciation with OSA (which is poorly misunderstood,yet real).Finally, REM behavior disorder is a fascinating

disorder that, again, is closely tied to parkinsonismand is discussed in detail within this article. In brief,REM sleep behavior disorder represents loss ofskeletal muscle paralysis such that active move-ment occurs during REM sleep. Thus, there isa loss of inhibition for this activity. The minimumcriteria for diagnosis are the following:

1. Suggestive history with polysomnographicabnormality during REM sleep showing ele-vated electromyographic (EMG) tone;

2. Documentation of abnormal REM sleep be-havior during the polysomnogram (PSG), suchas prominent limb or truncal jerking, or vigorous,complex or even violent behavior; and

3. Absence of electroencephalogram (EEG) epil-eptic form activity.

SPECIFIC DISORDERS AND THE ASSOCIATEDSLEEP MOVEMENT RESPONSE THAT MAYOCCURStroke

Strokes may occur in a number of discrete lociwithin the brain and, thus, sequelae vary depend-ing on the lesion. Unfortunately, strokes remaincommon. Hypersomnia occurs in 22% of patientsafter an ischemia stroke. Sleep apnea is alsocommon after stroke, occurring in up to 71% ofpatients after cortical stroke.1 Insomnia, likewise,is common after stroke.RLS and increased periodic limb movements of

sleep (PLMS) have been reported by numerousinvestigators to follow stroke. REM sleep behaviordisorder, likewise, has been seen to arise after

stroke. And, finally, seizures are well known tooccur as a new entity in patients following stroke.In particular, nocturnal frontal lobe epilepsy

(NFLE) may occur as a form fruste movementdisorder following stroke.2 NFLE arises from sleep90% of the time. It now encompasses what hadpreviously been called paroxysmal nocturnal dys-tonia (PND). PND is now known to be a form offrontal lobe seizure. NFLE can be very difficult todistinguish from parasomnia.Some useful differentiations include the

following:

1. Parasomnia onset is almost always in thoseyounger 10 years and NFLE can begin at anyage.

2. There are typically only 1 or 2 parasomnias pernight, whereas NFLEs are commonly 3 or 4 pernight. This equates to 20 to 40 NFLE episodesper month; whereas parasomnias tend to beless than four per month.

3. Parasomnias usually disappear in adolescence,although they can persistent into adulthood.

4. Episodes are seconds to 3 minutes for NFLE,whereas they are seconds to 30 minutes forparasomnias.

5. NFLEs are highly stereotyped, frequentlyvigorous. Parasomnias are rarely stereotypedbut can be violent.

6. There are no known triggers for NFLE exceptperhaps for sleep deprivation. Triggers for par-asomnias are thought to be stress or emotionaltrauma.

7. Frankly epileptiform ictal movements are only in10% of NFLEs, so EEG is not a perfect “goldstandard.” EEG shows activity plus SWS inparasomnia.

8. Parasomnias are almost always out of stage 3,whereas NFLEs primarily occur in stage 2.

Medications

Obviously, it will be important to realize that thetherapies that we initiate in any setting (outpatient,hospital, or skilled nursing facility/rehabilitationcenter) may have unexpected consequences. Itis extremely common for certain medications toworsen or induce new sleep disorders. RLS canbe induced by escitalopram, fluoxetine, L-dopa/carbidopa and pergolide, L-thyroxine, mianserin,mirtazapine, olanzapine, and tramadol. Periodiclimb movements of sleep are worsened by thislist but may also particularly be worsened bybupropion, citalopram, fluoxetine, paroxetine, ser-traline, and venlafaxine.3

Of course, it should be remembered that manymedications have predictable side effects, that

Sleep Movement Disorders 633

is, haloperidol and droperidol may induce torti-collis or parkisonian features.

Traumatic Brain Injury

Patients with traumatic brain injury (TBI) suffera variety of sequelae. It is interesting to note thathypocretin falls in many of these patients andthen normalizes. Consequently, they may actmuch like patients with narcolepsy and mayrequire stimulants, such as modafinil or ritalin.4

Severe hypersomnia is common in patients withTBI. Of course, seizures may also occur in thosepatients after TBI. Again, care must be used toseparate posttraumatic seizures from parasom-nias; however, in this particular group a seizurewould be much more common than a new-onsetparasomnia.1

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune demye-linating disease that can have multiple foci andthus can have a wide variety of different clinicalpresentations. Sleep disorders within patientswith MS are estimated to be between 25% and54%.5 These may include insomnia, sleep-disordered breathing, circadian rhythm disorder,RLS, narcolepsy, and REM sleep behaviordisorder. All of these may arise as complicationsof the MS-associated plaques, creating specificlesions in the brain. New origin of sleep behaviordisorder has been described with an increase ofabout 10-fold beyond the general age-matchedpublic. Clonazepam has appeared effective inthese patients, as it is in idiopathic rapid eyemovement sleep behavior disorder (RBD). RLS islikewise common.

REMEMBER, THE DIAGNOSTIC ACRONYMURGE

1. U: an urge to move the legs, usually associatedwith unpleasant leg sensations;

2. R: rest induces symptoms;3. G: getting active (physically and mentally)

brings relief;4. E: evening and nights make symptoms worse.

RLS is about twice more frequent in patients withMS as in the age-matched general population.Also of interest, cytokine levels are increased inMS. Proinflammatory cytokines, such as tumornecrosis factor-alpha, interleukin (IL)-1beta, andIL-6 have some sleep-inducing properties andare common in many disease states.

Muscular Dystrophy

Myotonic dystrophy type 1 (MD1) is a commonadult-onset muscular dystrophy. Obviously,because of the progression of skeletal muscleweakness, MD1 is commonly associated withhypo-ventilation at night, OSA, and respiratoryinsufficiency (sleep-disordered breathing). Peri-odic limb movements and RLS are also increasedin this population. REM sleep is dysregulated, sothese patients may have increased number ofsleep-onset REM periods (SOREMP); however,they do not have new-onset narcolepsy. Excessivedaytime sleepiness is common in these patients.They are often managed with central nervoussystem stimulant drugs. Other parasomnias havenot been particularly increased in myotonicdystrophy.6

Quadraplegia

Patients with quadriplegia do have disorderedsleep, as might be expected. This is primarilyOSA and mixed sleep apnea. In addition, theyhave a prolonged REM latency.7

Cerebellar Ataxias

Cerebellar ataxias are becoming more and moredescribed. They commonly do involve sleepdisturbance. In particular, RLS and periodic limbmovement disorder are increased. Spinalocerebe-lar ataxia types 1, 2, and 3 are known to do this.There are no good data for Friedreich ataxia, themost common recessive ataxia across the world;however, OSA and mixed apnea are increased inpatients with Friedreich ataxia. REM behaviordisorder is known to be increased in SCA2 andSCA3.8

SLEEP AND MOVEMENT DISORDERSParkinson Disease

Of all the movement disorders that may be seen bythe sleep medicine specialist, the most common isParkinson disease (PD). This is primarily becausemost patients with PD complain of some form ofdisturbed sleep. Tandberg and colleagues9

reported that approximately two-thirds of allpatients with PD suffer from sleep and nocturnaldisorders. This was compared with patients withdiabetes at 46% and healthy elderly at 33%. Thedisease is a neurologic disorder characterized byprogressive disability of motor function. Commonfindings include muscle rigidity, resting tremors,and slow movements. The pathophysiology isa neurodegenerative disorder that involves lossof dopaminergic neurons in the substantia nigra;however, it appears that other neurotransmitter

Boethel et al634

systems are not immune to the damage thatresults from this disease. There is evidence thatthe serotonergic, cholinergic, orexinergic, andnoradrenergic systems are affected as well,10

and the loss or damage to these neurons probablyaccounts for some of the sleep-related symptomsthese patients experience.In addition, the most common side effects seen

with medications used to treat PD are the develop-ment of sleep disturbance and/or daytime sleepi-ness. Age-related changes in sleep architectureand quality may also play a role in sleep-relateddysfunction. Therefore, when encounteringa patient with PD, the cause of the patient’scomplaint may not be so easy to elucidate, andproblems with sleep and wakefulness may resultfrom multiple causes. Not only does the disease it-self result in sleep pathology, the treatment mayworsen or aggravate sleep complaints. To betterunderstand the sleep issues that a patient withPD may have, it is worthwhile to address thedisease as it relates to multiple sleep disorders.It should also be noted that Lewy body dementia,progressive supranuclear palsy, and the grouping“neurodegenerative disorders” have all been re-ported to have these same associated sleepdisorders.

Sleep-Disordered Breathing

With it affecting upward of 2% to 9% of the USpopulation, OSA syndrome has become one ofthe most common sleep disorders. Multiplestudies have shown a prevalence of OSA of 20%to 67% among patients with PD11; however, dataare mixed on the relationship between the 2 disor-ders. Patients with PD are likely to snore, and ina series of 86 patients, 72% of the patients snored,and of these patients they had higher complaintsof excessive daytime sleepiness.12–14 Given thehigher risk of sleep apnea in REM sleep, the find-ings of less REM sleep and higher apnea-hypopnea index in patients with PD suggestsanother mechanism for the sleep-disorderedbreathing. Most likely, upper airway changes inmuscle tone at the level of the glottis lead toincreased airway collapsibility. It appears thatpatients with PD and OSA do not have the samesympathetic response to the obstructive eventsthat control patients with OSA encounter. Ina study performed by Valko and colleagues,15

patients with PD who had OSA and those withoutOSA had similar levels of heart rate variability,a marker of sympathetic nervous system tone.This was in stark contrast to control patients withOSA who showed greater heart rate variability.Patients with PD and OSA do not appear to have

the typical physiologic profile of a patient withOSA.However, there have been 2 recent studies that

show no increased risk of sleep apnea associatedwith PD. When comparing French patients withPD without sleepiness with age-matched, sex-matched, and body mass index (BMI)-matchedcontrol patients without neurologic diseases andwith patients with PD with excessive sleepiness,Cochen De Cock and colleagues16 showed thatpatients with PD did not have an increased riskof having OSA; however, the control patientswere recruited from hospitalized patients, andmay have had a higher risk for sleep apnea thanthe patients with PD. Interestingly, the averageBMI in both patient groups was 24. In anotherstudy that compared patients after 3 nights ofsleep studies with normative data from the SleepHeart Health Study, there was no increased inci-dence of sleep apnea in patients with PD.17 Itappears that the data are mixed when determiningwhether patients with PD are at higher risk of sleepapnea. There do not appear to be any studies thathave looked at sleep apnea as a risk factor for PD,and it is unclear if patients suffering from both PDand OSA have a more rapid progression of theirparkinson symptoms. Nor are there any popula-tion-based studies that test if OSA risk increasesas the PD progresses, but with the risk of upperairway collapse and changes in muscle tone,patients should be assessed for a concomitantsleep breathing disorder if they have PD andpresent with fatigue or snoring.

REM Sleep Behavior Disorder

Based on the International Classification of SleepDisorders (ICSD)-2, the minimal criteria to diag-nose RBD are as follows:

1. The presence of REM sleep without atonia,defined as sustained or intermittent elevationof submental EMG tone or excessive phasicmuscle activity in the limb EMG.

2. At least one of the following:a. Sleep related injurious or potentially inju-

rious disruptive behaviors by history.b. Abnormal REM behaviors documented on

polysomnogram.3. Absences of epileptiform activity during REM

sleep, unless RBD can be clearly distinguishedfrom any concurrent REM sleep-related seizuredisorder.

4. Sleep disturbance not better explained byanother sleep disorder, medical or neurologicdisorder, mental disorder, medication use, orsubstance use disorder.18

Sleep Movement Disorders 635

Since first identified by Drs Schenck and Maho-wald in 1986, RBD has been identified with neuro-degenerative disorders, notably PD.19 Then in1996, the same investigators reported the devel-opment of PD in patients initially diagnosed withidiopathic RBD. Of 29 patients, 38% developedPD symptoms. The RBD symptoms and signsanteceded the development of PD by on average12 years.20 Further studies have confirmed similarfindings, as one study showed a 10-year risk ofdevelopment of a neurodegenerative disease ondiagnosis of RBD to be 40.6%.21

Although history alone can often give enoughevidence to suggest a diagnosis of RBD, the useof a polysomnogram is helpful to give a definitivediagnosis. In a study by Frauscher andcolleagues22 that looked at 13 different musclesto localize the best group of muscles to helpsupport a diagnosis of RBD, they found thatEMG of the mentalis, flexor digitorum superficialis,and extensor digitorum brevis was superior to theroutine polysomnogram (PSG EMG) of mentalisplus left and right tibialis anterior. The use of this3-muscle montage, known as the SINBAR EMGmontage, provided the highest rates of REM sleepphasic EMG activity in subjects with RBD, andthere was no difference between idiopathic RBDpatients and those with PD. The SINBAR EMGwas later validated to detect upward of 94.4% ofmotor and vocal events occurring with PhasicREM sleep in RBD.23

As mentioned previously, the diagnosis usuallyinvolves a history of increased muscle activityduring REM sleep accompanied by abnormalmotor and vocal manifestations. These mayinclude jerking, hitting, punching, and kicking,which can affect the limbs. The facial musclesmay reveal grimaces, laughter, and shouting,and, occasionally, patients may even jump or fallout of bed. The first sign of RBD may be thepatients presenting with complaints of an acci-dental laceration from a fall across a nightstand.Physicians should rule out other sleep-relateddisorders, such as frontal lobe epilepsy and severesleep apnea, before diagnosing RBD.

RBD is characterized by complex behaviors thatcorrespond with dreams. These patients are notknown to engage in behaviors such as eating,drinking, or relieving oneself. There appears to bevariable penetrance of the degree to which thesebehaviors are violent. Some patients present withnonviolent behaviors, such as singing, dancing,whistling, or engaging in daytimelike activities,24

but the violent behaviors often will be frighteningto the bed partner or spouse.

Patients with PD suffer from RBD are more likelyto have mild cognitive impairment as opposed to

patients with PD without RBD. The patients withPD with RBD scored worse on neuropsychiatrictesting than patients with PD without the disease.Since RBD is associated with other neurocognitivedisorders, such as lewy body dementia and multi-system atrophy, it is fair to say that RBD predis-poses patients with PD to the early signs ofdementia.25,26

It appears that women are more likely than mento have non-violent RBD manifestations. Relyingon the REM Sleep Behavior Disorder ScreeningQuestionnaire, this was apparent in a study doneby Bjornara and colleagues27 that screened 107patients with PD for symptoms of RBD. Menappeared to have more fights and violent behaviordespite a similar representation of the disorder inboth sexes. The study did not use polysomno-graphic data to confirm the diagnosis.

This begs the question, is it necessary toperform a PSG on patients to confirm the diag-nosis of RBD? The ICSD-2 recommends a PSG,and a study performed by Eisensehr andcolleagues28 at the University of Munich showedthat sleep interview alone was not sufficient tomake the diagnosis of RBD in patients with PD.They theorize that factors such as the medicationsused to treat PD have a beneficial effect on RBDsymptoms. Therefore, patients with PD may notmanifest the same behaviors as idiopathic RBDpatients. Conversely, some of the medicationsused to treat PD can cause hallucinations, mostnotably levodopa. Therefore, differentiating thecause of nocturnal behaviors in patients with PDshould be done with a thorough history and phys-ical examination enhanced by a polysomnogram.

There are medications that can cause symp-toms of RBD to occur. Levodopa can cause hallu-cinations, but these may occur in the daytime aswell as at night. Other medications that havebeen implicated in causing RBD-like behaviorsinclude tricyclic antidepressants, selective sero-tonin reuptake inhibitors, serotonin norepinephrinereuptake inhibitors, mirtazapine, and bisoprolol.Other substances that have been noted to causesimilar symptoms include alcohol, caffeine, andeven chocolate.29

Treatment of RBD in patients with PD is thesame as all patients who suffer from RBD. Thelong-acting benzodiazepine clonazepam hasbeen the drug of choice since the original patientswere treated in the 1980s. The drug has a half-lifeof 30 hours, but it is rapidly absorbed over 1 to 4hours. It is recommended to take the drug30 minutes before bedtime. Cessation of thedrug can cause immediate relapse of RBD symp-toms. There are no randomized controlled trialsthat have looked at treatment of RBD with

Boethel et al636

clonazepam, so use of the medication is based onexpert opinion, and case series that have showna 90% response rate to the drug.30 Although thereare multiple case reports of various medicationsthat have been tried in RBD, other than clonaze-pam, the only other medication that can be recom-mended for therapy is melatonin. It appears toimprove desynchronization and lacks the sideeffects that commonly are associated with othertherapies.The efficacy of pramipexole for RBD symptoms

is inconclusive. Of 29 patients treated with prami-pexole at a dose sufficient to treat their PD, only 13had a favorable response in RBD symptoms. Thus,one can surmise that there may be other neuro-pathologic mechanisms involved in the develop-ment of RBD in patients with PD.30

The primary concern that should be dealt with inthese patients when first seen is safety. Thisincludes safety for both the patient and thepatient’s bed partner. Making the room safe fromaccidents that may occur while sleeping, such aslacerations caused by hitting furniture or falls thatmay cause fractures, should be addressed andneed to be discussed with the patient and family.A safe environment is key to therapy of all patientswith RBD. It is clear that RBD predates PD byupward of 12 years, but it is unfortunate that thereare no studies that have looked at the preventionof PD in this patient population. RBD appears topredate the development of PD; however, multi-system atrophy (MSA) and Lewy body dementiaare also predated by RBD. So, it is important forany patient presenting with RBD symptoms tohave a thorough evaluation and close follow-up.

Restless Legs Syndrome

RLS is amovement disorder that shares a commonpathophysiological pathway with PD. Both showa significant improvement in symptoms whentreated with medications that enhance dopaminein the brain. It appears that the two may be related,but it is unclear that RLS predisposes patients tothe development of PD over time. Patients withPD do have a higher rate of RLS symptoms incomparison with patients with idiopathic RLS inthe general population.10 In addition, mostpatients with PD may underreport their symptomsof RLS, as the symptoms may be within theconstellation of PD symptoms.31 Thus, patientswith PD may find their RLS symptoms occurringduring the daytime and may not find the need toreport nocturnal RLS symptoms.Most patients with RLS symptoms require

minimal to modest dosages of dopaminergicagonists to control symptoms at night, whereas

the dosages required of patients with PD to controltheir PD symptoms are much higher and can oftenelicit the augmentation symptoms (which entailRLS symptoms occurring earlier in the day).Although both disorders respond to treatmentwith dopaminergic agonists, there appears to bea divergence of pathobiology between the two.Low serum ferritin levels and low substantia nigrairon levels have been observed in patients withRLS.32 This is opposed to the findings in patientswith PD, in which the substantia nigra iron storesappear to be increased.33

Periodic limb movements are common inpatients with PD, and the movement disorderseems to disrupt sleep as a result, leading todecreased total sleep time, poorer sleep effi-ciency, and less sleep period time.34 Anotherstudy reported recently in the Journal of Neuro-logic Sciences compared patients with PD withhigh and low numbers of periodic limb move-ments. Patients with PD with higher levels ofPLMS had increased sleep complaints and poorerquality of life. The data showed that the patientswith PD with higher levels had more severeprogression of PD. This is despite similar objectivesleep measures between the two groups.35 Thereappears to be improvement in sleep quality inpatients with PD with levodopa and dopaminergicagonists. Hogl and colleagues36 found that the useof the D1 and D2 receptor agonist cabergoline,when given at bedtime, significantly improvedPLMS in patients with PD. Also, these patientshad improved movement and motor performanceon awakening and improved reports of subjectivesleepiness. This is despite the fact that the medi-cation cohort appeared to have worse sleep frag-mentation and increased nocturnal arousals andawakenings.

Insomnia

Insomnia is a common subjective complaint ofpatients with PD. They will present with eithersleep onset or sleep maintenance insomnia, andbecause of the numerous causes of sleep distur-bances in patients with PD, it helps to classifyinsomnia in these terms. RLS, as mentioned previ-ously, is commonly a comorbidity of PD, and cancause sleep-onset insomnia. A high proportion ofpatients with PD can present with symptoms ofdepression, anxiety, nocturnal hallucinations,panic attacks, and other mood disorders, all ofwhich can cause both sleep-onset insomnia andsleep maintenance insomnia. In addition, themedications used to treat PD can worsen sleep.Nocturia has also been implicated as a culprit ofsleep maintenance insomnia, although it is difficult

Sleep Movement Disorders 637

to separate its cause from other sleep problems.Because most patients with PD are elderly, age-related sleep changes can cause worseninginsomnia. Two recent studies have examined theuse of dopaminergic agonists versus placebo totreat sleep disturbances. The EASE-PD studyexplored the use of extended-release ropiniroleversus placebo and showed improvement in PDsleep scale scores.37 In the CLEOPATRA study,in which the clinical efficacy of pramipexole andtransdermal rotigotine in patients with advancedPD was explored, more than 400 patients withadvanced PD were evaluated. There was a smallbut significant improvement in PD sleep scalescores with both pramipexole and the transdermalrotigotine.38 It is not clear whether the improve-ments were because of improved sleep or if thiswas because of improvement in the akinesia andhypokinesia that accompanies PD and can leadto sleep disturbances in these patients.

A recent study examined the relationshipbetween nocturnal hypokinesia, the inability toturn in bed, and sleep quality; 240 patients werestudied. On the Parkinson Disease Quality of LifeQuestionnaire (PDQL), the question was asked,“How often in the last 3 months did you havetrouble turning over in bed?” It is then scored ona 5-point Likert scale. Patients were then askedto complete the Pittsburgh Sleep Quality Index(PSQI), which gives a good measure of the variousaspects of nocturnal sleep. A low value on thePSQI suggests good sleep. The authors foundthat 60% of the patients with PD had a PSQIgreater than 5, but the patients with nocturnal hy-pokinesia scored much higher on the PSQI. Thereappears to be a relationship between sleep main-tenance insomnia, sleep disruption, and nocturnalhypokinesia.39

In a longitudinal cohort study of patients with PDfrom Norway conducted over 8 years, 89 patientscompleted the study of an initial 231 patients. Ofthose 89, 83% experienced insomnia at 1 ormore of the study visits; 20% of the 89 developedinsomnia as their disease progressed. The datashowed a higher level of depression and insomniain female patients as opposed to males. In addi-tion, the insomnia appears to occur early andappears to be associated with the duration of thedisease.40

Measuring Sleep in Patients with PD

As can be judged from the previous information,sleep disturbances, including sleep apnea, RLS,RBD, and insomnia can all affect patients whosuffer from PD. For the practicing sleep clinician,there are a number of tools available that can

help to diagnose and aid in treatment of patientswith PD with sleep complaints. In addition to thecommonly used Epworth Sleepiness Scale, theBerlin Sleep Questionnaire is helpful at deter-mining if a patient is at high risk for OSA. The Ep-worth sleepiness scale provides a measure ofsubjective sleepiness based on a scale of 0 to 3.Patients with scores of 10 or greater are consid-ered to be excessively sleepy and in need offurther workup. The Berlin Sleep Questionnaireasks a serious of questions pertaining to snoring,apneas, and hypertension.

The Parkinson disease sleep scale (PDSS) isa visual analog scale of 15 questions that wasdeveloped to aid clinicians in diagnosing sleepdisturbances in patients with PD.41 The scalewas initially written by Dr Chaudhuri, and sinceits initial release has been revised to the ParkinsonDisease Sleep Scale-2 (PDSS-2). This scale hasbeen validated in multiple countries and is a reli-able and valid tool for measuring sleep disordersin patients with PD, and it adds to the originalPDSS by asking about nocturnal hypokinesia,RLS, sleep apnea, and pain.42

To question patients about both nocturnal sleepand daytime sleepiness, the Scales for Outcomesin PD-Sleep Scale (SCOPA-S) is available. It doesnot give evidence for a potential cause of the sleepdisorder as opposed to the PDSS-2, but it doesassess daytime sleepiness very well and appearsto be valid and reliable at assessing sleep inpatients with PD.43,44

Overnight PSG is highly recommended in thediagnosis of patients with RBD, as with all otherparasomnias. Actigraphy is useful in diagnosingcircadian rhythm disorders, and it appears to aidin the diagnosis of sleep disturbance in patientswith PD. Along with sleep logs or diaries, actigra-phy appears to correlate with the PDSS in patientswith PD. Although not many studies have beendone that have used actigraphy in patients withPD, it has value in assessing movement disordersin sleep medicine and may aid in diagnosis ofsleep disruption and assist in management.

Treatment and Its Side Effects

The main method of treatment of patients with PDis oral L-dopa and the dopamine agonists.However, these medications may benefit thepatient with PD in that the movement symptomsmay improve, but they may have side effects thatcan affect sleep and levels of wakefulness andalertness. In addition, dopamine agonists cancause patients to engage in behaviors that cancompromise their quality of life such as the dopa-minergic dysfunction syndrome. This disorder

Boethel et al638

causes loss of impulse control and has been asso-ciated with uncontrolled shopping, gambling, andsexual infidelity. These behaviors can cause greatfinancial and social loss to patients, so patientsshould be advised of this side effect wheneverstarting a dopaminergic agonist.One can hypothesize that the best way to treat

patients with PD is to catch them early and preventneurodegeneration. One study has looked at thisissue. By attempting to find patients with precursordisorders that suggest the development of PD, onecan find early patients and hopefully prevent thedamage. Hyposmia, loss of smell, and RBD fitthese criteria. The rate of development of PD in2 years is 10% in patients with hyposmia and40% to 50% in patients with RBD. Rasagiline,a selective monoamine oxidase B inhibitor, wasfound to show some neuroprotection and delay ofonset of need for symptomatic therapy in patientswith PD. Transcranial sonography may identifychanges in substania nigra echogenicity.26,45

SLEEP IN CHOREA AND DYSTONIAS

Movement disorders can be classified into hypoki-netic and hyperkinetic disorders. PD classicallyencompasses the hypokinetic disorder and ischaracterized as bradykinesia, akinesia, andrigidity. Disorders of hyperkinesis include tremor,chorea, ballism, dystonia, athetosis, tics, myoc-lonus, startle, and sterotypies. In this section, wefocus on the hyperkinetic movement disorders ofchorea and dystonia and their sleep-relatedissues.

Definitions

Chorea is a defined as random, irregular, brief,flowing movements. The term chorea is derivedfrom the Greek word choreia, which denotes anancient circle dance. Choreic movements areseen in a variety of illnesses, which can be furtherclassified into genetic disorders (Huntington),infectious (Syndham chorea, which is seen in chil-dren with rheumatic fever), drug-related (seen withuse of dopamine agonists), endocrine/metabolicconditions (hyperthyroidism), immunologic disor-ders (systemic lupus erythematosus), vasculardisorders (following stroke), and other conditions(cerebral palsy). Dystonia is distinct from choreaand characterized by sustained muscle contrac-tions that result in twisting and abnormalposturing.46

Huntington Disease and Sleep

Huntington disease (HD) is a rare autosomal domi-nant neurodegenerative disease with a prevalence

of 10 cases per 100,000 individuals. A trinucleotiderepeat of the sequence CAG in the gene thatencodes for the huntington protein is responsiblefor the disease. Affected individuals are young tomiddle age. Most cases develop in patientsbetween 30 and 55 years of age. Cognitive impair-ment, mood disorders, personality changes, andchorea are manifestations of the disease. Early inthe disease, patients may exhibit chorea only;however, as the disease progresses, psychiatricsymptoms ensue. Sleep becomes increasinglydisrupted. The prevalence of sleep problems inpatients with HD is 87.8% according to a surveyof community-dwelling patients with HD or theircaregivers.47 These sleep problems were rankedvery or moderately important in 61.7% ofresponders and were significant enough forpatients and caregivers to seek help.47 Frequentlyreported sleep problems included restless limbmovements, periodic jerky movements, wakingduring the night, sleepy by day, and earlywakening.47 More than half of those surveyedreported choreic movements.47 The role of sleepand HD is particularly important because theinability of caregivers to cope with nocturnal sleepdysfunction is one of the most common reasonsfor institutionalization of patients with neurodegen-erative disease.48

Using PSG, multiple studies report sleep distur-bances in patients with HD. Patients have pro-longed sleep-onset latency49,50 increase in thenumber of awakenings49 and reduced sleep effi-ciency.50,51 Higher degrees of clinical diseaseimpairment correlate with less total sleep time,more time spent awake, and reduced sleep effi-ciency.49 Mood disorders of depression, commonin HD, are associated with worse sleep quality asmeasured by the Pittsburgh Sleep Quality Index.52

There are 64% to 80% of patients who report51,52

sleep stage composition also differs amongpatientswithHDcomparedwith controls,with high-er percentages of “light” N1 sleep and wake49,51

and REM sleep.51 However, the decrease in REMsleep is not a reported finding in other studies.49

Multiple studies report higher sleep spindle densityin patients with HD.49,53 Although it seems thatsleep worsens as the disease progresses, thesesleep disturbances have not been shown to corre-late with the number of CAG repeats. The risk ofsleep-disordered breathing does not appear to beincreased in patients with HD compared withcontrols51,54 but if found, responds well to contin-uous positive airway pressure with improvementsin sleepstructure,memory, anddaytimehypersom-nolence in one report.55 The prevalence of OSA inHD is understudied and is worthy of further investi-gation, as sleep-disordered breathing is potentially

Sleep Movement Disorders 639

reversible. Excessive daytime sleepiness based onthe Epworth Sleepiness Scale affects between32%and 50%51,52 of patients with HD and appearsto be more common as the disease progresses.Although sleep-disordered breathing should beconsidered in this population, excessive daytimesleepiness attributed to side effects ofmedications,sleep-related movements, parasomnias, circadianrhythm dysfunction, and depression warrant addi-tional thought. Daytime somnolence in HD is asso-ciated with comorbid depression52 and correlateswith night time sleep disturbances.56

In studies examining circadian rhythms ofpatients with HD, both advanced51 and delayedsleep phase56 have been reported. Delayed sleepphase is associated with depression, lower func-tion, and cognitive performance.56 In the trans-genic R6/2 mouse model of HD, disruptions ofsleep wake circadian rhythms became morepronounced compared with wild-type mice onceneurodegenerative symptoms appeared.57 Acti-vity became less defined and more irregular inthe R6/2 mouse and was accompanied byabnormal expression of mPer2 mRNA in thesuprachiasmatic nucleus.57 Expression ofmBmal1b mRNA was also disrupted comparedwith wild-type mice.57 Use of a combination of al-prazolam to facilitate sleep and modafinil to facili-tate wakefulness in the R6/2 mice improvedcognitive function and apathy.58,59 Effects weremore robust with the combination compared witheach drug alone.58 Although these findings havenot been verified in human studies, profiles of thecircadian rhythm of melatonin in 9 patients withearly-stage HD exhibited a delay in the nocturnalrise of melatonin compared with controls.56

Mean diurnal melatonin levels were inversely asso-ciated with motor and functional disability inpatients with HD.56 Further research examiningcircadian rhythm dysfunction directly at the supra-chiasmatic nucleus level in patients with HD isneeded. The findings of circadian rhythm dysfunc-tion in this population should prompt studies of theeffects of photic and nonphotic therapies toresynchronize/restore the circadian rhythm in thispopulation.

Sleep-related movement disorders such as RLSand periodic limb movements have been reportedin patients with HD. Although there is no definiteknown association between RLS and HD, Eversand St}ogbauer60 described a family in which RLSand HD occurred in several members. In anothercase report, Savva and colleagues61 describeda typical case of RLS that responded to gabap-entin in a patient who developed signs and symp-toms of HD 3 years later. Using polysomnography,patients with HD have a significant increase in the

number of periodic limb movements, but these arenot associated with significant arousals whencompared with controls.51 Based on these find-ings, it is possible that the A11 dopaminergicsystem that is involved in the RLS may be involvedin the pathology of HD,61 although this is notproven.

REM sleep behavior disorder is a parasomniacharacterized by movements of skeletal muscleduring REM sleep. In a single study of 25patients with HD, 3 patients or 12% had findingsof REM sleep behavior disorder, reduction inREM sleep, and prolonged onset of REMsleep.51 Further studies of the effect of mutanthuntington protein on evaluating brain structuresinvolved in REM sleep generation should beperformed.

Other disorders of REM sleep generationinclude narcolepsy, a disorder of which compo-nents of REM sleep extend into wakefulness.Narcolepsy is classified as with or without cata-plexy. Patients with narcolepsy with cataplexyhave a reduction of hypocretin-1 also known asorexin-A levels is the cerebrospinal fluid.62 Asimilar finding by Petersen and colleagues63

shows a loss of hypocretin in a transgenic R6/2mouse model of HD. In this study, the R6/2 mousemodel displayed 72% fewer hypocretin neuronsand levels of hypocretin-1 in the cerebrospinalfluid. Translation in human studies unfortunatelyhave not been reproduced, as cerebrospinal fluidhypocretin-1 levels are normal in patients withHD64,65 and hence is not a biomarker for HD in hu-mans. The reduction in hypocretin-1 in HD may bespecific only to the mouse model.65 In a study of25 patients with HD, mean sleep latencies basedon the multiple sleep latency test were significantlylonger in patients with HD compared with patientswith narcolepsy.51 Sleep-onset REM periods werenot observed in patients with HD and symptomsof narcolepsy including sleep paralysis, cata-plexy, and hypnogogic hallucinations were notreported.51 It does not appear that dysfunctionof the hypocretin/orexin system plays a role inhuman HD.

Dystonias and Sleep

In dystonia, involuntary muscle contractionscause twisting and sometimes painful abnormalposturing. Prevalence rates vary widely likelybecause of underdiagnosis or misdiagnosis. Prev-alence data from 1950 to 1982 indicate that thereare 34 per million persons with generalized dysto-nia and 295 per million persons with focal dysto-nias.66 Cervical dystonia is the most commonfocal dystonia.66 Many types of disorders are

Boethel et al640

recognized as dystonia and can be classified byanatomic distribution of muscles affected, age atonset, and cause of the dystonia. The cause ofthe dystonia is further classified as primary orsecondary. In primary dystonia, no other under-lying disorders are found and the involuntarymuscle contractions are the sole symptom.67 Insecondary dystonia, the dystonia is due to a hered-itary neurologic disorder or andexogenous insult,46

such as Wilson disease, traumatic brain injury, ormedications.67 Examples of dystonias involvingcertain anatomic distributions include cervical dys-tonia and blepharospasm. Dystonia that involvescontiguous muscles are termed segmental andinclude oromandibular dystonia. Multifocal andhemidystonia further describe involved areas.Patients less than 26 years of age have early-onset disease. Although the motor symptoms ofdystonia are important for classification, the non-motor symptoms of dystonia, including sleep, aredrawing increased interest, as such symptomsmay impart negative effects on quality of life.The literature examining sleep in dystonia is

limited. A study using the Pittsburgh Sleep QualityIndex indicates that 44% of patients with cervicaldystonia and 46% of patients with blepharospasmreport impaired sleep quality compared with 20%of controls without known neurologic disorders.68

In patients who reported impaired sleep, associa-tion with cervical dystonia and blepharospasmwas reported in only 22% and 13% of patientsrespectively.68 Improvements in sleep occurredafter treatment with botulinum toxin in nearly 40%of patients with cervical dystonia68; 19% ofpatients met clinical criteria for RLS.68 Despiteimpaired quality of sleep, most patients did notself-report sleepiness.68 Avanzino reported similarfindings of higher Pittsburgh Sleep Quality Indexscores indicating poor sleep in 98 patients withcervical dystonia and blepharospasm comparedwith controls.69 However, in patients with cervicaldystonia, rates of depression were high andconfounded any effect of cervical dystonia onsleep quality.69 High rates of depression in dysto-nia are supported in additional studies.68,70 Higherscores in sleep latency, duration, and efficiencysuggest problems with insomnia.69 Interestingly,sleep quality did not correlate with severity of dys-tonia.69 It is unknown whether a separate mecha-nistic effect of dystonia on sleep exists.Limitations to these studies are the use of surveyinstruments that do not necessarily correlate withPSG measures of sleep.71,72

Using PSG in 10 patients with cervical dystonia,blepharospasm, and oromandibular dystonia,patients had reduced sleep efficiencies, increasein wake after sleep onset, and stage 1 and stage

2 of sleep and reductions in slow wave sleep andREM compared with reference values.73 Similarly,Jankel reported reduced sleep efficiency, pro-longed sleep onset, and an increase in stage 2sleep with an additional finding of changes inspindle activity.74 The number of muscle spasmsdecreased as sleep progresses.73,75

SUMMARY AND RECOMMENDATIONS

Patients with chorea and dystonia suffer fromsleep-related problems. While the exact etiologyof the sleep disturbance is unclear, sleep qualitycan be poor. Recognition of comorbid mood disor-ders, such as depression, sleep-related breathingdisorders, parasomnias, sleep-related movementdisorders, and circadian rhythm dysfunction isimportant. Future research should focus on thepathophysiology of the disease and its relation tosleep modulation, examine sleep specific treat-ment on comorbid disease and symptoms, andtheir effects on quality of life in patients and theircaregivers.

REFERENCES

1. Dyken JE, Afifi AK, et al. Sleep-related problems in

neurologic diseases. Chest 2012;141(2):528–44.

2. Derry C. Nocturnal frontal lobe epilepsy vs parasom-

nias. Sleep Dis 2012;14:451–63.

3. Hoque R, Chesson AL Jr. Pharmacologically

Induced/exacerbated restless legs syndrome, peri-

odic limb movements of sleep, and REM behavior

disorder/REM sleep without atonia: literature review,

qualitative scoring, and comparative analysis. Sleep

2010;6(1):79–83.

4. Anderson K. Sleep disturbance and neurological

disease. Sleep Dis 2011;11:271–4.

5. Brass SD, Duquette P, Proulx-Therrien J, et al. Sleep

disorders in patients with multiple sclerosis. Sleep

Med Rev 2012;1:121–9.

6. Dauvilliers YA, Laberge L. Myotonic dystrophy type

1, daytime sleepiness and REM sleep dysregulation.

Sleep Med Rev 2012;1:1–7.

7. Berlowitz DJ, Spong J, et al. Relationships between

objective sleep indices and symptoms in a commu-

nity sample of people with tetraplegia. Arch Phys

Med Rehabil 2012;93:1246–52.

8. Pedroso JL, Braga-Neto P, et al. Sleep disorders in

cerebellar ataxias. Arq Neuropsiquiatr 2011;69(2-A):

253–7.

9. Tandberg E, Larsen JP, et al. A community based

study of sleep disorders in patients with Parkinson’s

disease. Mov Disord 1998;13(6):895–9.

10. Suzuki K, Miyamoto M, et al. Sleep disturbances

associated with Parkinson’s disease. Parkinsons

Dis 2011;2011:1–10 Article ID 219056.

Sleep Movement Disorders 641

11. Lelieveld I, Muller M, et al. The role of serotonin in

sleep disordered breathing associated with Parkin-

son disease: a correlative [11C]DASB PET Imaging

study. PLoS One 2012;7(7):e40166.

12. Braga-Neto P, da Silva-Junior FP, et al. Snoring and

excessive daytime sleepiness in Parkinson’s

disease. J Neurol Sci 2004;217(1):41–5.

13. Hogl B, Seppi K, et al. Increased daytime sleepiness

in Parkinson’s disease: a questionnaire survey. Mov

Disord 2003;18(3):319–23.

14. Maria B, Sophia S, et al. Sleep breathing disorders in

patients with idiopathic Parkinson’s disease. Respir

Med 2003;97(10):1151–7.

15. Valko P, Hauser S, Werth E, et al. Heart rate vari-

ability in patients with idiopathic Parkinson’s disease

with and without obstructive sleep apnea syndrome.

Parkinsonism Relat Disord 2012;18:525–31.

16. De Cock VC, Abouda M, et al. Is obstructive sleep

apnea a problem in Parkinson’s disease? Sleep

Med 2010;11:247–52.

17. Trotti L, Bliwise D. No increased risk of obstructive

sleep apnea in Parkinson’s disease. Mov Disord

2010;25(13):2246–9.

18. American Academy of Sleep Medicine. International

classification of sleep disorders, 2nd ed.: diagnostic

and coding manual. Westchester (IL): American

Academy of Sleep Medicine; 2005.

19. Schenck C, Bundlie S, et al. Chronic behavioral

disorders of human REM sleep: a new category of

parasomnia. Sleep 1986;9(2):293–308.

20. Schenck C, Bundlie S, et al. Delayed emergence of

parkinsonian disorder in 38% or 29 older men

initially diagnosed with idiopathic rapid eye move-

ment sleep behavior disorder. Neurology 1996;46:

388–93.

21. Postuma R, Gagnon J, et al. Quantifying the risk of

neurodegenerative disease in idiopathic REM sleep

behavior disorder. Neurology 2009;72(15):1296–300.

22. Frauscher B, Iranzo A, et al. Quantification of elec-

tromyographic activity during REM sleep in multiple

muscles in REM sleep behavior disorder. Sleep

2008;31(5):724–31.

23. Iranzo A, Frauscher B, et al. Usefulness of the SIN-

BAR electromyographic montage to detect the

motor and vocal manifestations occurring in REM

sleep behavior disorder. Sleep Med 2011;12:284–8.

24. Ouidette D, De Cock VC, et al. Nonviolent elaborate

behaviors may also occur in REM sleep behavior

disorder. Neurology 2009;72:551–7.

25. Gagnon JF, Vendette M, et al. Mild cognitive impair-

ment in rapid eye movement sleep behavior disor-

der and Parkinson’s disease. Ann Neurol 2009;

66(1):39–47.

26. Postuma R, Lang A, et al. Caffeine for treatment of

Parkinson’s disease. Neurology 2012;79:651–8.

27. Bjornara K, Dietrichs E, et al. REM sleep behavior

disorder in Parkinson’s disease—Is there a gender

difference? Parkinsonism Relat Disord 2012. Available

at: http://dx.doi.org/10.1016/j.parkreldis.2012.05.027.

Accessed October 12, 2012.

28. Eisensehr I, v Lindeiner H, et al. REM sleep behavior

disorder in sleep-disordered patients with versus

without Parkinson’s disease: is there a need for poly-

somnography? J Neurol Sci 2001;186:7–11.

29. Frenette E. REM sleep behavior disorder. Med Clin

North Am 2010;94:593–614.

30. Aurora RN, Zak R, et al. Best practice guide for the

treatment of REM sleep behavior disorder (RBD).

J Clin Sleep Med 2010;6(1):85–95.

31. Ondo W, Vuong K, et al. Exploring the relationship

between Parkinson disease and restless leg

syndrome. Arch Neurol 2002;59(3):421–4.

32. Connor J, Boyer P, et al. Neuropathological exami-

nation suggests impaired brain iron acquisition in

restless legs syndrome. Neurology 2003;61:301–9.

33. Morris C, Edwardson J. Iron histochemistry of the

substantia nigra in Parkinson’s disease. Neurode-

generation 1994;3(4):277–82.

34. Wetter T, Pollmacher T. Restless legs and periodic

limb movements in sleep syndromes. J Neurol 1997;

244(Suppl 1):S37–45.

35. Covassin N, Neikrug A, et al. Clinical correlates of

periodic limb movements in sleep in Parkinson’s

disease. J Neurol Sci 2012;316(1):131–6.

36. Hogl B, Rothdach A, et al. The effect of cabergoline on

sleep, periodic leg movements in sleep, and early

morning motor function in patients with Parkinson’s

disease.Neuropsychopharmacology2003;28:1866–70.

37. Pahwa R, Stacy M, et al. Ropinirole 24 hour pro-

longed release randomized, controlled study in

advanced Parkinson’s disease. Neurology 2007;

68(14):1108–15.

38. PoeweW,RascolO, et al. Efficacyof pramipexoleand

transdermal rotigotine in advanced Parkinson’s

disease: adouble-blind, double-dummy, randomised

controlled trial. Lancet Neurol 2007;6(6):513–20.

39. Louter M, Munneke M, et al. Nocturnal hypokinesia

and sleepquality in Parkinson’s disease. J AmGeriatr

Soc 2012;60(6):1104–8.

40. Gjerstad M, Wentzel-Larsen T, et al. Insomnia in

Parkinson’s disease: frequency and progression

over time. J Neurol Neurosurg Psychiatry 2007;

78:476–9.

41. Chaudhuri K, Pal S, DiMarco A, et al. The Parkinson’s

disease sleep scale: a new instrument for assessing

sleep and nocturnal disability in Parkinson’s disease.

J Neurol Neurosurg Psychiatry 2002;73:629–35.

42. Trenkwalder C, Kohnen R, et al. Parkinson’s disease

sleep scale—validation of the revised version PDSS-

2. Mov Disord 2011;26(4):644–52.

43. Martinez-Martin P, Visser M, et al. SCOPA-Sleep and

PDSS: two scales for assessment of sleep disorder

in Parkinson’s disease. Mov Disord 2008;23(12):

1681–8.

Boethel et al642

44. Diederich N, McIntyre D. Sleep disorders in Parkin-

son’s disease: many causes, few therapeutic

options. J Neurol Sci 2012;314:12–9.

45. Antonini A. The conundrum of neuroprotection in

Parkinson’s disease. Lancet Neurol 2011;10:396–7.

46. Geyer HL, Bressman SB. The diagnosis of dystonia.

Lancet Neurol 2006;5:780–90.

47. Taylor N, Bramble D. Sleep disturbance and Hun-

tingdon’s disease. Br J Psychiatry 1997;171:393.

48. Bianchetti A, Scuratti A, Zanetti O, et al. Predictors

of mortality and institutionalization in Alzheimer

disease patients 1 year after discharge from an Alz-

heimer dementia unit. Dementia 1995;6:108–12.

49. WiegandM,MollerAA,LauerCJ, etal.Nocturnal sleep

in Huntington’s disease. J Neurol 1991;238:203–8.

50. Hansotia P, Wall R, Berendes J. Sleep disturbances

and severity of Huntington’s disease. Neurology

1985;35:1672–4.

51. Arnulf I, Nielson J, Lohmann E, et al. Rapid eye

movement sleep disturbances in Huntington’s

disease. Arch Neurol 2008;65:482–8.

52. Videnovic A, LeurganS, FanW, et al. Daytime somno-

lenceandnocturnal sleepdisturbances inHuntington

disease. Parkinsonism Relat Disord 2009;15:471–4.

53. Emser W, Brenner M, Stobere T, et al. Changes in

nocturnal sleep in Huntington’s and Parkinson’s

disease. J Neurol 1988;235:177–9.

54. Bollen EL, Den Heijer JC, Ponsioen C, et al. Respira-

tion during sleep in Huntington’s chorea. J Neurol

Sci 1998;84:63–8.

55. Banno K, Hobson DE, Kryger MH. Long-term treat-

ment of sleep breathing disorder in a patient with

Huntington’s disease. Parkinsonism Relat Disord

2005;11:261–4.

56. Aziz NA, Anguelova GV, Marinus J, et al. Sleep and

circadian rhythm alterations correlate with depres-

sion and cognitive impairment in Huntington’s

disease. Parkinsonism Relat Disord 2010;345:350.

57. Morton AJ, Wood NI, Hastings MH, et al. Disintegra-

tion of the sleep-wake cycle and circadian timing in

Huntington’s disease. J Neurosci 2005;25:157–63.

58. Pallier PN, Morton AJ. Management of sleep/wake

cycles improves cognitive function in transgenic

mouse model of Huntington’s disease. Brain Res

2009;1279:90–8.

59. Aziz NA, Pijl H, Frolich M, et al. Delayed onset of the

diurnal melatonin rise in patients with Huntington’s

disease. J Neurol 2009;256:1961–5.

60. Evers S, St}ogbauer F. Genetic association of Hun-

tington’s disease and restless legs syndrome? A

family report. Mov Disord 2003;18:225–7.

61. Savva E, Schnorf H, Burkhard RP. Restless legs

syndrome: an early manifestation of Huntington’s

disease? Acta Neurol Scand 2009;119:274–6.

62. 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;59:1553–62.

63. Petersen A, Gil J, Maat-Schieman ML, et al. Orexin

loss in Huntington’s disease. Hum Mol Genet 2005;

14:39–47.

64. Meier A, Molenhauer B, Cohrs S, Rodenbeck A,

et al. Normal hypocretin-1 (orexin-A) levels in the

cerebrospinal fluid of patients with Huntington’s

disease. Brain Res 2005;1063:201–3.

65. Gaus SE, Ling L, Mignot E. CSF hypocretin levels

are normal in Huntington’s disease patients. Sleep

2005;28:1607–8.

66. Nutt JG, Muenter MD, Aronson A, et al. Epidemi-

ology of focal and generalized dystonia in Roches-

ter, Minnesota. Mov Disord 1988;3:188.

67. Hanson M. Use of chemodenervation in dystonic

conditions. Cleve Clin J Med 2012;79:S25–9.

68. Paus S, Gross J, Moll-Muller M, et al. Impaired sleep

quality and restless legs syndrome in idiopathic

focal dystonia: a case controlled study. J Neurol

2011;258:1835–40.

69. Avanzino L, Martino D, Marchese R, et al. Quality of

sleep in primary focal dystonia: a case control study.

Eur J Neurol 2010;17:576–81.

70. Miller KM, Okun MS, Fenandez HF, et al. Depression

symptoms in movement disorders: comparing Par-

kinson’s disease, dystonia, and essential tremor.

Mov Disord 2007;22:666–72.

71. Buysse DJ, Reynolds CF, Monk TH, et al. The Pitts-

burgh Sleep Quality Index: a new instrument for

psychiatric practice and research. Psychiatry Res

1989;28:193–213.

72. Olson LG, Cole MF, Ambrogetti A. Correlations

among Epworth sleepiness scale scores, multiple

sleep latency tests and psychological symptoms.

J Sleep Res 1998;7:248–53.

73. Sforza E, Montagna P, Defazio G, et al. Sleep and

cranial dystonia. Electroencephalogr Clin Neurophy-

siol 1991;79:166–9.

74. Jankel WR, Allen RP, Nedermeyer E, et al. Polysom-

nographic findings in dystonia musculorum defor-

mans. Sleep 1983;6:281–5.

75. Lobbezoo F, Thu Thon M, Remillard G, et al. Rela-

tionships between sleep, neck muscle activity and

pain in cervical dystonia. Can J Neurol Sci 1996;

23:285–90.