Shortest 0,4 minutes Longest 18,9 minutes Fig. 30.3 Polysomnogram for the subject in Case 30.4. MT, large body movements; S1 \200\223 S4, stages 1 \200\2234 of non-REM sleep; LM, leg movement. although some imaging studies have demonstrated reduced putam- inal D2 postsynaptic recepto r density (30), recently confi rmed by post-mortem data (31). Th e latter study also implie d that there were signifi cantly higher levels of phosphorylated tyrosine hydrox- ylase, pa radoxically suggestive of increased dopamine turnover. Th is counter-intuitive fi nding may explain the reduced levels of postsynaptic dopamine receptors as a result of \200\230down regulation \200\231. Of potential relevance, rodent models of iron defi ciency have shown s imilar dynamic changes in dopaminergic pathways (32). Furthermore, there were striking and enhanced diurnal changes in brain dopamine levels in the iron-defi cient mice such that, du r- ing the active period, extracellular striatal levels were particularly high (32). In the presence of reduced postsynaptic receptor density, the relative underactivity of the dopam inergic pathways in the rest period might produce a functional dopamine defi ciency and hav e relevance for the human condition. appears increased. Together with the observation that mitochon- dria numbers overall are si gnifi cantly increased in the substantia nigra neurons of RLS subjects, it has been propose d that there is a cellular response resembling that seen in hypoxia (35). Th is may produce increased dopamine turnover, as seen in animal models of simple iron defi ciency, and poss ibly a relative dopamine defi ciency during the evening to explain the diurnal pattern of R LS symp- toms. Th e ultimate reason why RLS patients may have altered brain iron handling e ven when peripheral stores are superfi cially normal remains elusive. A strong association of three genetic loci with RLS and PLM prevalence was discovered throu gh several genome-wide searches in a range of geographical populations (36). Perhaps disapp oint- ingly and contrary to expectations, none of the likely gene products appeared to have direct involvement in either iron or dopamine metabolism. In fact, the relevant single-nuc leotide polymorphisms (SNPs) were intronic or intergenic, strongly suggesting a regulatory role in neural development, perhaps in the spinal cord. However, intriguingly and through a n unknown mechanism, one of the loci (BTBD9) did seem to correlate directly with low levels of serum ferritin and was particularly seen in subjects with PLMs rather than isolated RLS without PLMs (37). Remarkably, at least in European Accumulating evidence appears to suggest that alterations in brain iron handling are import ant, even in those with primary or idio- pathic RLS. For example, both imaging and limited post-mortem data imply reduced brain iron stores and lower CSF levels of ferritin than expe cted in seemingly idiopathic cases (31, 33, 34). Although cytosolic levels of ferritin are reduced, mitochondrial ferritin Oxford Textbook of Movement Disorders 332 populations, the population attributable risk of RLS for the BTBD9 marker was 50%. In other words, in the absence of this polymorphism, the number of clinical cases would be expected to halve. stereotyped and may produce either fl exion or extension move- ments of trunk and limbs. Th e jerks superfi cially resemble startle refl exes (46) although, unlike these, asymmetry o f limb movements is commonly observed. Generally, these wake \200\223sleep transition phe- nomena are infrequent and more likely to occur in a sleep-deprived young population, potent ially aggravated by caff eine excess. If events are captured during sleep investigations, b rief autonomic and EEG arousals usually follow the jerks but sleep onset occurs normally th ereaft er and there are no adverse clinical consequences. Treatment It is mandatory to address and possibly treat reversible conditions that may be c ausing or fueling signifi cant symptoms of RLS and PLMs. Th e most common is iron defi cien cy even in the absence of frank anemia. By consensus, iron replacement is recommended if se rum ferritin levels are less than 45 g/L (38), although any sub- sequent clinical respons e to oral iron is usually slow. Furthermore, drugs such as neuroleptics, antihistamines, an d the majority of com- monly used antidepressants, namely SSRIs and tricyclics, should be d iscontinued if possible as they frequently exacerbate symptoms. Anecdotally, excessive caff eine or chocolate can also worsen RLS. Rarely, sleep starts may be frequent or dramatic enough to cause signifi cant insomnia (1), especially if they recur through the night at each sleep \200\223wake transition. Occasion ally, myoclonic seizure activity may be mistakenly suspected (47). Anxiety secondary to the sleep starts may also fuel the subject \200\231s inability to fall asleep. Furthermore, a minority of subjects experience prominent audi- tory or even visual phenomena, occasionally in the absence of any motor phenomena or myoclonic movements (48). Sensory descrip- tions of \200\230bangs \200\231, \200\230shocks \200\231, or even \200\230explosions \200\231, usually in the head, are typical. Understandably, these can produce concern and require re assurances that they are not due to epilepsy or cerebral vascular pathology. If there are no obvious remediable factors and clinical symptoms are deemed severe or frequ ent enough to warrant drug therapy, dopamine agonists are considered fi rst-line agents (39 ). Although levodopa is oft en eff ective, its use is reserved for occasional or intermitte nt RLS symptoms, given the high risk of augmentation (39). In this phenomenon, symptoms are experienced earlier in the day than previously and are more severe, frequently with spread to other body parts such as the upper limbs. However, augmentation can also be seen with d opamine agonists, and an increasing trend is to use long-acting preparations such as the tr ansdermal dopamine patch, rotigotine, in an attempt to minimize the problem (40). Dopamine agonist doses are typically much lower than those used in Parkinson \200\231s disease altho ugh standard side eff ects, including the development of impulse control disorders, need to be continually monitored (41). Because of their benign nature, systematic studies of sleep starts are minimal and their pa thophysiology is poorly understood. Th ey usually arise from early stage I sleep and may be preceded by a ver- tex sharp wave or K-complex (49). Th ere is brief generalized EMG activ ation which many assume refl ects activation of the descending audiogenic startle refl ex p athways from the brainstem. Th e return of an alpha rhythm on the EEG refl ects cortical ar ousal. At a sim- plistic level, sleep starts probably refl ect a temporary fault in the usu ally smooth transition from wake to sleep such that part of the brain fails to \200\230fal l asleep \200\231 and an alerting brainstem mechanism is subsequently activated when this m ismatch is detected. An inter- esting and somewhat bizarre probably related phenomenon, the \200\230blip syndrome \200\231, has been described in which subjects suddenly feel as tho ugh only part of their brain has lost consciousness when drowsy (50). Th is brief disconcer ting phenomenon probably rarely comes to medical attention but may also refl ect a partial failure of smooth transition from wake to light sleep. In the absence of signifi cant controlled evidence or data, second-line therapies can be us ed as either alternatives or supple- ments to dopaminergic agents (39). Th ese include gaba pentin or pregabalin at standard doses, which may be particularly helpful if the dysaesthet ic component of the RLS symptomology is promi- nent. Some authorities recommend long-acting opiates such as methadone as an alternative, although side eff ects and concerns over depe ndency oft en limit this approach (42). Sleep starts rarely necessitate drug therapy unless there is result- ing signifi cant insom nia. In such cases, brief courses of routinely used hypnotic agents such as short-acting be nzodiazepines are usu- ally eff ective, although controlled trials are lacking. Extremely severe or resistant cases may become tolerant to standard therapies and pose a si gnifi cant management problem. Anecdotal evidence suggests that it may be worthwhile using apomorphine infusions through the evening and overnight (43), potentially with other more c onventional treatments during the aft ernoon or even morning, if required. Although there a re poten- tial concerns regarding severe allergic reactions that necessitate strict adminis tration protocols, infusions of intravenous iron can also be eff ective in resistant RLS su bjects even in the absence of obvious iron defi ciency (29). It appears that the precise fo rmulation may be important (44). In particular, iron dextran is probably the most likely to increase brain iron levels as a putative mechanism of symptom relief that may last for sev eral months (45). Propriospinal myoclonus at sleep onset Th e term \200\230propriospinal myoclonus \200\231 (PSM) was introduced in 1991 to describe non-rhythmic axial jerks causing symmetric fl exio n of the neck, trunk, and lower limbs in three index cases (51). Detailed electrophysiology implied that the movements were caused by elec- trical discharges arising from a spinal \200\230pattern \200\231 generator with spread both rostrally and caudally via relatively s low (<5 m/s) pathways presumed, from animal evidence, to be in the long propriospinal tract s. In some subjects, there are long-duration bursts (100 \200\223300 ms) of EMG activity ca using repetitive jerks with a frequency of 1 \200\2237 Hz (52). Subsequent reports of the p henomenon have empha- sized the important roles of body position and behavioral state. In p articular, PSM was observed to be much more common when the subject was recumbent and extre mely drowsy, at the point of sleep onset (53). Indeed, when the movements are confi ned to the Sleep starts Th e majority of people will recognize or recall infrequent mildly unsettling episodes of abrupt generalized jolts occurring just at the point of sleep onset. Th e sensa tion is oft en likened to briefl y \200\230fall- ing through space \200\231. Phenotypicall y, these myoclonic jerks are not CHAPTER 30 Sleep-Related Movement Disorders 333 wake \200\223sleep transition, it can be considered a parasomnia, adversely aff ecting slee p onset and altering subsequent sleep structure. In this situation, it is commonly observed that mental activity, voluntary movements of the limbs and indeed sleep itself can all sup press the myoclonic movements. Rarely, as seen in other forms of myo- clonus, PSM appears t o be stimulus sensitive, triggered variously by sudden noises or external tactile stimulati on to either the back or the abdomen (54). umbilicus syndrome \200\231, \200\230belly dancer \200\231s dyskinesia \200\231, or \200 \230diaphragmatic fl utter \200\231, appear as diff erent phenomena to PSM. In these, the a ff ected muscles demonstrate irregular or writhing contractions at high rates of 30 \200 \22390 per minute. PLMs, although fairly frequently seen in relaxed wakefulness, invariably start in the distal musculature and, in stark contrast to PSM, predominate during non-REM sleep. However, when PLMs are associated with restless legs syndrome they may co-exist with PSM (58). A variety of spinal cord pathologies, including trauma, have been reported to trigger or pr ecipitate PSM, oft en with consider- able delay in symptom onset aft er the presumed primar y pathol- ogy (55). Although the majority of cases have normal conventional spinal cord MRI , one recent review suggests that detailed diff usion tensor imaging may reveal subtle diso rganization of white matter tracts in the majority of cases (56). Th e surprising demonstration that the characteristic EMG pattern of muscle activation ascr ibed to PSM can be identically observed in healthy volunteer subjects asked to mimic the ax ial myoclonic movements has led some to question the organicity of PSM in oth- erwise typic al cases (59). Th e disappearance of PSM with mental distraction and sleep onset might also suggest a psychological aeti- ology. Indeed, a striking 34 of 35 consecutive patients with possible PSM referred to a Dutch tertiary movement disorders service were ultimately diagn osed with a psychogenic movement disorder (60). Clinical clues pointing to a functional dis order were the presence of a Bereitschaft spotential prior to movements, regular eye blinki ng, sustained eye gaze, or head movements in association with axial jerks, or inconsistent polygraphic fi ndings over prolonged record- ing. In addition, the fact that some subjects with PSM report a pre- monitory \200\230inner tension \200\231 or \200\230shock-like \200 \231 sensation just prior to the movements might suggest an adult-onset tic disorder, espec ially if there are associated vocalizations or rebound phenomena aft er movement suppressio n (56, 61). Confi rming PSM by investigation can be laborious and requires signifi cant resources as fu ll video-polysomnography is required to demonstrate the specifi c association of the moveme nts with the drowsy state (53, 57). In addition, numerous EMG electrodes situated at 2-cm i ntervals along the bellies of involved muscles are advocated in order to document the slow spread of EMG activa- tion from a putative spinal source, usually in the mid-thoracic regio n (Fig. 30.4). Th e pattern of propagation, absence of a cortical pre-movement potential, a nd lack of involvement of cranial mus- cles all distinguish PSM from other disorders such a s cortical and reticular refl ex myoclonus. Intensifi ed hypnic jerks or sleep starts may mimic PSM, especially when they result in sig nifi cant sleep-onset insomnia. However, they usually involve isolated body segments and do not primarily aff ect the abdominal musculature. Focal abnormal involuntary movements of t he abdominal wall, variously described as \200\230moving Not surprisingly, given the rarity of PSM, evidence for eff ect- ive clinical management is very limited. Even in the absence of clinical signs of spinal cord pathology, it is probab ly appropriate to image cervical and thoracic regions, as benign unsuspected lesions have r arely been reported as likely precipitants (62). PSM tends not to improve spontaneously and can produce severe insomnia, warranting drug therapy. Clonazepam before bedtime has been u sed with variable success, and anecdotal evidence sug- gests that the antiepileptic agent z onisamide may occasionally help in resistant cases (59). Other agents that have been report ed to be helpful are gabapentin (up to 800 mg/day), levetiracetam (up to 2000 mg/day), and carbamazepine (up to 400 mg/day) (52, 53). Transcutaneous electrical nerve stimulation (TEN S) applied to an area supplied by the low-thoracic spinal level has been reported to be use ful in a middle-aged man with probable PSM (63). Rectus abdominis T7-T8 200 V Rectus abdominis T9-T10 100 V Rectus abdominis T11-T12 100 V Rhythmical movement disorder of sleep Sleep-related rhythmic movement disorder (RMD) is a r elatively poorly researched phenomenon that is most commonly seen at the wake \200\223sleep transition, although it can occur in drowsy wakefulness or, surprisingly given its nature, during any stage of sleep includ- ing REM sleep (64 \200\22366). Occasionally it can be se en in association with partial arousals from sleep (65). RMD is characterized by a variety of sustained stereotypic movements involving the major muscle groups. Th e cadence of movem ents is strikingly regular at a frequency of 0.5 \200\2232 Hz. Typical movements include he ad rolling or banging, axial rocking, and even rhythmical striking of the head with the han ds. Some subjects exhibit more than one type of RMD, depending on body position during slee p (67), with vigorous head rolling most commonly seen in the prone position. Synchronous hu mming or moaning is not uncommon, although subsequent Iliopsoas 200 V Vastus lateralis 100 V Gastrocnemius 100 V 100 ms Fig. 30.4 A neurophysiological demonstration of a typical axial jerk of a subject with prop riospinal myoclonus at sleep onset. Using a number of EMG electrodes spaced across several myotomes, the electrical discharge is seen to spread proximally and distally from a presume d spinal source that innervates the iliopsoas muscle. Conventional MRI of the subject \200 \231s cervical and thoracic spinal cord was normal. Oxford Textbook of Movement Disorders 334 recollection of such activity is usually absent. It is relatively rare for RMD to be of maj or concern to the subjects themselves and, cer- tainly in adults, it is the bed partner who se sleep is predominantly disturbed, especially since the movements can continue for period s of 30 minutes or so. Th e prototypical RMD, namely head banging, was fi rst described in children in 1905 indepe ndently by German and French work- ers who coined the terms jactatio capitas nocturna and t ics dans le sommeil , respectively (see ref. 68 for a historical review). Head banging is c ommon and may aff ect up to 5% of young children (69). It is seen more oft en in males and is more persistent if there is developmental disability, in which case similar rocking move - ments may also be witnessed during wakefulness. Indeed, many adult subjects may exhibit s imilar patterns of movement in quiet wakefulness, such as when listening to music. Secondar y injuries are very rare although soft tissue damage or dermal scarring has been reported. Body rocking is even more prevalent as a rhyth- mic movement of sleep (around 15% of young children), but is rarely perceived as a problem and usually resolves before 5 years of age (70). In children, an association of RMD with attention defi cit hyperactivity disorder has been reported, although sample sizes were small (71). z Video 30.4 A clip of Case 30.5 demonstrating an unusual form of rhythmical movement disor der of sleep in a narcoleptic patient (see text for full details). If treatment is thought necessary, benzodiazepines such as clonazepam have been used, but o nly with limited success (74). Behavioral therapies including hypnosis have also been studi ed in small series (75). In children, some have advocated techniques such as sleep restrict ion and, perhaps more intriguingly, the use of a water bed (76). In a minority of subjects, RMD persists into adulthood, although prevalence fi gures are di ffi cult to establish as it is relatively rare for the phenomenon to present to a sleep cli nic. Of interest, in adults movements may be more varied and can be seen even in deep non-R EM sleep, or even REM sleep when all signifi cant movements would normally be suppressed (7 2). Th e diagnosis is usually clear simply from a video recording without the need for deta iled poly- somnography (Case 30.5). However, investigations may sometimes usefully demonstr ate a degree of sleep disruption or an association of RMD with other sleep disorders such a s periodic limb move- ments or apnoea-induced arousals. Sleep-related bruxism Sleep bruxism (SB) is probably an exaggerated form of normal masticat ory movements or \200\230chewing automatisms \200\231 commonly wit- nessed during sleep, w ith additional tooth grinding as a potentially troublesome feature. Well over 50% of normal subjects will have episodes of rhythmic masticatory muscle activity, defi ned as three or more consecutive rhythmic contractions at 1 Hz frequency, once or twice an hour during slee p (77). Th ese contractions are sustained or phasic, in which case the disturbing sounds of tooth-grinding occur. Although SB has a prevalence of around 8% in adults (78), many subje cts are unaware that they grind their teeth at night and the bed partner is the main compla inant. However, excessive tooth wear, dental or temporomandibular pain, and a strong associ a- tion with migrainous and other headache syndromes are frequent observations. Of note, to oth grinding has been seen in over 50% of children diagnosed with tension-type headaches (7 9). Th e mechanisms behind RMD remain obscure although a vari- ety of behavioral or psychologic al theories have been espoused, especially for childhood forms. A form of anxiety relief ha s been thought likely even if there is no overt psychopathology (73). Of possible relevance , RMD, like many sleep disorders, usually wors- ens during stressful periods. However, most authorities regard RMD as a \200\230tic-like \200\231 phenomenon or simply as a \200\230 bad habit \200\231 which may be under partial voluntary control, at least in the early stag es. Case 30.5 Th e wife of a 35-year-old man with narcolepsy and cataplexy complained that he m oved continuously for several minutes prior to sleep onset, disturbing her. Th is could rec ur through the night in association with spontaneous arousals and his attempts to return to sleep. Th e subject was not particularly concerned by these movements and thought that the y had devel- oped as a comforting \200\230reaction \200\231 to frequent unpleasant percep- tions that a stranger was in the room as he entered sleep from drowsiness \200\224so-calle d extra-campine hallucinations, a phenom- enon occasionally reported in narcolepsy. Secondary SB has been associated with a wide variety of medica- tions and drugs of abuse, i ncluding most psychoactive agents and central stimulants. SSRIs and haloperidol have been m ost strongly implicated (80). Not surprisingly, hyperkinetic disorders, such as generalized dystonia and Huntington \200\231s disease, have also been linked to signifi cant SB (81). Furthermore, SB tends to worsen when sleep patterns are non-specifi cally poor, either in t he context of psychological distress or when there are frequent arousals due to obstructive sleep apnoea for example. It is rare for SB itself to trigger a full arousal from sleep, a nd it seems that the jaw activity is simultanous or secondary to EEG arousals (82). In gene ral, SB also appears to be more common in those with hypervigilant or highly motivated pers onalities (83). Video 30.4 shows him attempting to sleep, with an increas- ing frequency of lateral rhythmi c movements involving his trunk and head occurring in the drowsy state. No treatment was th ought necessary for this phenomenon which was characteristic of rhythmic movement disorder of sleep. Not infrequently, SB is picked up incidentally on polysomno- graphic recordings as a 1 Hz i nterference or movement artifact CHAPTER 30 Sleep-Related Movement Disorders 335 Hypnagogic foot tremor Hypnagogic foot tremor (HFT) and the related phenomenon alter- natin g leg muscle activation (ALMA) represent further benign movement disorders commonly witness ed in subjects who are drowsy or in light sleep (1). Although oft en overlooked, regular do rsifl exion of either one foot or both feet in alternation with a frequency of 1 \200\2232 Hz may be seen as incidental fi ndings in around 5% of polysomnograms, usually around the s leep \200\223wake transi- tion (1, 14). Rarely, these movements may disturb the bed partner , but usually they are viewed as somewhat curious or even amusing phenomena, potentially si milar in nature to rhythmical movement disorders of sleep, simply requiring reassurance and no active treatment. seen throughout the EEG traces. Episodes last between 0.25 and 2 seconds, occurring at inte rvals of 3 seconds or more. For a specifi c diagnosis of SB, contemporaneous audio recordin gs are strongly recommended, as are extra EMG electrodes in either masseter or temporalis m uscles alongside the standard submental lead (14). Somewhat arbitrarily, SB can be diagnose d if there are at least four episodes per hour or at least 25 individual muscle bursts per hour of sleep (1). Th e EMG activity also needs to be accompa- nied by at least two episode s of teeth-grinding noises. Typically, subjects are symptomatic between three and fi ve nig hts a week over a period of months. Masseter muscle hypertrophy may be observed in severe c ases. SB is seen mostly in light non-REM sleep, although some subjects seem particularly af f ected at sleep stage transitions, particularly from light non-REM sleep to REM sleep (84) . Key points If SB is deemed signifi cant, most would advocate the use of soft or hard occlusal applianc es. Mandibular advancement devices may also provide benefi t and have the added advantage o f improving snoring or any associated obstructive breathing-related disorder (85). Orthodon tic procedures probably do not help SB specifi cally but can limit any potential secondary tooth damage. Various drug treatments have been studied in small randomized trials, usually with negative results. Examples include propranolol and a vari- ety of antidepressants suc h as tricyclics and serotonergic agents (86). Muscle relaxants, including benzodiazepines a nd botuli- num toxin, have not been studied systematically. Of interest, the alpha-2-agonis t, clonidine, appeared to reduce SB by 60% in a small study, although early morning hypoten sion was seen in some sub- jects as a limiting side eff ect and REM sleep was strongly inhi bited in most (87). Normal sleep is associated with changes in body position approx- imately every 15 minutes. Minor myoclonic movements of the face and extremities can also occur in any sleep stage. \227\206 Periodic limb movements are frequently seen in the elderly, usu- ally as incidental phenome na. Th ey are also present in the vast majority of subjects with restless legs syndrome and appear to respond to the same drug treatment strategies. Dopaminergic agents are considere d the fi rst-line therapy if symptoms are severe and likely to be disturbing sleep continui ty. \227\206 Startling and unusual sensory phenomena may accompany sleep onset and cause insomnia, somet imes justifying short-acting hypnotic drug therapy. \227\206 Head banging or body rocking when very drowsy and at the point of sleep onset is common in infancy and sometimes persists into adulthood, when it may occur during both non-REM and RE M sleep stages. Th e rhythmical movements rarely disturb the sub- ject but can adversely af f ect the bed partner \200\231s sleep continuity. \227\206 Fragmentary myoclonus Infrequent small \200\230quivering \200\231 movements of the mouth o r extremi- ties, particularly during sleep, are physiological and of no clinical signifi ca nce. However, in some individuals, the frequency of these minor movements can appear striki ng and the term \200\230excessive fragmentary myoclonus \200\231 (EFM) has been used (1). When studied systematically, it appears that the frequency of such movements during sleep i s inversely related to the degree of EEG synchro- nization, such that stage I non-REM and R EM sleep have the highest incidence. Th e EMG potentials are very brief (75 \200\223150 ms) and occur both asynchronously and asymmetrically, most oft en in the extremities. If there are more than fi ve minor jerks per minute continuously for more than 20 minutes, it may b e deemed excessive. Sleep bruxism is common and oft en overlooked. Apart from causing excessive tooth wear, it may fuel headache syndromes and disturb sleep maintenance. Dental occlusal devices are usua lly eff ective. \227\206 References 1. International Classifi cation of Sleep Disorders (Diagnostic and Coding Manua l) (2nd edn). Westchester, IL: American Academy of Sleep Medicine, 2005. 2. Ashkenazy JJM, Yahr MD . Parkinsonian tremor loses its alternating aspect during non-RE M sleep and is inhibited by REM sleep. J Neurol Neurosurg Psychiatry 1990; 53 : 749 \200 \2235 3 . EFM is a controversial entity since the relationship with either sleep disruption or any co nsequent daytime somnolence is far from established. In a detailed study of 11 subjects, co mpared with a control group, an index of fragmentary myoclonus was calculated throughout th e sleep cycle (88). 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