Pediatrics Movement Disorder

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Movement Disorders  Disorders in Movement Children Bradley L. Schlaggar, MD, PhD,* Jonathan W. Mink, MD, PhD†

Objectives   After completing completing this article, article, readers should should be able to: 1. 2. 3. 4.

Describe the prevalence Describe prevalence of tic disorder. disorder. Characterize Characte rize the treatment treatment of tic disorder. Explain how movement movement disorders can differ from autism and mental retardation. Describee the use of stimulant medication in the treatment of attention-deficit Describ attention-deficit/  /  hyperactivity disorder associated with a tic disorder. 5. Compar Comparee and contrast dopa-responsive dopa-responsive dystonia dystonia and cerebral palsy.

Introduction Supremee Cour Suprem Courtt Jus Justic ticee Pot Potter ter Ste Stewar wart, t, in 196 1964, 4, whi while le try trying ing to defi define ne “obs “obscen cenity ity,” ,” articulated the now well-known “I shall not today attempt to define the kinds of material I understand to be embraced . . . [b]ut I know it when I see it . . . .” In some respects, a similar simi lar comm comment ent can be made about mov movemen ementt diso disorder rders. s. A mov moveme ement nt diso disorder rder typically is defined as movem dysfunction dysfunctio n in thenction implementati implementation onre, of the appropriate appropr iate and  velo  velocity city of intended inte nded movements, ents, dysfuncti dysfu on of postu posture, presence presen cetargeting of abno abnormal rmal involunt invo luntary ary move movement ments, s, or the per perform formance ance of norm normal-a al-appe ppearin aring g move movemen ments ts at inappro inap propria priate te or unin unintend tended ed time times. s. The move movement ment abnormaliti abnormalities es are not due to  weakness  weak ness or abnor a bnormal mal muscl musclee tone, to ne, but may be accom a ccompanie panied d by b y weakne we akness ss or o r abnorma ab normall tone. By convention, movement disorders are divided into two major categories. The first is hyperkinetic movement disorders, sometimes referred to as dyskinesias. This term refers to abnormal, repetitive involuntary movements and encompasses most of the childhood movement disorders, including tics, chorea/ballismus, dystonia, myoclonus, myoclonus, stere stereotypie otypies, s, and tremo tremor. r. The secon second d category is hypokinetic movement disorders, sometimes reAbbreviations ferred to as akinetic/rigid disorders. The primary movement disorder in this category is parkinsonism, manifested primarADHD:   attention-deficit/hyperactiv attention-deficit/hyperactivity ity disorder ily in ad adul ulth thoo ood d as Par Parki kins nson on di dise seas asee or on onee of ma many ny fo form rmss of  ARF:   acute rheumatic fever DRD:   dopa-responsive dystonia GABHS:   group A beta-hemolytic streptococcal IVIG:   intravenous immunoglobulin NIH:   National Institutes of Health OCD:   obsessive compulsive disorder PANDAS:  pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection SC:   Sydenham chorea SLE:   systemic lupus erythematosus SSRI:   selective serotonin reuptake inhibitor TD:   tardive dyskinesia TS:   Tourette syndrome

secondary parkinsonism. Hypokinetic disorders are relatively  uncommo unco mmon n in chi childr ldren. en. Alt Althou hough gh ata ataxia xia,, wea weakne kness ss,, and spasticity are characterized by motor dysfunction, by common con conven ventio tion n the these se ent entiti ities es are not inc includ luded ed amo among ng “movement disorders.” This review focuses on dyskinesias because they represent the bulk of movement disorders in children. The components of the central nervous system typically  implicated in disorders of movement are the basal ganglia (caudate, (caudat e, putam putamen, en, globus pallidus, subthalamic subthalamic nucleu nucleus, s, substantia nigra) and frontal cortex. The accomplishment of  smooth, coordinated movement requires a multifaceted net work of brain regions, including basal ganglia and frontal cortex cor tex,, but als also o thal thalamu amus, s, cer cerebe ebellum llum,, spi spinal nal cor cord, d, per periph iphera erall

*Assistant Professor of Neurol *Assistant Neurology, ogy, Radiology, Radiology, and Pediatrics, Washington Washington University School of Medici Medicine ne and St. Louis Children’s Children’s Hospital, St. Louis, MO. † Associate Associ ate Professor of Neurol Neurology, ogy, Neurobiology Neurobiology & Anatom Anatomy, y, and Pediatrics; Chief, Child Neurol Neurology, ogy, University University of Roches Rochester ter School of Medicine and Dentistry and Golisano Children’s Hospital at Strong, Rochester, NY.

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Table Tab le 1.

 Phenomenologic Classification of Movement Disorders

Move Mo veme ment nt Di Diso sord rder er

Brie Br ieff De Desc scri ript ptio ion n

Tics Ti cs

Stereo Ster eoty type ped d head inte in term rmit itte tent nt,, su sudd dden en,, di disc scre rete te,, re repe peti titi tive ve,, no nonr nrhy hyth thmi micc mo move veme ment nts, s, mo most st fr freq eque uent ntly ly involving and upper body. Chaoti Cha otic, c, ran random dom,, rep repeti etitiv tive, e, bri brief, ef, pur purpos posele eless ss mov moveme ements nts.. Rap Rapid, id, but not as rap rapid id as myoclonus. myocl onus. When of very large ampli amplitude, tude, choreic limb movem movements ents often are calle called d ballismus. Repe Re peti titi tive ve,, su sust stai aine ned, d, ab abno norm rmal al po post stur ures es an and d mo move veme ment nts. s. Ab Abno norm rmal al po post stur ures es ty typi pica call llyy ha have ve a twisting quality. Sudd Su dden en,, br brie ief, f, sh shoc ockl klik ikee mo move veme ment ntss th that at ma mayy be re repe peti titi tive ve or rh rhyt ythm hmic ic.. Patt Pa tter erne ned, d, ep epis isod odic ic,, re repe peti titi tive ve,, pu purp rpos osel eles ess, s, rh rhyt ythm hmic ic mo move veme ment nts. s. Rhyt Rh ythm hmic ic os osci cill llat atio ion n ab abou outt a ce cent ntra rall po poin intt or po posi siti tion on in invo volv lvin ing g on onee or mo more re bo body dy pa part rts. s. Hypo Hy pokin kinet etic ic sy synd ndro rome me ch char arac acte teri rize zed d by re rest st tr trem emor or,, sl slow ow mo move veme ment nt (b (brad radyk ykin ines esia ia), ), ri rigi gidi dity ty,, and postural instability.

Chorea Cho rea/ba /balli llismu smuss Dyst Dy ston onia ia Myoclo Myoc lonu nuss Ster St ereo eoty typy py Trem Tr emor or Park Pa rkin inso soni nism sm

ner nerve, ve, and mus muscle cle.. It is imp importa ortant nt to rec recogn ognize ize the multiple components of the nervous system involved in

an und underl erlyin ying g pat pathol hology ogy.. For exa exampl mple, e, fre freque quent nt eye blinking can be normal and appropriate in one setting

motor control because determining the cause often depends on localization.  When faced with a movement disorder, the following key questions questions need to be asked:

(a sand storm), but excessive in another (tic disorders). Movements that are worrisome for a degenerative disorder in adolesc adolescents ents (myoclonus) (myoclonus) may be completely completely normal in an infant (benign neonatal myoclonus). In this article, we discuss most of the hyperkinetic movement disorders, but focus on tics, chorea, and dystonia. Druginduced movement disorders, a common entity in childhood, fall under the same classification scheme as the other movement disorders (Table 1), but are considered in this discussion in a separate section.

Is the pattern of movements normal or abnormal? Is the number of movements excessive or diminished? Is the movement paroxysmal (sudden onset and offset), continual (repeated again and again), or continuous (without stop)? Has the movement disorder changed over time? Do environmental stimuli or emotional states modulate the movement disorder? Can the movements be suppressed voluntarily? Is the abnormal movement heralded by a premonitory 

Tics Defi De finitions

In clinical practice, the diagnosis of a movement disorder requires a qualitative appreciation of the movement type and context. Abnormal movements can be dif ficult to define. To classify the disorder phenomenologically, one should describe the characteristics of the movements (Table 1), but even under the best circumstances,, movem stances movement ent disorders may be dif ficult to characterize.. Chorea can resem terize resemble ble myoclonus; dystonia can

Tics commonly are defined as stereotyped intermittent, sudden,, discret sudden discrete, e, repet repetitive itive movem movements. ents. Movem Movements ents that involve skeletal muscle are termed   “motor”  tics; those thatt inv tha involv olvee the dia diaphr phragm agm or lary larynge ngeal-p al-phary harynge ngeal al mus mus-cles, producing a sound, are termed  “phonic” or “ vocal” tics. Tics occur many times a day, nearly every day. They  typical typ ically ly chan change ge ana anatom tomic ic loc locati ation, on, fre freque quency ncy,, typ type, e, complexity, and severity over time. Tics can be classi fied by mo mode de of ma mani nife festa stati tion on (m (mot otor or or vo vocal cal)) an and d com compl plex ex-ity (simple (simple or com comple plex). x). Motor tics can be clas classi sified furt fu rthe herr by sp spee eed d an and d qu quali ality ty as cl clon onic ic (a (abr brup uptt an and d fa fast st)) or dystonic/ton dyston ic/tonic ic (slow and sustain sustained). ed). Simple motor tics include blinking, nose twitching, grimacing, neck jerking,, shou ing shoulde lderr ele elevat vation ion,, sust sustain ained ed eye clo closure sure,, gaz gazee shi shifts fts,, bruxism, and abdominal tensing. Simple vocal tics include clu de snif fing, thro throat at cle clearin aring, g, gru grunti nting, ng, squ squeak eaking ing,,

resemble spasticity; and paroxysmal movement disorders such as dystonia and tics may resemble other paroxysmal neurologic problems, namely, seizures. Movements in some contexts may be normal and in others may indicate

humming, hummin g, cou coughi ghing, ng, blo blowin wing, g, and suck sucking ing sou sounds. nds. Complex tics appear more “ purposeful” than simple tics and may inc includ ludee com combin binatio ations ns of mov moveme ements nts of mul multip tiple le body parts. Examples are head shaking, trunk   flexion,

sensation or urge?  Are there   findings on the examination suggestive of  focal neurologic deficit or systemic disease? Is there a family history of a similar or related condition? Does the movement disorder abate with sleep?

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 Classification and  Classifi Diagnosis of Tic Disorders Table 2.

Transient Tic Disord Transient Disorder er (<1 y duration; diagnosis made retrospectively) ● ● ●

 Motor  Vocal  Motor and vocal

Chronic Tic Disorder (>1 y duration) ● ●

 Motor (common)  Vocal (rare)

Tourette Syndrome ●

Motor and vocal (at some point, but not necessarily, concurrently)

scratching, touching,   finger tapping, hitting, jumping, kicking, and gestures (obscene gestures are termed copropraxi rop raxia). a). Com Comple plexx voc vocal al tic ticss can enc encomp ompass ass spo spoken ken syllables words or phrases; shouting of obscenities or profanities (coprolalia); repetition of the words of others (echolalia); (echol alia); and repet repetition ition of the fi nal syllable, word, or phrase of one’s own words (palil (palillalia) lalia).. The definition of tic disorders can be guided by the Diagnostic and Statistical Manual of Mental Disorders , 4th edition (DSM-IV) classification scheme. The primary distinctions are between transient and chronic tic disorders and between chronic motor tic disorder and Tourette syndrome (TS) (Table 2). Transient tic disorder is a disorder of childhood in which one or several tics are ind indisti istingu nguisha ishable ble from the tic ticss of chro chronic nic tic dis disorde order, r, but the condition lasts only several months. These frequently are interpreted as allergic manifestations. The most common chronic tic disorder is TS, manifested as chronic motor and vocal tics of greater than 1 year’s durat du ratio ion n wi with th on onse sett pr prio iorr to ag agee 18 ye years ars.. Ch Chro roni nicc mo moto torr ticc di ti diso sorde rderr is ch chara aract cter eriz ized ed by mo moto torr ti tics cs fo forr mo more re th than an 1  year, but no vocal tics. Chronic vocal tic disorder is uncommon.

been recognized recognized as having a famili familial al inheritance pattern and a greater prevalence among males. The specific genetic inheritance is being investigated in ongoing research, but a reasonable description of the pattern is autosom aut osomal al dom domina inant, nt, wit with h inc incomp omplet letee and gen gender der-biased penetration (male:female ratio of 3:1). Tics usually appear in the   first decade of life, with a median age of onset of about 6 to 7 years. They have been reported at 2 years of age, but may occur earlier. In most children (96%), tics present before age 11. The most common presenting tic is eye blinking. Vocal tics are the presenting symptom in up to one third of indi viduals, with the most common initial tics being snif fing or throat clearing. Typically, vocal tics emerge later than motor tics, with a median onset of around 8 to 10 years of age. The most common course is for tics to worsen,  with peak severity occurring around 10 to 12 years of  age. By age 18 years, approximately 50% of chronic tic disorder patients are tic-free. Tic severity in childhood doess not pre doe predict dict adult sev severi erity; ty; tic sev severi erity ty rare rarely ly is greater in adulthood than in childhood.

Clinical Features

Recent studies show the prevalence of tics to be approximately 20% of the population and the rate of chronic tic disorders to be about 3% among children. (The discrepancy between prevalence of tics and rate of chronic tic

Tics frequently are preceded by a premonitory sensation or ur urge ge,, an and d pe perf rfor orma manc ncee of th thee ti ticc usu usual ally ly is fo foll llow owed ed by  a sense of relief. The common occurrence of eye blinking, snif fing, and throat clearing tics preceded by the sensation of an itch leads to the frequent misdiagnosis of  ticss as all tic allerg ergic ic sym sympto ptoms. ms. For som somee pat patien ients, ts, the pre premon mon-itory ito ry urg urgee is man manife ifeste sted d nons nonspec peciifically as a sense of  anxiety. This sense of anxiety seems particularly true in  younger children, perhaps because they are unable to characterize charact erize the feelin feeling. g. Younger children are less likely  to describe premonitory urges. For some patients, the premonitory urge may create greater morbidity than the tic itself and, therefore, represents the reason to treat. The premonitory urge has been compared with a compulsive urge, but the latter is believed to have a more cognitive component (ie,   “If I don’t wash my hands, I  will get sick.”). Some individuals can suppress tics for limited periods of ti time me.. Th Thee abi abili lity ty to su supp ppre ress ss ti tics cs se sets ts ti ticc di diso sord rders ers ap apart art from fr om mo most st ot othe herr mo move veme ment nt di disor sorde ders rs.. Ho Howe weve ver, r,  younger children are less likely to be able to suppress tics, making this point of differentiation less useful in that popu po pula lati tion on.. Vo Volu lunt ntary ary ti ticc su supp ppre ressi ssion on of ofte ten n is at a cos costt of  rising anxiety or discomfort and usually requires such

disorders is likely accounted for by transient tic disorders de rs.) .) Th Thus us,, ti tics cs an and d ti ticc di diso sord rder erss ar aree at le leas astt on onee or orde derr of  magn ma gnit itud udee mo more re com commo mon n th than an wa wass th thou ough ghtt ju just st 15 ye years ars ago. From the earliest descriptions, tic disorders have

active concentration that it may prevent the patient from attending to other tasks. Thus, voluntary suppression is not a useful strategy strategy for manag managing ing tics.  A hallmark of tics is variable severity over time. Tics


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Table Tab le 3. ● ● ● ● ● ● ●

● ●

 Causes of Secondary Tics

 Infections  Drugs  Toxins  Developmental disorders  Chromosomal disorders  Stroke  Heredodegenerative disorders —Huntington disease —Neuroacanthocytosis —Pantothenate kinase-associated neurodegeneration (PKAN)* —Wilson disease  Neurocutaneous disorders  Head trauma

*Also known as Hallervorden-Spatz syndrome

Figure.   Po Pote tent ntia iall

comorb como rbid id co cond ndit itio ions ns se seen en wi with th ti tics cs.. OCD obsessive-compulsive disorder, TS Tourette syndrome, ADHD attention-de attention-defi ficit/hyperactivity disorder. 

others. For example, selective serotonin reuptake inhibitors (SSRIs) may be beneficial for OCD or anxiety, but they are not effective for tics or ADHD and might be associated with worsened rage control.


tend d to occu occurr in bou bouts, ts, wit with h int inters ersper persed sed per period iodss of  ten quiescence. Often a pre-existing tic abates as a new tic emer em erge ges. s. Ti Tics cs te tend nd to wa waxx an and d wa wane ne ov over er we week ekss to months. Tic severity seems to be modulated by environmental stimuli, stress, intercurrent infection, and poor sleep. Children commonly experience exacerbations of  tics at the outset of the school year and at the time of  return from school holidays. Tics also may increase during relaxation after a period of stress. Tics typically disappear with sleep, but in some individuals they persist during all stages of sleep sleep.. In ad addi diti tion on to ti tics cs,, pa pati tien ents ts wh who o ha have ve ti ticc di diso sorde rders rs ma may  y  have a number of comorbid behavioral symptoms (Figure). ure ). The These se inc includ ludee sym sympto ptoms ms of att attent entionion-de deficit/ hyperactivit hypera ctivityy disord disorder er (ADHD (ADHD), ), obsessi obsessive-com ve-compulsiv pulsivee beha be havi vior orss or fr fran ank k ob obse sessi ssive ve-co -comp mpul ulsiv sivee di disor sorde derr (OCD), anxiety disorders, mood disorders, learning disorders, sleep disorders, conduct and oppositional behavior, and self self-inj -injuri urious ous beh behavi avior. or. Zin Zinner ner has disc discuss ussed ed these conditions conditions and their treatments treatments in detail (see Suggested ges ted Rea Reading ding). ). Rec Recent ent evi eviden dence ce sug sugges gests ts tha thatt exp explosi losive ve outbursts or rage attacks are common among children  who have TS, occurring in roughly 25%. When affected children have explosive outbursts, they also are more

 When considering the differential diagnosis of tics, both causee and clas caus classi sificati cation on mus mustt be add address ressed. ed. As not noted ed previously, tics are protean in their manifestation. Clonic tics can resemble movements seen in myoclonus, chorea, and seizures. Dystonic tics can resemble the movements seen see n in pri primar maryy dys dyston tonias ias.. Ton Tonic ic tic ticss can rese resembl mblee mus muscle cle spasms and cramps. Complex motor tics can be very  dif ficult to discern from mannerisms, stereotypies, restless legs, complex partial or supplementary motor seizures, and akathisia (an inability to sit still due to an uncomfortabl uncomf ortablee sensati sensation on of motor restlessness). restlessness). Most individuals who have tics have a primary tic disorder. Transient tic disorder is the most common; TS is the second most common. Secondary tic disord disorders ers do exist, but the theyy are unco uncommo mmon. n. In sec second ondary ary tic diso disorde rders, rs, other signs and symptoms are present and distract from the consideration consideration of a primar primaryy tic disorde disorderr (Table 3).  An interesting but unproven autoimmune mechanism for tics and TS (and OCD) has been postulated. The best-k bes t-know nown n con concep ceptt is that of ped pediat iatric ric aut autoim oimmun munee neuropsychiatric disorder associated with streptococcal infect inf ection ion (PA (PANDA NDAS). S). The hyp hypoth othesi esiss tha thatt an ant antece eceden dentt group A beta-hemolytic streptococcal (GABHS) infec-

likely to have other comorbid features, such as ADHD, OCD, and oppositional defiant disorder. An important feature fea ture of com comorb orbid id sym sympto ptomat matolo ology gy is tha thatt cer certai tain n medications are effective for some symptoms but not for

tion cou tion could ld resu result lt in a neu neurop ropsych sychiat iatric ric man manife ifestat station ion such as TS TS,, OC OCD, D, or bo both th is co conce ncept ptua uall llyy ba base sed d on Sy Syde denh nham am chorea, a recognized neuropsychiatric manifestation of  acute rheumatic fever (ARF). The postul postulated ated PANDAS

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subgroup has been described as having the following characteristics: presence of OCD/chronic tic disorder, prepubertal onset, episodic course with acute and severe onsett and exp onse explosi losive ve exa exacer cerbat bation ions, s, neu neurol rologi ogicc abno abnorma rmallities other than chorea during the exacerbations, and a documented temporal relationship between GABHS infections fectio ns and the episod episodic ic exacerb exacerbations ations.. Wheth Whether er patients whose TS (and OCD) manifestations appear to be trigger trig gered ed by str strept eptococ ococcal cal inf infect ection ionss can be dist distininguished clearly from the entire population remains unclear. For this reason, the National Institutes of Health

ratoryy st rator stud udie ies, s, an and d me measu asure reme ment nt of an anti tibo bodi dies es to GABHS are not indicated. Individuals who have other neurologic abnormalities or developmental abnormalities deserve further evaluation and should be referred to a neurologist.

Treatment The pri primar maryy que questio stion n whe when n cons conside iderin ring g tre treatm atment ent of tics is whether the patient has suf ficient morbidity to warrant pharma pha rmacol cologi ogicc tre treatm atment ent.. Rea Reassur ssuranc ancee tha thatt tic ticss are a common feature on the landscape of human behaviors that (typically) cause no injury and frequentl que ntlyy are tra transie nsient nt can suc success cessful fully ly bypass the desire to start medication. Anticipatory ticipa tory guidance and educat education ion for parents, siblings, and teachers can aid immeasurably in preventing the initiation tio n of med medica icatio tions. ns. One imp importa ortant nt

Most patients who have uncomplicated tic disorders do well without pharmacologic intervention. (NIH) is sponsoring a prospective multicenter epidemiologic study to ascertain whether a PANDAS subgroup of TS and OCD patients exists. Intense interest in the idea of PANDAS has led to small experimental trials of antibiotic prophylaxis and immunomodulation with intravenous immunoglobulin (IVIG) with or without plasma exchange. At present, these interventions have not been proven effective. Indeed, in July 2000, the National Institute of Mental Health released a statement (  events/pandaalert.cfm ) that treatment of PANDAS, TS, or OCD with IVIG or plasma exchange is considered experi exp erimen mental tal and tha thatt the these se int interv ervent ention ionss sho should uld be use used d onlyy in NIH onl NIH-app -approv roved ed rese research arch pro protoc tocols. ols. The Theref refore ore,, for patients whose tics appear to be exacerbated by GABHS infections, we recommend that: ●

Standard pharma Standard pharmacologi cologicc and nonpha nonpharmacol rmacologic ogic approachess be used to treat tics and exacerbations. proache exacerbations. Until evidence supports their clinical implementation, the use of immune modulation, including plasma exchange and IVIG, be reserv reserved ed for clinic clinical al studies.  Antibiotics not be used to treat tic exacerbations. exac erbations.  Antibiotic prophylaxis be reserved for patients who have ARF.


Most children who have tics have a primar primaryy tic disorde disorder, r, and di diag agno nosis sis is ba base sed d on hi hist story ory pl plus us no norm rmal al findi ndings ngs on neurologic examination aside from tics. Imaging, labo-

component of anticipatory guidance is recognition of the natural history of tic disorders. disorde rs. For examp example, le, for a significant proportion propor tion of patients, tics peak in severi severity ty at ages 10 to 13 years and diminish substantially in the late teenage  years. For many individuals, the tics become so mild by  adulthood that they no longer are noticed or may abate completely. Most patients who have uncomplicated tic disorders do well without pharmacologic intervention. However, the symptoms cause suf ficient morbidity for some patients to warrant consideration of medication. Zinner recently reviewed therapeutic considerations of pharma pharmacother cotherapy apy for this publication publication (see Suggested Suggested Reading). If the patient has tics alone, we recommend starting startin g treatm treatment ent with an alphaalpha-2-adren 2-adrenergic ergic agonist such as clonidi clonidine ne or guanf guanfacine. acine. Guanfacine Guanfacine may be less sedating than clonidine, but it also may be less effective. Neuroleptics Neurol eptics,, both typical and atypi atypical, cal, are effect effective ive for tics. Good evidence supports the use of typical neuroleptics ti cs suc such h as hal halop oper erid idol ol an and d pi pimo mozi zide de,, bu butt ad adve verse rse ef effe fects cts freque fre quentl ntlyy are lim limiti iting. ng. Aty Atypic pical al neu neurole rolepti ptics cs suc such h as risperidone appear to be effective for tics and impulsivity  and an d ar aree le less ss li like kely ly to ca cause use ex extr trap apyr yram amid idal al ad adve verse rse ef effe fect cts, s, but they still have significant morbidity in the form of   weight gain and diabetes mellitus. A newer atypical neuroleptic, ziprasidone, shows promise as an anti-tic medication, and early experience suggests that it may not cause weight gain or diabetes mellitus. In addition to medications, behavioral therapies may be helpful. The clinician should determine the relati clinician relative ve burden imposed by ti tics cs an and d any co como morbi rbidi diti ties es.. Fo Forr ex exam ampl ple, e, if OC OCD D is th thee primar pri maryy pro proble blem m and tics are mil mild, d, pha pharma rmacot cother herapy  apy  should target the OCD. The incidence of comorbidities Pediatrics in Review  Vol.24 No.2 February 2003   43


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is significant. Across series, an average of approximately  50% of indivi individuals duals who have TS have ADHD, 50% have OCD, 20% have a mood disorder, disorder, and 20% have anxiety  disorder.

ADHD Stimulant Treatment and Tics  According to the   Physician’s Physician’s Desk Refere Reference  nce , methy methyllphenidate is contraindicated  “in patients with motor tics or with a family history or diagnosis of Tourette syndrome.” This statement apparently is based on a number of case rep reports orts and ret retrosp rospect ective ive seri series es that pro probab bably ly hav havee not considered that ADHD is present in approximately  50% of all patients who have TS and that the natural history in these patients is for ADHD symptoms to tend to pr prec eced edee th thee on onse sett of ti tics cs.. Th Thee ba basi siss fo forr th thee PDR listing is a good example of the shortfalls of anecdotal and retrospective analysis. Several recent studies have indicated that stimulant medications typically do not exacerbate tic bate tics, s, and if the theyy do, the exa exacerb cerbati ation on usu usuall allyy is transient. However, most prescribing physicians, by stating in g th thee wa warn rnin ing g in th thee PDR in th thee discussion of risks and benefits of  treati tre ating ng wit with h sti stimul mulant ants, s, pri prime me parent par entss to ant antici icipat patee tics tics.. Whe When n tics emerge or worsen (tic disorders likely wax and wane independent of medication) in the presencee of stim enc stimulan ulants, ts, the med medica icatio tion n is conside considered red the culpri culprit. t.  A recent study by the Tourette Synd Sy ndro rome me St Stud udyy Gr Grou oup p ad addre dresse ssed d th this is iss issue ue in a ra rand ndom om-ized, placebo-controlle placebo-controlled, d, double double-blind -blind study to assess the ef ficacy of methy methylpheni lphenidate date and clonid clonidine ine indivi individudually or in combination for treatment of ADHD among children who had chronic tics or TS. The study provided solid evidence that methylphenidate, if anything, lessens tic severity. The study concluded,  “ Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.”  Whether these results can be generalized to other stimulants (such as pemoline and dextroamphetamines) is not known known..

tude, chorea may cause the appearance appearance of  fi  fi dgeting, but  when they are of large amplitude, chorea can involve dramatic, fling inging ing lim limb b mov moveme ements. nts. Whe When n the amp amplit litude ude is very large, the term ballismus often is used. Choreic movements can be sudden and jerky or continuous and flowing. In the latter case, the term choreoathetosis is used. In current parlance, the term   “choreiform”   frequently is used to describe the minimal twitching or “piano playing” movements seen in many normal young children childre n when arms are extended during the neurol neurologic ogic examination. We do not  fi nd the term  “ choreiform”  to be useful because historically its usage has meant  “ chorea.”  Instead, we prefer the descriptive term   “minimal chorea.”

Causes Chorea can be classified by cause into primary and secondary ond ary diso disorde rders. rs. Pri Primar maryy chor chorea, ea, whi which ch is unc uncomm ommon on in childhood, can be caused by benign familial (hereditary) chorea cho rea and Hun Huntin tingto gton n dis diseas ease. e. Hun Huntin tingto gton n dis diseas easee

In a randomized, placebo-controlled trial, methylphenidate and clonidine (for treatment of ADHD) did not worsen tics.

Chorea Defi De finitions Chorea is char Chorea charact acteriz erized ed by fre freque quent, nt, brie brief, f, unp unpred redict ictabl able, e, purpos pur posele eless ss mov moveme ements nts that ten tend d to flow fr from om bo body dy pa part rt to body part chaotically and unpredictably. The movements of chorea are more chaotic and less brief and “shocklike”  than myoclonus. They are briefer than the sustained contractions of dystonia. When of low ampli44   Pediatrics in Review  Vol.24 No.2 February 2003

rarely presents in childh childhood ood with chorea; juveni juvenile-ons le-onset et Huntington disease usually is characterized by parkinsonism and dystonia. Most chorea in childhood is secondary. More than 100 causes of secondary chorea have been identified, but usually chorea is not the only sign or symptom. The most common cause of chorea in childhood is ARF. Other important causes include systemic lupus erythematosus (SLE), pregnancy (chorea gravidarum), vascular disorde disorders, rs, drug ingest ingestion, ion, hypert hyperthyroidhyroidism,, inf ism infect ection ion,, inflamm ammati ation, on, card cardiac iac surg surgery ery (“postpump pum p cho chorea rea”), deg degene enerati rative ve diso disorde rders, rs, diso disorde rders rs of  inte in term rmed ediar iaryy me meta tabo boli lism sm,, an and d pe perin rinat atal al hy hypo poxi xiaaischemia (Table 4). A diagnostic strategy based on the more likely causes, with an emphasis on treatable causes, is shown in Table 5.

Sydenham (Rheumatic) Chorea Chorea is one of the major Jones criteria for diagnosing  ARF. In fact, the presence of chorea without any other criteriaa is suf ficient to make the diagnosis. Although it is criteri  widely accepted that chorea can follow GABHS infec-


neurology   movement disorders

 Causes of Secondary Chorea

 Diagnostic Testing in Chorea

Tablee 4. Tabl

Table Tab le 5.


● ● ● ●

 Hypo/hypernatremia  Hypo/hyperglycemia  Hypocalcemia  Hyperthyroidism

Perinatal Hypoxia-Ischemia

● ● ● ● ● ● ●

Infectious ● ● ● ●

 Epstein-Barr virus  Human immunodefi immunodeficiency virus  Rheumatic fever  Viral encephalitis

Psychogenic  Vascular  Antiphospholipid antibody syndrome  Stroke  Global hypoxia  Moyamoya syndrome

● ● ● ● ●

 Throat culture  Antistreptolysin O titer  AntiDNase  AntiD Nase B titer  Electrocardiogram  Echocardiogram  Thyroid function tests  Complete blood count  Antinuclear antibody  Erythrocyte sedimentation rate  Magnetic resonance imaging of brain  Serum ceruloplasmin  Antiphospholipid/anticardiolipin antibodies  Urine drug scree screen n

Other testing for rare diseases is based on presence of other symptoms and cli clinic nical al sus suspic picion ion.. If res result ultss of theabove tes tests ts arenorma arenormal, l, ref referr erral al to a neurologist is recommended.

● ●

tion, it can be dif ficult to demonstrate the antecedent infection. Depending on the series, 10% to 40% of children dre n wh who o ha have ve AR ARF F ha have ve ch chore orea. a. Sy Syde denh nham am ch chor orea ea (S (SC) C) is most common in children ages 5 to 15 years. There is a 2:1 female predominance after 10 years of age. SC begins several weeks to several months after a GABHS infection. The onset of symptoms usually is insidious,  with gradually progressive clumsiness and behavior change, usually accompanied by emotional lability. After a week or more, choreic movements become more obvious and typic typically ally become gener generalized alized.. There frequently  frequently  is as asym ymme metr try, y, an and d in so some me cas cases es,, th thee ch chor orea ea ca can n be unilateral. unilate ral. Hypot Hypotonia onia and dysarth dysarthria ria commo commonly nly accom-

ultimate resolution of the chorea. Some individuals have behavioral changes that persist for months. Relapse(s) can occ occur ur wit with h or wit withou houtt sub subseq sequen uentt GAB GABHS HS inf infect ection ion,, and an increased risk of relapse is associated with pregnancy (chorea gravidarum) or oral contraceptives. The diagnosis of SC is based on clinical history and can be supported by laboratory data. However, laboratory data should not be viewed as con firmatory. Most affected children have positive serology (antistreptolysin O and antiDNase B antibodies) for GABHS, but more than 25% are serologically negative. Most children who have SC have negative throat cultures for GABHS. Magnetic resonance imaging may show signal abnorm abnormalitie alitiess in the basal ganglia, but diagnostically this technique is neither sensitive nor specific for SC. The presence of  carditi card itiss or oth other er man manife ifesta statio tions ns of ARF supports supports the diagnosis diagno sis of SC. Every child believed believed to have SC should be evaluated for rheumatic heart disease. Depending on the series, 40% to 75% of children who have SC have carditis. carditi s. Arthritis is less common. Treatment of SC depends on the impairment or disability associated with the chorea. In many cases, the chorea cho rea cau causes ses onl onlyy mil mild d disa disabil bility ity,, and sym sympto ptomat matic ic treatm tre atment ent is not required required bec because ause SC is usu usuall allyy sel selfflimite lim ited. d. Whe When n sym sympto ptomat matic ic tre treatm atment ent is des desire ired, d, ant antiep iepiileptic medications such as carbamazepine or valproate can be ef effe fect ctiv ivee an and d us usua ually lly as assoc socia iate ted d wi with th fe fewe werr ad adve vers rsee

pany the chorea. Behavioral changes may be striking and incl in clud udee im impu puls lsiv ivit ity, y, ag aggr gres essi sion on,, an and d ob obse sess ssiv iveecompul com pulsiv sivee beh behavi aviors. ors. The typ typical ical natu natural ral his history tory of SC is  weeks to months of a waxing and waning course, with

effects than phenothiazines or butyrophenones. Benzodiazepines also may be beneficial. Sympt Symptomati omaticc treatment for 2 to 4 months generally is suf ficient. Some authors have advocated the use of corticosteroids, IVIG,

● ●

Toxins ● ● ●

 Manganese  Methanol  Carbon monoxide

Heredodegenerative Disease ● ● ● ●

 Ataxia telangiectasia  Niemann-Pick type C  Gangliosidoses  Lesch-Nyhan disease

Pediatrics in Review  Vol.24 No.2 February 2003   45


neurology   movement disorders

Tablee 6. Tabl

 Classifi  Classi fication of Dystonia

Age of Onset ● ●

 Childhood onset  Adult onset

Cause ● ●

 Primary (idiopathic)  Secondary

Somatic Distribution ● ● ● ● ●

 Focal  Segmental  Multifocal  Hemi  Generalized

mutation or unknown cause. Secondary dystonias are those disorders in which the dystonia is due to another identifiable cause. Focal dystonia occurs when a single body part is affected. Almost any part of the body can be affected. Examples of focal dystonia include torticollis and wri writer ter’s cram cramp. p. Seg Segmen mental tal dys dyston tonia ia ref refers ers to inv involv olveement of more than one adjacent body part; multifocal dystonia is involvement of multiple nonadjacent body  parts. Hemidystonia affects only one side of the body, and generalized dystonia involves the entire body. Note thatt the tha these se cla classi ssification schemes are overla overlapping pping.. For example, childhood-onset primary dystonia frequently  starts in the lower extremities, trunk, or arms and most commonly progresses to generalized involvement, with involu inv olunta ntary ry twi twisti sting ng of nea nearly rly all par parts ts of the bod body. y. Adu Adultltonset primary dystonias more typically are focal or segmental.

plasm asmaa ex excha chang ngee ba base sed d on th thee pr pres esum umed ed au auto toim immu mune ne or pl cause,, bu cause butt th ther eree ha hass be been en no stu study dy of lo long ng-te -term rm ou outc tcom omee of these treatments compared with placebo. Penicillin prophylaxis to prevent repeated bouts of  GABHS GAB HS is rec recomm ommend ended ed and des descri cribed bed in det detail ail by  Dajani et al (see Suggested Reading).

Chorea in SLE Choreaa is an un Chore unco comm mmon on ma mani nife festa stati tion on of SL SLE, E, bu butt it ca can n be the presenting symptom. When chorea is the sole manifestation of SLE, it can remain so for years. Although fewer than 10% of children who have SLE have chore cho rea, a, ab abou outt 50 50% % of in indi divi vidu duals als wh who o ha have ve ch chore oreaa du duee to SLE are younger than 16 years of age. The presence of  neurologic neurol ogic manif manifestatio estations ns such as chorea chorea in SLE conve conveys ys a less favorable prognosis. The diagnosis and treatment of SL SLE E ar aree be beyo yond nd th thee sc scop opee of th this is re revi view ew.. Wh When en ch chor orea ea is due to SLE, treatment of the underlying SLE is indicated. Additional symptomatic treatment of the chorea may be indicated if the condition is bothersome. Haloperidol has been reported to be effective for SLE chorea, butt th bu thee ot othe herr tr trea eatm tmen ents ts de desc scrib ribed ed pr prev evio iousl uslyy fo forr SC als also o may be effective.

Dystonia Defi De finitions Dystonia Dyston ia is a syn syndro drome me of sust sustaine ained d mus muscle cle cont contrac ractio tions, ns, frequently causing twisting and repetitive movements or abnor abn orma mall po post sture ures. s. Th Ther eree are se seve vera rall cl class assiification schemes for dystonia, based on age of onset, cause, or body part affected (Table 6). Primary dystonias are those disorders in which dystonia is the only feature or the primary feature, are accompanied only by other movementt dis men disorde orders, rs, and hav havee a spe speci cific causati causative ve genet genetic ic 46   Pediatrics in Review  Vol.24 No.2 February 2003

Clinical Features

There are several characteristic clinical features of dystonia. Stress exacerbates most forms of dystonia. Dystonia commonly is triggered or exacerbated by attempted voluntary movement and may   fluct uctuat uatee in pre presen sence ce and severity over time. Dystonic contractions resolve during sleep. The dystonic posturing may occur only with selected movement movementss and parado paradoxically xically not with others others that mayy use th ma thee sam samee mu muscl scles es.. Fo Forr ex exam ampl ple, e, wa walk lkin ing g fo forw rward ard may eli elicit cit sev severe ere low lower er ext extrem remity ity and tru truncal ncal twi twisti sting, ng, yet  walking backward, running, or swimming may be completely normal. Individuals who have dystonia often fi nd that touching one part of the body relieves the dystonic spasms; this phenomenon is called a sensory trick or  geste  antagoniste . For example, rubbing the back of the hand may diminish writer’s cramp.

Causes Historically, dystonia has been divided into primary (idiopathic) and secondary causes. A full discussion of the many causes of dystonia is beyond the scope of this review. The two most important types of primary dystonia in children are dopa-responsive dystonia and idiopathic torsion dystonia associated with the  DYT1  mutation ti on.. Th Thee mo most st im impo port rtant ant cau cause sess of se seco cond ndar aryy dy dyst ston onia ia in children childre n are listed in Table 7.

Dopa-responsive Dystonia Dopa-responsive dystonia (DRD) is the most common cause of primar primaryy dystonia with onset in childh childhood. ood. This syndrome is characterized by childhood-onset, progressive dystonia that has a sustained, dramatic response to low doses of levodopa. DRD is also known as hereditary 


neurology   movement disorders

 Causes of Secondary Dystonia in Children Tablee 7. Tabl

Heredodegenerative Disorders ● ● ● ● ● ● ● ● ● ●

 Ataxia telangiectasia  Gangliosidoses  Glutaric aciduria  Huntington disease  Lesch-Nyham disease  Metachromatic leukodystrophy  Methylmalonic acidemia  Mitochondrial disorders  Niemann-Pick type C  Pantothenate kinase-associated neurodegeneration (PKAN)*  Wilson disease

Drugs/Toxin Drugs /Toxinss (see Table 8) Psychogenic Structural Brain Lesions ● ● ● ● ●

 Acute disseminated encephalomyelitis  Infection  Perinatal hypoxia-ischemia  Stroke  Tumor

*Also known as Hallervorden-Spatz syndrome

progressive dystonia with diurnal  fl uctuations or Segawa syndrome. DRD typically presents with a gait disturbance due to foot dystonia starting between 1 and 12  years of age. In untreated older children, c hildren, diurnal diurna l  fl uctuation may develop, with worsening of symptoms toward the end of the day and marked improvement in the morning. The diurnal  fl uctuation need not be a presenting feature. In late adolescence or early adulthood, features of parkinsonism can develop. develop. There are two major forms of DRD: a more common autosomal dominant form due to deficiency of GTP cyclohydrolase and a relativ rel atively ely unco uncommo mmon n aut autoso osomal mal rec recess essive ive for form m caus caused ed by  a deficiency in tyrosine hydroxylase. Both forms produce dopamine deficiency without loss of nigrostriatal dopamine neurons. A few clinical differences may help distinguish the two deficiencies, but these are neither sensitive nor specific. DRD due to tyr tyrosi osine ne hyd hydroxy roxylase lase deficiency  can be dis distin tingui guishe shed d from GTP cyc cycloh lohydr ydrolas olasee deficiency  by measuring cerebrospinal  fl uid (CSF) catecholamines, their metabolites, metabolites, and pteri pterins. ns. In practi practice, ce, the exquisi exquisite te response respon se to levodopa generally is suf ficient for the diagnosis of DRD. In some cases, a specific diagnosis for the purpose of genetic counseling or in atypical cases may 

 warrant CSF investigations. Although the locus for GTP cyclohydrolase is known, the variability in the genetic defect is suf ficiently great for genetic testing not to be routinely available. It is important to recognize the entity of DRD because it respon responds ds dramatically to low doses of levodo levodopa. pa. DRD frequently is misdiagnosed as cerebral palsy, particularly spastic diplegia, so it is important to develop an index of suspicion for DRD in children who have motor impairment, prominent dystonia, and a slowly progressive rather than static course. With appropriate diagnosis and treatment, affected children can lead normal lives.

Idiopathic Generalized Torsion Dystonia Childhood-onset idiopathic torsion dystonia, formerly  known as dystonia musculorum deformans, is an autosomal dominant condition that has incomplete (30%) penetrance. Genetic studies have found that a GAG deletion at the  DYT1  locus on chromosome 9 causes most autosomal dominant, early-onset primary generalized aliz ed dyst dystonia onia affe affectin cting g Ashk Ashkenaz enazii Jewi Jewish sh fami families lies (90%) and nonJews (50% to 60%). In childhood-onset idiopathic torsion dystonia, symptoms usually begin in a limb at a mean onset age of 12.5 years. Onset usually  is before 28 years of age, but seldom before age 6  years.  year s. The legs gener generally ally are affec affected ted befor beforee the arms arms,, and symptoms typically become generalized within 5  years.  year s. Diag Diagnosi nosiss is base based d on ident identifyin ifying g a GAG dele dele-tion in the   DYT1   gene; genetic testing is available commercially.

Treatment Most ty Most type pess of dy dysto stoni niaa are di dif  f ficu cult lt to tr trea eat, t, an and d of ofte ten n th thee respons resp onsee is inc incomp omplet lete. e. The cle clear ar exc except eption ion is DRD DRD,,  which responds dramatically to low doses of levodopa. Forr th Fo this is re reas ason on,, a tr tria iall of le levo vodo dopa pa is re reco comm mmen ende ded d fo forr al alll children who have primary dystonia. Because some secondary dystonias also may respond to levodopa, a trial of  thee dru th drug g is re reco comm mmen ende ded d fo forr an anyy chi child ld in wh whom om dy dysto stoni niaa is a promi prominent nent component component of the neurologic neurologic syndro syndrome. me. The anticho anticholinerg linergic ic medic medication ation trihex trihexyphen yphenidyl idyl has been used with good success in some patients who have dystonia. Some patients who were believed to have idiopathic torsion dystonia and experienced a dramatic response spo nse to anti anticho cholin linerg ergic ic med medica icatio tion n hav havee bee been n show shown n to have DRD due to a GTPCH mutation. Thus, a dramatic response to trihexyphenidyl suggests the possibility of  DRD. If there is inadequate benefit from levodopa or trihexyphenidy hexyp henidyl, l, baclofen alone or in combi combination nation with Pediatrics in Review  Vol.24 No.2 February 2003   47


neurology   movement disorders

trihexyphenidyl may be beneficial. Intrathecal baclofen has been fo found und to be ef effec fecti tive ve in dy dysto stonia nia due to cerebral palsy, but adverse effects are frequent and can be serious. For that reason, we recommend an adequate trial of oral baclofen before considering intrathecal baclofen. Benzodiazepines also may be bene ficial, but often the benefit is limited by adverse effects or tolerance. If oral medications are ineffective, botulinum toxin injections may be highly effective, especially if the impairment or disabil disa bility ity can be att attribu ributed ted to a few muscle groups. groups. Ster St ereo eota taxi xicc ne neuro urosu surg rger eryy ha hass been used with increa increasing sing success for a select group of patients who havee dy hav dyst ston onia ia an and d ma mayy be th thee most effective treatment for dystonia due to the  DYT1  mutation.

generat gene rativ ivee di dise sease ases, s, su such ch as pr prog ogre ress ssiv ivee my myocl oclon onic ic epilepsy, Lafora body disease, neuronal ceroid lipofuscinosis no sis,, an and d mi mito tocho chond ndri rial al di dise sease asess suc such h as ME MERR RRF. F. It ca can n be a man manife ifesta statio tion n of oth other er neu neurod rodege egener nerati ative ve pro proces cesses ses,, includ inc luding ing lys lysosom osomal al stor storage age dise diseases ases,, Wil Wilson son dis disease ease,, and Huntington disease. Diffuse central nervous system in jury from virtually any cause (toxic, infectious, metabolic, hypoxic) can result in myoclonus. Essential myoclonus typically is a diagnosis of exclusion. Myoclonus, even nonepileptic forms, tends to respond to anticonvulsant medications such as valproate, carbamazepine, and clon-

Dopa-responsive dystonia, the most common cause of primary dystonia

Myoclonus Myoclon Myo clonus us has bee been n call called ed the

with onset in childhood, responds dramatically to low doses of levodopa.

most protean of abnormal movements because of its presence in normal (associated with sleep, exercise, anxiety) and numerous mer ous pat pathol hologi ogicc situ situati ations ons,, bot both h epi epilep leptic tic and non nonepi epi-leptic. Thus, an appropriately detailed description is be yond the scope of this text. Myoclonic movements are  very brief, abrupt, involuntary, nonsuppressible, jerky  contractions (or interruption of contraction) involving a single muscle or muscle group. The rapidity of these movements warrants the descriptor  “ shocklike,”  as if an electrical shock had been applied to the peripheral nerve innervating the muscle. Myoclonus can be rhythmic, in  which case it often appears tremorlike. However, the movement movem ent in true tremor oscillates with near equal amplitud pli tudee aro around und a mid midpoi point; nt; in myo myoclo clonus, nus, the mov moveme ement nt has a more “ saw-tooth” character. In some cases, myoclonus can be elicited by a sensory stimulus stimulus (reflex myoclonus, the most famous example of which is the acoustic startle response in infancy) or volitional movement (action myoclonus). Myoclonus can be focal, multifocal, segmental, or generalized. The loc locati ation on and qua qualit lityy of myo myoclo clonic nic mov moveme ements nts can be helpful in determining the cause. For example, segmental men tal myo myoclo clonus nus of the tho thorac racic ic mus muscle cless sug sugges gests ts spi spinal nal cord pat pathol hology ogy,, and seg segmen mental tal myo myoclo clonus nus of pal palata atall muscless sugge muscle suggests sts a brainst brainstem em lesion or Whipp Whipple le disease. Negative myoclonus, as in asterixis, suggests metabolic

Stereotypiess are interm Stereotypie intermitten ittent, t, involu involuntary, ntary, repet repetitive itive,, purpos pur posele eless, ss, pat patter terned ned mov moveme ements nts tha thatt are usu usually ally rhy rhyththmic. Examples of stereotypies occurring in children are arm flapp apping ing,, roc rockin king, g, lic lickin king, g, mou mouth th ope openin ning, g, and han hand d  waving. Stereotypies commonly are associated with mental retardation, autism, Rett syndrome, and blindness, butt th bu they ey al also so oc occu curr in ot othe herw rwis isee no norm rmal al chi child ldre ren. n. St Ster ereo eo-typies occurring in the absence of other neurologic or behavioral features are likely to be benign. Many other terms have been used to describe stereotypies, including “rhythmic habit patterns,” “gratification phenomena,” and  “ motor rhythmias.” Stereotypie Stere otypiess usually begin in infanc infancyy and, unlike tics, tend not to change in type over time. The course is  variable, with resolution over a short period of time in some children and persistence for years in others. The movements tend to occur in bouts and usually are associated with excitement, stress, or fatigue. Stereotypies cease when the child is distracted. Many children appear

encephalopathy. Myoclonus in the setting of opsoclonus or ataxia suggests paraneoplastic syndrome (eg, neuroblastoma) or a peri-infectious autoimmune process. Myoclonus can be the manifestation of epileptic neurode-

not to be aware that they are making the movements. movements. Stereo Ste reotyp typies ies mus mustt be dis distin tingui guishe shed d fro from m com comple plexx tic tics, s,  which are more likely to change over time, have an associated premonitory urge, and occur in the setting of 

48   Pediatrics in Review  Vol.24 No.2 February 2003

azepam. Given the complex differential diagnosis associated with myoclonus, we recommend that any pedia pediatric tric pati pa tien entt no note ted d to hav havee my myocl oclon onus us be ev eval alua uate ted d by a neurologist.



neurology   movement disorders

 Common Drug-induced Movement Disorders Table Tab le 8.

Medications* Dopamine antagonists (antipsychotics)  Haloperidol  Pimozide  Chlorpromazine  Metoclopromide  Prochlorperzine  Risperidone Antiepileptics  Phenytoin  Carbamazepine  Sodium valproate Beta-adrenergic agonists  Metaproterenol Amphetamines   ● ● ● ●

Reaction Acute dystonic reaction Tardive dyskinesia Withdrawal dyskinesia Parkinsonism Neuroleptic malignant syndrome

● ●

● ●

Chorea Dystonia Tremor


Cocaine Lithium


Chorea Tremor Chorea Chorea Tremor

*Common examples are listed, but the list is not intended to be comprehensive.

other tics. Stereotypies typically do not bother the patient, but can be distressing to the parents. Stereotypies Stereotypies respond inconsistently to medications such as clonazepam, SSRIs, and haloperidol. Medical therapy usually is not indicated.


The most important childhood tremors are action tremors and include clu de phy physiol siologi ogicc tre tremor mor and essentia sen tiall (fa (famil milial ial)) tre tremor mor.. Phy Physiosiologic tremor is a normal phenomenon, consisting of a 6- to 12-Hz 12Hz osc oscill illatio ation n tha thatt usu usuall allyy is noticed by the individual or other observer ser verss onl onlyy und under er cer certai tain n con condiditions. A few individuals have visible physiologic tremor that is termed “enh enhance anced d phy physio siolog logic ic tre tremor mor..” These individuals individuals are otherwise indistin dis tingui guisha shable ble fro from m tho those se who have ha ve no en enha hanc nced ed ph phys ysio iolo logi gicc tremor. Physiologic tremor may increase cre ase wit with h anxi anxiety ety,, exci excitem tement ent,, fear, fea r, or cert certain ain med medicat ication ions, s, inc includlud-

ing sodium valpro valproate, ate, theop theophyllin hylline, e, beta-agonist beta-a gonists, s, cortic corticosteroi osteroids, ds, and stimul sti mulant ants. s. The tre tremor mor of hyp hypererthyroidism is an enhanced physiologic tremor. Essent Ess ential ial tre tremor mor fre freque quentl ntlyy is con conside sidered red a diso disorde rderr of  adul ad ults, ts, bu butt it ca can n be begi gin n in in infa fanc ncyy or chi child ldho hood od.. Es Esse sent ntia iall tremor is present with posture and with action, but it usually is greatest with maintained posture. It typically  involves the upper extremities, but may involve the head and neck, voice, and legs. By definition, essential tremor is unaccom unaccompanied panied by other neurologic abnormalities, abnormalities, although althou gh indivi individuals duals may have slight clumsi clumsiness. ness. Essential tremor is  “ familial”  (autosomal dominant) in about 60% of cases. There have been no treatment studies of  essential tremor in children, but experience has shown that children respond to the same medications that are effective in adults. The most effective medications are propra pro pranol nolol ol (or oth other er bet beta-bl a-block ockers ers)) and pri primid midone one.. Clonazepam Clonaze pam may be effective in some cases.

Tremor is a rhythmic oscillation about a central point or posi po siti tion on th that at in invo volv lves es on onee or mo more re bo body dy pa part rts. s. Tr Trem emor or in childhood is not rare, but few epidemiologic data are available to indicate the incidence or prevalence. Tremor is classified by when it occurs: with rest, intention, or action. Rest tremor is defined as tremor involving a body  part that is inactive and supported against gravity. It is associated most commonly with other signs of parkinsonis son ism, m, but it ma mayy oc occu curr in iso isola lati tion on.. Th Thee mo most st co comm mmon on cause of rest tremor in children is antipsychotic (neuroleptic lep tic)) med medica icatio tions. ns. Int Intent ention ion tre tremor mor occ occurs urs as a mov moving ing body part approaches a target and usually is associated  with other signs of cerebellar dysfunction. Action tremor occurs during maintained posture, voluntary movement, or both. When evaluating the child who has tremor, attention should be paid to possible other neurologic signs or symptoms. When present, these features usually 

The phe phenom nomeno enolog logic ic clas classi sificat cation ion of dru drug-i g-indu nduced ced movement disorders is the same as for nondrug-induced disorders. However, because medications are a relatively  common cause of movement disorders in children, they  deserve special consideration. Perhaps the best known drug-induced movement disorders are those associated  with antipsychotic (neuroleptic) treatment. These med-

direct dire ct th thee di diag agno nosti sticc ev eval alua uati tion on.. Wh When en tr trem emor or is th thee on only  ly  abnormality, it is important to identify potential tremorenhancing enhanci ng medications. medications. The primary laboratory tests to be considered are thyroid function tests.

ications are dopamine receptor antagonists ications antagonists and cause both acute and tardive (ie,  “ late”) syndromes. The acute adversee effect advers effectss of dopam dopamine ine antagonists include parkinsonism and acute dystonic reactions. Acute dystonic re-

Drug-induced Movement Disorders

Pediatrics in Review  Vol.24 No.2 February 2003   49


neurology   movement disorders

actio ions ns can oc occu curr af afte terr a si sing ngle le do dose se of a do dopa pami mine ne act antagonist. antago nist. The typica typicall acute dystonic reaction involves involuntary gaze deviation (oculogyric crisis), torticollis, and appendicular twisting postures involving axial more than appendicular muscles. It can last for hours, but is treated treate d readil readilyy with anticholinergic anticholinergic medications such as diphenhydramine (1 mg/kg per dose every 6 h) and benztropine (0.5 to 2 mg per day bid). The most severe reaction to dopamine antagonists is the neuroleptic malignant syndrome, which is characterized by hyperthermia, hypertonia, dystonia posturing, tremor, and autonomic nom ic ins instab tabili ility, ty, and can be fat fatal. al. Tre Treatm atment ent pri primar marily ily is supportive and includes fever control and correction of  metabolic abnormalities. Dantrolene should be given to diminish excessive muscle contraction. Dopamine agonistss suc nist such h as brom bromocri ocripti ptine ne may be eff effect ective ive.. Neu Neurole rolepti pticc medications should be discontinued. Tardivee dyskin Tardiv dyskinesia esia (TD) is uncomm uncommon on in childhood.

done, quetiapine, olanzapine, and ziprasidone, have a demonstrably demon strably lower incide incidence nce of such extrap extrapyramid yramidal al adverse effects. Treatment of TD can be dif ficult and requires referral to a neurologist or psychiatrist experienced in its treatment. Prevention of TD requires care to avoid indiscriminate indiscriminate use of antips antipsychoti ychoticc medic medications ations and attempts attempts to lim limit it the duration duration of tre treatm atment ent and minimize the total daily dose. Many other medications have been associated with movement movem ent disorders. The more commo common n ones are summarize mar ized d in Tab Table le 8. The tre treatm atment ent of dru drug-i g-indu nduced ced movement movem ent disorders is to eliminate the offend offending ing agent  whenever possible. In most cases, it does not make sense to use an anot othe herr me medi dicat catio ion n to tr trea eatt adv adver erse se ef effe fect ctss fr from om an offending medication.

The dyskinesia can manifest as any of the hyperkinetic movement disorders. TD typically manifests as an orobuccal-lingual stereotypy, but it can involve other body  part pa rts. s. Th Thee ri risk sk of TD in incr crea ease sess wi with th to total tal do dose se an and d treatm tre atment ent dur durati ation on of ant antips ipsych ychoti oticc med medicat ication ion and wit with h thee ag th agee of th thee pa pati tien ent. t. Th Ther eree is som somee ev evid iden ence ce th that at children who have had brain injuries are more likely to develop TD. Extrapyramidal adverse effects such as acute dystonic reaction, parkinsonism, and TD are substantially more likely to occur with the older, so-called “ typical” neuroleptic lep ticss such as hal halope operido ridoll and pim pimozi ozide de and oth other er dopamine-blocking agents such as metoclopramide and prochlorperaz prochlo rperazine. ine. Atypi Atypical cal neurol neuroleptic eptics, s, such as risperi risperi--

Budoutb Budman manursts C, in Bruun Bru un ren R, with ParkTour K, Les Lesser M, Ols Olson M.Acad Explos Exp losive ive outbursts children child Tourette etteser ’s disord disorder. er.on  J Am Child   Adolesc Psychiatry. 2000;39:1270 –1276 Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S. Treatment of  acute streptococcal streptococcal phary pharyngiti ngitiss and prev preventio ention n of rheum rheumatic atic fever: a statement for health professionals.  Pediatrics. 1995;96: 758 –764 Fernandez-Alvarez E, Aicardi J.  Movement Disorders in Children . London, England: MacKeith Press; 2001 Robertson MM. Tourette syndrome, associated conditions and the complexities of treatment. Brain.  2000;123:425– 462 Touret Tou rette te Syn Syndro drome me Stu Study dy Gro Group. up. Tre Treatm atment ent of ADH ADHD D in chi childr ldren en  with tics: a randomized controlled trial.   Neurology.  2002;58: 527–536  Watts RL, Koller WC.   Movement Disorders: Neurologic Principles  and Practice . New York, NY: McGraw-Hill; 1997 Zinner SH. Tourette disorder.  Pediatr Rev.  2000;21:372–383

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PIR Quiz Quiz also available online at 1. The recommende recommended d initial intervention intervention for treatment of tics (with suf ficient morbidity) associated with Tourette syndrome is a (an): A. Alpha-2-adrener Alpha-2-adrenergic gic agonist. B. Biofe Biofeedbac edbackk prog program ram to assis assistt with voluntary suppressio suppression. n. C. Neuro Neurolepti leptic. c. D. Stimu Stimulant. lant. E. Sele Selective ctive serotonin serotonin reuptake inhibitor (SSRI). (SSRI). 50   Pediatrics in Review  Vol.24 No.2 February 2003


neurology   movement disorders

2. You have diagnosed diagnosed atten attentiontion-de defi ficit/hyperactivity disorder in an 11-year-old boy whose attention dif ficulti culties es are causing signi signifi ficant learning impairments. The boy also has a 1-year history of brief, mild, intermittent facial twitching and throat-clearing when he is anxious or tired. A psychological assessment reveals no additional learning disability. The  Physician s Desk Reference  states   states that methylphenidate is contraindicated in children who have tics. Of the following, which is the  best  plan   plan of action? A. Begi Begin n a trial of methylphenida methylphenidate te after discussing discussing with the parents that initiation initiation of this therapy therapy may correlate with a transient increase in tics, but that tics are unlikely to worsen and may improve overall. B. Imple Implement ment a behav behavior ior plan for ADHD and forego medical medical inter intervent vention. ion. C. Initia Initiate te a medi medication cation trial using a seco second-li nd-line ne drug for ADHD ADHD,, such as a tricyclic antidepres antidepressant. sant. D. Initia Initiate te a medi medication cation trial with an SSRI to treat the anxiety anxiety because it seems to be causi causing ng the tics. E. Initia Initiate te treatment treatment with an alpha alpha-2-ad -2-adrene renergic rgic agonist because because it has been demo demonstra nstrated ted as supe superior rior to methylphenidate in treating both ADHD and tics. ’  

3. Of the foll followi owing ng medication medications, s, the one that is  most  likely   likely to cause a clinically signifi signi ficant movement disorder is: A. Albut Albuterol. erol. B. Cocai Cocaine. ne. C. Lithi Lithium. um. D. Methylphenidate. E. Neuro Neurolepti leptics. cs. 4. The  best   intervention for acute drug-induced dystonia is: A. Baclo Baclofen. fen. B. Cloni Clonidine. dine. C. Dantr Dantrolene olene.. D. Diphenhydramine. E. Prop Propranol ranolol. ol. 5. Of the following, following, a true  statement  statement regarding the diagnosis of Sydenham chorea (SC) is that: A. An anteceden antecedentt grou group p A betabeta-hemo hemolytic lytic streptococca streptococcall (GAB (GABHS) HS) infection (ie, a posi positive tive throat culture) must be identifi identified before SC can be diagnosed. B. Asym Asymmetry metry of involuntary involuntary movements movements is incom incompatib patible le with the diagnosis diagnosis of SC and indic indicates ates a focal neurologic lesion. C. Coex Coexisting isting carditis carditis or arthritis must be present present for the diagnosis diagnosis of SC. D. Posit Positive ive serology serology tests (ie, antistreptoly antistreptolysin sin O and antiDNase antiDNase B antibo antibodies dies)) for GABHS are requi required red to diagnose SC defi definitively. E. The appearanc appearancee of signifi significant behavior problems in conjunction with chorea is consistent with the diagnosis of SC. 6. Of A. B. C. D. E.

the following, following, the most  common   common cause of chorea in childhood is: Acute rheumatic rheumatic fever. fever. Hallerverden-Spatz Hallerverden-S patz disease. Hyperthyroidism.. Hyperthyroidism Juvenile Juve nile Huntington Huntington disease. Systemic lupus erythematosus.

7. The factor factor that best  differentiates  differentiates Tourette syndrome from other chronic tic disorders is the presence of: A. A familial inheritance inheritance pattern. pattern. B. Both motor motor and vocal tics. tics. C. Comp Complex lex motor tics. tics. D. Copr Coprolali olalia. a. E. Male gender gender..

Pediatrics in Review  Vol.24 No.2 February 2003   51

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