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Clin Rheumatol 2007; 26 : 2145 \200\2237 . encephalitis.] Rinsho Shinkeigaku 2008; 48 : 920 \200\2232 . 21. Irani SR, Bera K, Waters P, et al. N -methyl- d -aspartat e antibody encepha- litis: te mporal progression of clinical and paraclinical observations in a predominantly non-paraneo plasti c disorder of both sexes. Brain 2010; 133 : 1655 \200\2236 7 . 46. Garcia-Moreno JM, Chacon J. Juvenile parkinsonism as a manifestation of systemic lupus erythematosus: case report and review of the literature. Mov Disord 2002; 17 : 1329 \200 \2233 5 . 22. Florance NR, Davis RL, Lam C, et al. Anti- N -methyl- d -aspartat e recep- tor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009; 66 : 11 \200\22318 . 47. Orzechowski NM, Wolanskyj AP, Ahlskog JE, et al. Antiphospholipid antibody-associate d chorea. J Rheumatol 2008; 35 : 2165 \200\2237 0 . 48. Cervera R, Piette JC, Font J, et al. 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Cunnah D, Chew S, Wass J. Cyclosporin for central nervous system sar- coidosis. Am J Med 1988; 85 : 580 \200\2231 . 61. Swanson JW, Kelly JJ, Jr, McConahey WM. Neurologic aspects of thyroid 89. Ferrara J, Jankovic J. Acquired hepatocerebral degeneration. J Neurol dysfunction. Mayo Clin Proc 1981; 56 : 504 \200\2231 2 . 2009; 256 : 320 \200\2233 2 . 62. Fischbeck KH, Layzer RB. Paroxysmal choreoathetosis associated with 90. Burkhard PR, Delavelle J, Du Pasquier R, et al. Chronic parkinsonism associated with ci rrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch Neurol 2003; 60 : 521 \200\2238 . thyrotoxicosis. Ann Neurol 1979; 6 : 453 \200\2234 . 63. Klawans HL, Jr, Shenker DM. Observations on the dopaminergic nature of hyperthyroid chorea. J Neural Transm 1972; 33 : 73 \200\2238 1 . 91. Aggarwal A, Vaidya S, Shah S, et al. Reversible Parkinsonism and T 1 W pallidal hyperin tensities in acute liver failure. Mov Disord 2006; 21 : 1986 \200\2239 0 . 64. Harayama H, Ohno T, Miyatake T. Quantitative analysis of stance in ataxic myxoedema. J Neurol Neurosurg Psychiatry 1983; 46 : 579 \200\2238 1 . 65. Athappan G, Ariyamuthu VK. Ima ges in clinical medicine. Chvostek \200\231s 92. Powell EE, Pender MP, Chalk JB, et al. Improvement in chronic hepa- tocerebral degenera tion following liver transplantation. Gastroenterology 1990; 98 : 1079 \200\2238 2 . sign and carpopedal spasm. N Engl J Med 2009; 360 : e24 . 66. Sachs C, Sjoberg HE, Ericson K. Basal ganglia calcifi cations on CT: rela- 93. Albers JW, Nostrant TT, Riggs JE. Neurologic manifestations of gas- tion to hypoparathyroidism. Neurology 1982; 32 : 779 \200\2238 2 . trointestinal disease. Neurol Clin 1989; 7 : 525 \200\2234 8 . 67. Kaminski HJ, Ruff RL. Neurologic complications of endocrine diseases. 94. Mostile G, Jankovic J. Alcohol in essential tremor and other movement Neurol Clin 1989; 7 : 489 \200\22350 8 . disorders. Mov Disord 2010; 25 : 2274 \200\2238 4 . 68. Christiansen NJ, Hansen PF. Choreiform movements in hypoparathy- 95. Brust JC. Substance abuse and movement disorders. Mov Disord 2010; roidism. N Engl J Med 1972; 287 : 569 \200\2237 0 . 25 : 2010 \200\2232 0 . 69. Barabas G, Tucker SM. Idiopathic hypoparathyroidism and paroxysmal 96. Shandling M, Carlen PL, Lang AE. Parkinsonism in alcohol withdrawal: dystonic choreoathetosis. Ann Neurol 1988; 24 : 585 . a follow-u p study. Mov Disord 1990; 5 : 36 \200\2239 . 70. Newman RP, Kinkel WR. Paroxysmal choreoathetosis due to hypoglyc- 97. Neiman J, Lang AE, Fornazzari L, et al. Movement disorders in alcohol- emia. Arch Neurol 1984; 41 : 341 \200\2232 . ism: a review. Neurology 1990; 40 : 741 \200\2236 . 71. Rector WG, Jr, Herlong HF, Moses H 3rd. Nonketotic hyperglycemia appearing as choreoath etosis or ballism. Arch Intern Med 1982; 142 : 154 \200\2235 . 98. Yokota O, Tsuchiya K, Terada S, et al. 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Paroxysmal dyskinesias in patients with HIV infection. Neurology 1999; 52 : 109 \200\2231 4 . 102. Cornford ME, Holden JK, Boyd MC, et al. Neuropathology of the acquired immune defi cie ncy syndrome (AIDS): report of 39 autopsies from Vancouver, British Columbia. Can J Neurol Sci 1992; 19 : 442 \200\2235 2 . 75. Lin JJ, Chang MK. Hemiballism \200\223hemichore a and non-ketoti c hypergly- caemia. J Neurol Neurosurg Psychiatry 1994; 57 : 748 \200\2235 0 . 76. Nabatame H, Nakamura K, Matsuda M, et al. Hemichorea in hypergly- cemia associated with increased blood fl ow in the contralateral striatum and thalamus. Intern Med 1994; 33 : 47 2 \200\2235 . 103. Hriso E, Kuhn T, Masdeu JC, et al. Extrapyramidal symptoms due to dopamine-blockin g a gents in patients with AIDS encephalopathy. Am J Psychiatry 1991; 148 : 1558 \200\2236 1 . 77. Sitburana O, Ondo WG. Tetrabenazine for hyperglycemic-induce d 104. Cardoso F. Infectious and transmissible movement disorders. In: Jankovic J, Tolosa E ( eds) Parkinson \200\231s disease and movement disorders (3rd edn), pp. 945 \200\22366 . Bal timore, MD : Williams & Wilkins , 1998 . 105. Church AJ, Cardoso F, Dale RC, et al. Anti-ba sa l ganglia antibodies in acute and persistent Sydenham \200\231s chorea. Neurology 2002; 59 : 227 \200\2233 1 . hemichorea-hemiballismu s. Mov Disord 2006; 21 : 2023 \200\2235 . 78. Andermann E, Andermann F, Carpenter S, et al. Action myoclonus-re- na l failure syndrom e: a previously unrecognized neurological disorder unmasked by advances in nephrology. Adv Neurol 1986; 43 : 87 \200\22310 3 . 79. Raskin NH, Fishman RA. Neurologic disorders in rena l failure (second 106. Paz JA, Silva CA, Marques-Dias MJ. Randomized double-blin d study with prednisone in S ydenham \200\231s chorea. Pediatr Neurol 2006; 34 : 264 \200\2239 . of two parts). N Engl J Med 1976; 294 : 204 \200\2231 0 . 80. Stark RJ. Reversible myoclonus with uraemia. Br Med J (Clin Res Ed) 1981; 282 : 1119 \200\2232 0 . Oxford Textbook of Movement Disorders 326 111. Alarcon F, Maldonado JC, Rivera JW. Movement disorders identifi ed in 107. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neu- ropsychiatric disorde rs associated with streptococcal infections: clinical description of the fi rst 50 cases. A m J Psychiatry 1998; 155 : 264 \200\2237 1 . patients with intracranial tuberculomas. Neurologia 2011 ; 26 : 343 \200\22350 . 112. Schwa rtz MA, Selhorst JB, Ochs AL, et al. Oculomasticatory myorhyth- mia: a unique movement diso rder occurring in Whipple \200\231s disease. Ann Neurol 1986; 20 : 677 \200\2238 3 . 108. Kurlan R. Th e PANDAS hypothesis: losing its bite? Mov Disord 2004; 19 : 371 \200\2234 . 113. Desnues B, Al Moussawi K, Fenollar F. New insights into Whipple \200\231s disease and Tropheryma whipplei infections. Microbes Infect 2010; 12 : 1102 \200\2231 0 . 109. Singer HS, Gause C, Morris C, et al. Serial immune markers do not cor- relate with cli nical exacerbations in pediatric autoimmune neuropsy- chiatric disorders associated with st reptococcal infections. Pediatrics 2008; 121 : 1198 \200\22320 5 . 114. Senanayake N, de Silva HJ. Delayed cerebellar ataxia complicating falciparum malaria: a clinical study of 74 patients. J Neurol 1994; 241 : 456 \200\2239 . 110. Schrag A, Gilbert R, Giovannoni G, et al. Streptococcal infection, Tourette syndrome, and OCD: is there a connection? Neurology 2009; 73 : 1256 \200\2236 3 . 115. Garg RK, Karak B, Misra S. Neurological manifestations of malaria: an update. Neurol India 1999; 47 : 85 \200\2239 1 . CHAPTER 30 Sleep-related Movement Disorders Paul J. Reading Introduction As in many areas of sleep medicine, it is oft en a challenge deciding whether or not movements during sleep refl ect truly abnormal noc- turnal phenomenona or are simply physiological variants. Indeed, when asleep, subconscious shift s of body position occurri ng every 15 minutes or so are considered entirely normal, as are minor jerks of the extremi ties and face, particularly during periods of rapid eye movement (REM) sleep. However, if n octurnal movements are observed to be excessive, violent, or arousing, either to the subjec t or bed partner, they will usually indicate a defi ned disorder, espe- cially if the event s are stereotypic through the night. Although the second edition of the International Class ifi cation of Sleep Disorders (ICSD) was revised in 2005 (1) to include a new section dedic ated to movement disorders occurring specifi cally during the state of sleep, diagnostic pr ecision of such phenomena is oft en lacking and evidenced-based treatment protocols, when i ndicated, are poorly developed. Furthermore, if a sleep-related movement disorder is recogn ized, it can be very diffi cult to determine its true clinical signifi cance for sleep qual ity and subsequent daytime wakefulness, especially in the elderly patient. is discussed, partly because of its close association with periodic limb movements during s leep. Similarly, nocturnal epilepsy will not be addressed, and REM sleep behavior disorder is discussed in Chapter 9. Restless legs syndrome and periodic limb movements Restless legs syndrome (RLS) is best con ceived as a sensorimotor disorder, defi ned wholly by subjective symptoms and characterized predominantly by a strong urge to move the legs, particularly in the late evening (6). Th ere is nearly always associated limb discomfort that can be diffi cult both to describe and to localize. A common report is that of an unpleasant \200\230crawling \200\231 sensation under the skin around the shins. Symptomatic but temporary relief is obtained by moving or rubbing the aff ected limb(s). Th e adverse consequences on both sleep onset and maintenan ce are oft en severe (Case 30.1) and may lead to the potentially sterile debate of whether RLS is more a movement or a sleep disorder. In any event, RLS is common and aff ects around 3% of Caucasian populations when screened by personal interview using validated criteria ( 7). Given the rela- tively non-specifi c nature of these symptom-based diagnostic cri- teri a, self-completed questionnaires may lack diagnostic precision and have led to overestimate s of RLS prevalence in the past (8). Furthermore, there is clearly an extremely wide spectr um of RLS symptom severity and frequency with approximately 20% of sub- jects reporting cli nically signifi cant symptoms on more than two evenings each week, potentially justifying a ttempts at drug therapy (9). In severe or atypical cases, leg restlessness and discomfort m ay extend to other body parts, particularly the arms. With the exception of rare conditions such as palatal tremor or spinal segmental myoclonus, it is a common perception that the vast majority of \200\230waking \200\231 movement diso rders eff ectively disap- pear during sleep. Th is is only partly true, since parkinsonian tremor, for example, may persist into light non-REM sleep stages (2), as may dyskinesias (3 ), potentially contributing to impaired sleep maintenance and poor-quality nocturnal sleep. Moreover, most hyperkinetic movement disorders, such as Huntington \200\231s disease, are associated with generalized restlessness during sleep, again interfering with its quality, even at early disease stages (4). Perhaps counter-intuitively, motor tics and even vocaliza tions are seen throughout all stages of sleep in the majority of subjects with Tourette \200\231s syndrome (5). RLS aff ects females preferentially and there is an association with increasing age up unti l the eighth decade (10). However, RLS also aff ects children and, as such, is oft en unrec ognized in younger populations (11). A positive family history is frequently obtained, espe cially if symptom onset occurs before 40 years of age (12). However, this chapter will address those movement disorders that are intimately or exclusiv ely related to the state of sleep or the sleep \200\223wake transition. By convention, para somnias causing abnor- mal arousals from deep non-REM sleep, such as sleepwalking or night terrors, will not be covered, although restless legs syndrome Many subjects with RLS will also be aware of involuntary limb movements which may occur at regular intervals during the wakeful state, usually when drowsy or at the point of sleep on set. Oxford Textbook of Movement Disorders 328 Case 30.1 A 57-year-old graphic designer was referred with a 10-year history of \200\230re stless sleep \200\231 such that he was prone to \200\230wearing out \200\231 the bed sheet s, invariably waking in a report- edly exhausted state. On direct questioning, he admitted to an unpleasant sensation of \200\230creeping discomfort \200\231 in both shins that alwa ys came on at 8 p.m. and was relieved by vigorous rubbing or moving around the room. He was experiencing severe somno- lence at work, particularly in the mid-aft ernoon period. He wa s taking an opiate preparation for persistent shoulder pain which also improved his leg sym ptoms to some extent. Th ere was no relevant family history and no markers for iron defi ci ency in his routine blood tests. Case 30.2 A 40-year-old man was referred to the sleep clinic with a 2-year history of sever e excessive daytime sleepiness. A detailed sleep history failed to reveal any obvious cause for his somnolence, although he awoke aft er 8 hours of nocturnal sleep feeling unrefreshe d. He had no bed partner, but was not known to be a snorer and was not aware of excessive l eg movements dur- ing sleep. For several years, he reported mild and unobtrusive symptoms o f restless legs syndrome on one or two evenings a week. All routine blood tests were normal . His polysomnogram was abnormal and demonstrated dif- fi culty falling asleep and several ar ousals from deep non-REM sleep (Fig. 30.2). Of likely signifi cance, he exhibited numerous PLMs throughout the night which were thought to be adversely aff ecting his sleep quality. Video 30.1 shows a representative clip of his polysomnogram recording which demonstrates re gular leg movements at 26-second intervals typical for PLMs. His left leg appears particula rly involved as revealed by the EMG trace. Th e movements themselves appear quite subtle bu t are associated with micro-arousals on the EEG. A polysomnogram revealed sleep onset insomnia and an extremely high number of periodic limb movements when asleep (Fig. 30.1). He rarely entered deep non-REM sleep during the night o f recording, potentially explaining the unrefreshing nature of the nocturnal sleep period. He was started on a rotigotine patch (2 mg once daily) and made an excellent response in te rms of reducing his general rest- lessness and daytime somnolence. He responded well to dopamine agonist therapy, supporting the diagnosis of PLMD. However, these periodic limb movements (PLMs) are most fre- quently observed or noticed by bed partners during non-REM sleep in the fi rst third of the night and aff ect the vast maj ority of RLS subjects (Case 30.2). Most authorities consider the clinical phenomena of RLS and PLMs to share both a common underlying neurobiology and a potential for adverse health consequences (13). Phenotypically, PLMs usually resemble a slowed version of a with- drawal refl ex in a lower limb, starting with great toe and then foot dorsifl exion. Th e slow fl exor jerk may then extend to involve the knee and hip over 0.5 \200\2231 seconds, potentia lly leading to a more gen- eralized movement or arousal from sleep which may mimic sim- ple restlessness (Case 30.3). Th e duration of movements associated with a PLM may last up to 10 seconds, as recognized by recently modifi ed scoring criteria (14). Automated polysomnog rams using bilateral lower limb EMG monitors will usually record movements as PLMs if they recur with a precise periodicity (typically around 25 seconds) at least four times in succe ssion. PLMs can continue in clusters for several minutes, sometimes hours. An index of the number of PLMs per hour is oft en calculated, with severely aff ected subjects exhibiting l evels of 150 or more. Th e deeper the level of non-REM sleep, the longer the inter-movement interval tends to be (15). PLMs can also occur in REM sleep but are usually of shorter duration and less frequent. Th e striking and defi ning periodicity of PLMs remains unex- plained. Of possible relevanc e, as early as 1972 it was proposed there was an endogenous pacemaker to explain the appare nt subtle perio- dicity (20 \200\22340 seconds duration) of minor changes in several physi- ological measures such as heart rate and blood pressure (16). Th is comparison has intuiti ve appeal given the observation that subtle EEG and ECG changes may precede the actual obse rved movement associated with a PLM (17). Th e location of any putative pacemaker needs to explain the presence of PLMs observed in patients with complete spinal transactions or sign ifi cant syringomyelia (18). Th e similarity of PLMs to an abnormal plantar (Babinski) resp onse has led to the suggestion that they arise due to diminished supraspinal inhibitory inf l uences (19). Of note, an extensor plantar response can be elicited in control subjects du ring normal non-REM sleep, suggesting that there may be an exaggeration of this observed ph e- nomenon in PLMs (20). Certainly, the relative lack of supraspinal inhibitory infl uences is supported by the observation that the spinal MT Wake REM S1 S2 S3 S4 PLM [1] LM [1] 00:00 01:00 02:00 03:00 04:00 05:00 Fig. 30.1 Polysomnogram for the subject in Case 30.1. MT, movement time; S1 \200\223S4, non -REM sleep stages 1 \200\2234; PLM, periodic limb movement; LM, leg movement. CHAPTER 30 Sleep-Related Movement Disorders 329 00:00 02:00 04:00 06:00 Arousal MT Wake REM S1 S2 S3 S4 Button Supine Left Prone Right Upright LM PLM Desat 100 90 80 70 60 SpO2 [%] 125 Pulse [bpm] 100 75 Snore high Snore low Fig. 30.2 Polysomnogram for the subject in Case 30.2. MT, movement time; S1 \200\223S4, non -REM sleep stages 1 \200\2234; PLM, periodic limb movement; LM, leg movement. PLMs are linked to micro-arousals, defi ned as a return to alpha or theta EEG activity for 3 \200\22315 seconds (22). However, this remains a controversial area, largely due to issue s around reliably scoring and defi ning these minor EEG changes (23). PLMs during sleep may also be observed in up to 30% of normal elderly populations, but are usually at a low level and have no likely clinical signifi cance (24). Indeed, a number of studies have failed to demonstrate a clear relation between the frequency of PLMs during th e night and reports of poor sleep quality or daytime somnolence, even when the PLMs are rep orted to have caused micro-arousals (25). Rarely, subjects are identifi ed with signifi can t and potentially arousing PLMs seen during sleep recordings in the absence of RLS, refl ec ting periodic limb movement disorder (PLMD). In such sub- jects, especially if there is no bed partner, PLMs may not be sus- pected from history alone even though sleep continuity is adversely aff ected and the deeper stages of non-REM sleep are poorly main- tained (Case 3 0.2). As a result, it is important to recognize and treat PLMD is it may rarely cause signi fi cant daytime somnolence. Furthermore, troublesome adult sleepwalking may sometimes be tr iggered by sleep disorders such as PLMD when subjects are par- tially aroused from deep slo w-wave non-REM sleep by their exces- sive limb movements (Case 30.4). z Video 30.1 A short clip showing Case 30.2 during his polysomnogram. Periodic limb movemen ts predominantly involving the left leg are demonstrated. fl exor refl ex has a lower threshold and a greater spatial spread in those with PLMs in th e context of RLS (21). PLMs during sleep can aff ect the sleep quality of bed partners but may well not be recogni zed or recalled by the subjects them- selves. When monitored, transient heart rate rises of t en coincide with PLMs, indicating minor associated autonomic arousals in the absence of d efi nite EEG changes. In general, up to a third of Pathophysiology Despite major recent advances in unraveling the complex genetics of RLS and associated PLMs, the precise underlying neurobiological basis remains elusive and most lik ely has several elements. Although Oxford Textbook of Movement Disorders 330 Case 30.3 A 42-year-old businessman was referred with a six- month history of disturbed sle ep. His wife reported virtually continuous non-specifi c movements throughout the sleep per iod involving all four limbs. He did not report waking through the night, but was unrefresh ed in the morning and experiencing severe fatigue during the day. However, he was able to a void nap- ping. He denied symptoms suggestive of restless legs syndrome in the evening or b efore bed. An overnight recording revealed that he was a heavy snorer in the absence of sleep apnoea o r signifi cant nocturnal oxygen desaturations. He spent the majority of the sleep period in light non-REM sleep and appeared to fi dget continuously. Th e auto- mated sleep analysis soft ware did not report any periodicity in the leg movements. Two representative video clips are shown (Videos 30.2 and 30.3). On the second clip, the in itial movement is seen to start with great toe extension, almost certainly refl ecting a fo rm of PLM. On detailed examination of his restlessness, it was apparent that many of the mo vements were preceded by great toe extension before more generalized movements that lasted for 10 seconds or more. z Video 30.3 A clip of Case 30.3 from later in the same night. Th is bout of generalized mo vement starts with extension of his great toe suggesting that he is exhibiting a form of ex tended arousal in the context of periodic limb movement disorder (see text for fuller expla nation). investigations revealed unexpected and severe iron-defi cient anemia (hemoglobin level was 5.2 g/L), subse- quently found to be secondary to slowly bleeding hemorrhoids. Appropriate treatment of these and a prolonged course of oral iron replacement restored his hemoglobin levels and led to complete resolution of his sleep problems. Routine Case 30.4 A 26-year-old marine with a long history of benign childhood sleepwalking caused concern to his colleagues when he started to experience agitated nocturnal disturbances on active duty in Iraq. On several nights during the week, within an hour of sleep onset, he r eportedly screamed and would run from the dormitory, oft en brandishing his army weapon. He also reported that his nocturnal sleep was generally unrefreshing, potentially fueling a m oderate degree of excessive daytime sleepiness. He denied symptoms of RLS although was awar e his legs may have moved excessively during sleep. In retrospect, during sleep, he was almost certainly exhibiting atypical PLMs which were ca using more generalized and pro- longed movements, refl ecting partial arousals. His severe iron defi ciency had almost certainly triggered the PLMD. His polysomnogram (Fig. 30.3) reveals an excess of light non-REM sleep (stage 2 occupies 71 % of total sleep time) and an extremely high number of leg movements throughout the night. Th e vast majority of these are periodic in nature and many appear to cause micro-arousals, most likely preventing him achieving deep non-REM sleep. On the few occasions he enters de ep sleep, he arouses abruptly to apparent wakefulness although appears confused. Th is feat ure refl ects his propensity for non-REM sleep parasomnia activity, his main symptom of con cern. Treatment of his PLMs with a dopamine agonist before bed improved his sleep quality and red uced both his parasomnia activity and daytime somnolence. or underactivity of dopaminergic pathways, perhaps in the small but extensive descending A1 1 projection from the hypothalamus to the spinal cord (27). Secondly, the link to iron depl etion or disorders of iron handling might suggest that there is actual or functional iron d efi ciency in specifi c parts of the brain (28). Certainly, intravenous iron infusions may be an eff ective treatment even in the absence of obvious systemic defi ciency (29). Th e f act that the rate-limiting enzyme for dopamine production in the brain, tyrosine hydroxy- l ase, requires iron as a co-factor has been proposed as a link between these two putative pa thophysiological mechanisms. z Video 30.2 A short clip early in the night of Case 30.3. He exhibits general \201 dgeti ng in light non-REM sleep. the distinction may be somewhat artifi cial, RLS can be considered \200\230primary \200 \231 or \200\230secondary \200\231 when it is associated with a variety of other condition s such as iron defi ciency, uraemia, and pregnancy (26). RLS is also worsened by dopamine-b locking agents and antihista- mines. Th ese observations have led to two possibly related t heories of RLS causation. First, supported by the fact that dopaminergic drugs are usually eff ective treatments, RLS may refl ect dysfunction Recent data from a variety of sources may have clarifi ed some of the issues, although many unanswered questions remain. Th ere is little evidence for direct pathology of dopaminergi c systems, CHAPTER 30 Sleep-Related Movement Disorders 331 Date of Recording : 09/05/2006 (7 hours and 59 minutes, starting at 21:22:35) MT Wake REM S1 S2 S3 S4 PLM [1] LM [1] 00:00 01:00 02:00 03:00 04:00 05:00 Limb Movements [1] During PLM Number 689 0 95 594 Index 131,9 - 18,2 113,7 Index 139,7 - 18,2 121,5 Total 730 0 95 635 EMG-Tib LM LM with Arousal LM following apnea LM with no association 155,6 130,4 137,1 123,6 132,5 120 35 487 56 34 74 3 204,4 133,4 149,4 130,9 146,9 200 0 46 498 61 36 82 5 LM during wake LM during sleep stage S1 LM during sleep stage S2 LM during sleep stage S3 L M during sleep stage S4 LM during REM sleep LM during movement time Limb Movements [1] Number of LM 730 Sequence duration Mean 1,6 seconds Shortest 1 seconds Longest 3,5 seconds Periodic Limb Movements [1] Number of PLM-sequences 56 Sequence duration Mean 4,6 minutes 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).