Dystonia in Wilson \200\231s disease . Mov Disord 2001; 16 : 719 \200\22323 . 23. Risvoll H, Kerty E. To test or not? Th e value of diagnostic tests in cervical Do not assume that it cannot be WD because the patient is \200\230too old \200\231. \227\206 dystonia . Mov Disord 2001; 16 : 286 \200\2239 . 24. Oder W, Grimm G, Kollegger H, Ferenci P, Schneider B, Deecke L. Neurological and neurop sychiatric spectrum of Wilson \200\231s disease: a pro- spective study of 45 cases . J Neur ol 1991; 238 : 281 \200\2237 . WD is complicated. Try to see these patients in a multidiscipli- nary clinic together with hepatologists or metabolic physicians. \227\206 25. Machado A, Chien HF, Deguti MM et al. Neurological manifestations in Wilson \200\231s d isease: report of 119 cases . Mov Disord 2006; 21 : 2192 \200\2236 . 26. Haggstrom G, Hirs chowitz BI. Disordered esophageal motility in Life-long close monitoring of WD patients may be more important than the initial decision a s to which drug the patient should be started on. \227\206 Wilson \200\231s disease . J Clin Gastroenterol 1980; 2 : 273 \200\2235 . 27. Dening TR, Berrios GE, Walshe JM. Wilson \200\231s disease and epilepsy . Brain References 1. Hoogenraad TU. S.A. Kinnier Wilson (1878 \200\223937) . J Neurol 2001; 248 : 1988; 111 : 1139 \200\22355 . 28. Ingster-Moati I, Bui Quoc E, Pless M, et al. Ocular motility and Wilson \200\231s disea se: a study on 34 patients . J Neurol Neurosurg Psychiatry 2007; 78 : 1199 \200\223201 . 71 \200\2232 . 2. Walshe JM. Th e conquest of Wilson \200\231s disease . Brain 2009; 132 : 2289 \200\22395 . Oxford Textbook of Movement Disorders 246 40. Dahlman T, Hartvig P, L fh olm M, Nordlinder H, L f L, Westermark K. Long-ter m treatment of Wilson \200\231s disease with triethylene tetramine dihydrochloride (trientin e) . QJM 1995; 88 : 609 \200\22316 . 29. Dening TR, Berrios GE. Wilson \200\231s disease: psychiatric symptoms in 195 cases . Arch Gen Psychiatry 1989; 46 : 1126 \200\22334 . 30. Portala K, Westermark K, von Knorring L, Ekselius L. Psychopathology in treated Wilson \200\231s disease determined by means of CPRS expert and self-rating s . Acta Psychiatr Sca nd 2000; 101 : 104 \200\2239 . 41. Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK. Treatment of Wilson \200\231s disease with zinc. XV: Long-ter m follow-u p stud- ies . J Lab Clin Med 1998; 132 : 264 \200\22378 . 31. Svetel M, Potrebi \207 A, Pekmezovi \207 T, et al. Neuropsychiatric aspects of treate d Wilson \200\231s disease . Parkinsonism Relat Disord 2009; 15 : 772 \200\2235 . 32. Gold ing DN, Walshe JM. Arthropathy of Wilson \200\231s disease: study of clini- cal and radiolo gical features in 32 patients . Ann Rheum Dis 1977; 36 : 99 \200\22311 1 . 42. Czlonkowska A, Gajda J, Rodo M. Eff ects of long-ter m treatment in Wilson \200\231s di sease with D-penicillamin e and zinc sulfate . J Neurol 1996; 243 : 269 \200\22373 . 43. Schumacher G, Platz KP, Mueller AR, et al. Liver transplantation in neu- rologic Wilson \200\231s disease . Transplant Proc 2001; 33 : 1518 \200\22319 . 33. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson \200\231s disease . 44. Wu JC, Huang CC, Jeng LB, Chu NS. Correlation of neurological mani- festations and MR i mages in a patient with Wilson \200\231s disease aft er liver transplantation . Acta Neurol Scand 2000; 102 : 135 \200\2239 . Lancet 2007; 369 : 397 \200\223408 . 34. Tauber J, Steinert RF. Pseudo-Kayser \200\223Fleische r ring of the cornea associ- ated with non-Wilsonia n liver disease: a case report and literature review . Cornea 1993; 12 : 74 \200\2237 . 45. Leinweber B, M ller JC, Scherag A, et al. Evaluation of the Unifi ed Wilson \200\231 s Disease Rating Scale (UWDRS) in German patients with treated Wilson \200\231s disease . M ov Disord 2008; 23 : 54 \200\22362 . 35. McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H. Th e neurologi- cal presentation of ceruloplasmin gene mutations . Eur Neurol 2008; 60 : 200 \200\2235 . 46. Lang PA, Schenck M, Nicolay JP, et al. Liver cell death and anemia in Wilson disease in volve acid sphingomyelinase and ceramide . Nat Med 2007; 13 : 164 \200\22370 . 36. Gromadzka G, Chabik G, Mendel T, et al. Middle-age d heterozygous carriers of Wilson \200\231s disease do not present with signifi cant phenotypic deviations related to copper metabolism . J Genet 2010; 89 : 463 \200\2237 . 37. Prashanth LK, Sinha S, Taly AB, Vasude v MK. Do MRI features distin- guish Wilson \200\231s disease from other early onset extrapy ramidal disorders? An analysis of 100 cases . Mov Disord 2010; 25 : 672 \200\2238 . 47. Zhang S, Chen S, Li W, et al. Rescue of ATP7B function in hepatocyte-lik e cells from W ilson \200\231s disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin . Hum Mol Genet 2011; 20 : 3176 \200\22387 . 48. Starosta-Rubinstein S, Young AB, Kluin K, et al. Clinical assessment of 31 patients wit h Wilson \200\231s disease: correlations with structural changes on magnetic resonance imag ing . Arch Neurol 1987; 44 : 365 \200\22370 . 38. Vilensky JA, Robertson WM, Gilman S. Denny-Brow n, Wilson \200\231s disease, and BAL (B ritish antilewisite (2,3-dimercaptopropano l)) . Neurology 2002; 59 : 914 \200\22316 . 49. Jha SK, Behari M, Ahuja GK. Wilson \200\231s disease: clinical and radiological 39. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurologic syndrome in patients wi th Wilson \200\231s disease with initial penicillamine therapy . Arch Neurol 1987; 44 : 490 \200\2233 . features . J Assoc Physicians India 1998; 46 : 602 \200\2235 . CHAPTER 24 Tic Disorders and Stereotypies Erika F. Augustine and Jonathan W. Mink Tics and stereotypies are among the most common movement dis- orders in childhood. Th ese e arly-onset involuntary movements are stereotyped in nature, but diff er in phenomenology, a ge at onset, and co-morbid conditions. Th is chapter will outline the key identi- fying fea tures, natural history, and treatment of each. involuntary movements, family history, and thorough examina- tion may provide clues to the diagnosis. An individual child may have multiple stereo typies; however, the overall repert oire of move- ments is relatively constant over time, in contrast with chronic tic disorder s where the catalog of tics evolves (see Table 24.1 for other features diff erentiating ste reotypies from tics). Stereotypies may demonstrate rhythmicity similar to tremor. Whereas t remor involves oscillation around a single joint, stereotypies involve mul- tiple limb part s. Also, the duration of expression of stereotypies is oft en shorter than that of tremor. As it relates to prominent head stereotypies without other common motor stereotypies, espec ially in the setting of motor delay or clumsiness, cerebellar pathology or alternate diagno ses (spasmus nutans, bobble-head doll, head tremor, or hydrocephalus) should be considered (6, 7). Stereotypies Stereotypies are involuntary, patterned, co-ordinated, repetitive, and non-ref l exive movements that occur in the same fashion with each repetition (1). Although these n on-functional movements are typi- cally simple, fl eeting, and rhythmic in appearance, more complex, sustained, and non-rhythmic movements can be seen. Stereotypies occur multiple ti mes daily, particularly in settings of excitement, nervousness, fatigue, or engrossment. Th ese predictable and some- times suppressible movements are brief, lasting seconds to minut es, and most commonly involve the head, torso, and upper extremities in a symmetric manner. Neurobiology The neurobiology of complex motor stereotypy is not well understood. Conventio nal imaging and electrophysiological studies are unrevealing in healthy children with stere otypy. Psychological factors, including self-stimulation and response to social deprivation , have been proposed. Dopamine and both direct and indirect dopamine receptor agonists can induce stereotypy, suggesting disruption of the striatal dopaminergic system as a factor. T he efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of stereoty py raises a possible role for serotonin in the production of stereotypy, although it remain s unclear whether this is through indirect effects on the dopaminergic system. Reductions i n frontal white matter and caudate volume in healthy boys with stereotypies may implicate a bnormalities of the cortico-striatal-thalamo-cortical (CSTC) circuitry, as seen in other mo vement disorders (8, 9). Th e Diagnostic and Statistical Manual of Mental Disorders-IV TR (DSM-IV TR) criteria for s tereotyped movement disorder include interference with normal activities or self-injury (2) . Th ese fea- tures are unusual for most typically developing children. Although stereo typ ies may briefl y interrupt activity, they do not generally interfere with intended motor mo vements or impose functional limitations. Examples of common stereotypies include hand fl a p- ping, clapping, fi nger wiggling, body rocking, head nodding, and walking in circles, so metimes in conjunction with facial grimacing or vocalizations (3 \200\2235). Di \200 erential diagnosis It may be diffi cult to diff erentiate stereotypies from other involun- tary movements, particularly complex motor tics. Although both types of movement a re distractible and suppressible, the absence of premonitory urge in stereotypies is a help ful distinguishing feature. However, much like very young children with tics, young childre n with stereotypies may not be able to describe the feelings present during the movements, or may be unaware of the move- ments al together. In these circumstances, close review of o ther Epidemiology Stereotypies almost always begin before the age of 3 years and occur with high er frequency in boys (male-to-female ratios range from 1.6 to 3:1). Familial tendencies sug gest a genetic component, with a positive family history in 25 \200\22330% (4, 10). Oxford Textbook of Movement Disorders 248 years. Stereotypy was associated with the diagnosis of autism (odds ratio (OR) 7.20, p < 0. 001). Children with autism demonstrated a mean 13.42 stereotypies compared with 8.24 in the non-autism group ( p = 0.03). Analogous patterns were observed with respect to number of s tereotypies and non-verbal IQ. Children with autism demonstrate a wider range of stereotypi c behaviors with respect to type and diversity of movement (14 \200\22317). Table 24.1 Stereotypies versus tics Stereotypies <3 years Tics 5 \200\2237 years Age at onset Premonitory urge No Yes Suppressible Sometimes Yes Duration Seconds to minutes Second(s) Rhythmicity Yes No Stereotypies are a cardinal feature of Rett syndrome and one of the diagnostic criteria, pr esent in virtually all patients (18). Midline hand-wringing movements are most common follo wed by brux- ism; both can be frequent to constant in occurrence (19). Almost unique to Ret t syndrome, stereotypies oft en involve the hand and mouth and can be quite complex, with i ndependent stereotypies performed simultaneously with each hand. Prominent stereotyp- ies p recede or arise along with loss of purposeful hand movement between 6 months and 3 years of age. Mutation-positive girls with Rett syndrome tend to display a greater number of stereo typies than mutation-negative patients with a Rett phenotype (20). Th ere are confl icting reports regarding persistence of stereotypies over time in Rett syndrome. Some centers have observed a decrease in expression of stereotypies aft er age 10 years or approximately 5 y ears of disease evolution in mutation-positive patients (19, 21), particu- larly stereotypi es that do not involve the hands (20). Another cen- tre has observed persistence of stereot ypies into adolescence and adulthood, although they were simpler because of the development of rigidity (22). Typical anatomical distribution Hands, arms, whole body Eyes, face, neck, shoulders Evolution over time Little Considerable Persistence in sleep No Possible Time course of improvement Early childhood Adolescence Response to medication Poor Good Clinical features and course Motor stereotypies occurred in 2 \200\2233% of a cohort of 3- to 6-year-old children without developmental delay. Nail biting and thumb suck- ing, which are oft en considered to be stereotypies, were catego- rized separately, occurring in 23% a nd 25%, respectively (11). In a cohort of 100 typically developing children with motor ster eotyp- ies, involuntary movements began before age 2 years in over 80% of the sample. Distr actibility was reported by 99% of parents. Aft er a mean 6.8 years of follow-up, only 6% of subjects reported ces- sation of stereotypies which were present for 11 \200\22312 years i n two subjects prior to resolution. Th ose with head nodding were more likely to report res olution than those with other types of stereotypy. Symptoms were stable for the majority of children, with worsening in only a small subset (10). Stereotyped behaviors occur frequently in blind children. Although the same range of motor stereotypies seen in typically developing and developmentally impaired children does occur, blind children also have certain fairly specifi c oculodigital stere- otypies including ey e rubbing, pressing, and poking. Th ese occur with greatest frequency in those with periphe ral causes of blind- ness. In a sample of 26 children with congenital blindness, 73.1% demo nstrated stereotypies, including eye pressing or poking in 30% (23). Prognosis has traditionally been thought to be very good for stereotypies in typically deve loping children, with improvement in involuntary movements beginning by the age of 4 years. However, some studies show that stereotypies oft en persist, and that neu- ropsychiatric c o-morbidity is common, occurring in up to 46 \200\22370% (4, 10, 12). In the cohort mention ed above, 9% demonstrated early motor delay, and 6% demonstrated early language delay. Fort y-six% of children over age 7 years in the same cohort carried a co- morbid diagnosis, incl uding attention defi cit \200\223hyperactivity disorder (ADHD), tics, and/or obsessive \200 \223compulsive behaviors (10). Th us stereotypies may not be quite as benign as once though t. Stereotypies have also been described in association with genetic, metabolic, neurodegenera tive, paraneoplastic, and infec- tious conditions, including Down \200\231s syndrome, cri d u chat (24), Prader \200\223Willi syndrome (25), CDKL5 mutations (26), Primrose syndrome (2 7), Smith \200\223Magenis syndrome (28, 29), Rubinstein \200\223 Taybi syndrome (30), fragi le X syndrome (31), FOXG1 mutations (32), phenylketonuria (33), Wilson disease (34), herpes encepha- litis (35), encephalitis lethargica (36), and congenital cerebellar malformations (7). Complex motor stereotypies are found in a majority (84%) of patients presenting with anti-NMDA receptor encephalitis (37). Long standing stereotypies such as foot tapping, hair twirling, and nail biting have been reported in adults with normal cognition. Stereotypies in neurodevelopmental and neurodegenerative disorders Many types of repetitive behavior are seen in autism, including restricted interests, compulsions, routines, and st ereotypies. In a study of 60 children with autism spectrum disorders aged 2 \200\2235 years , some of whom were later diagnosed with autism, stereotyp- ies were present with increasin g frequency in pervasive develop- mental delay (PDD) (9%), high-functioning autism (31%), a nd low-functioning autism (56%) ( p < 0.05). Th e presence and sever- ity of stereotypies m ay correlate with the severity of the underlying disorder (13). Goldman et al. (14) reporte d similar fi ndings from a study of videotaped sessions of the play of 129 autistic and 148 non-autistic developmentally delayed (NADD) children aged 2 \200\2238 Evaluation Evaluation is largely based on observation of the movement in ques- tion, unders tanding the settings in which it occurs, and response to redirection. When the movement doe s not occur during the course of the offi ce visit, home video can be an invaluable tool to aid in diagnosis. Th e opportunity to observe the movement and recognize it as stereotypy may avoid unnecessary work-up with EEG, MRI, and/or lumbar puncture. Diagnostic evaluation should be guided by the history and fi ndings, if any, on neurological examination. Given t he potential prominence of stereotypies in children with develop- mental disabilities or vi sual impairment, it is not uncommon for parents to express concern. A greater frequency and repertoire of CHAPTER 24 Tic Disorders and Stereotypies 249 Simple phonic tics are meaningless utterances or sounds such as sniffi ng, coughing, throat clearing, clicks, humming, animal sounds, or whistling. Children with sniffi ng, coughing, or throat-clearing tics may fi rst present to the allergist or otolaryngologist with con- cerns about seasonal allergies or asthma. Following failure of ini- tial treatments or appe arance of other classic tics, the focus is then re directed towards neurological evaluation . stereotypies in a developmentally delayed child may raise concern for an underlying disorde r such as autism or genetic syndromes. Treatment Most children with stereotypies do not require treatment, particu- larly if the m ovements do not interfere with daily activities and are not causing self-harm or discomfort . However, when movements are severe and cause injury or social impairment, treatment may b e considered. In terms of behavioral strategies, habit reversal, as used in tic disorders, has been a successful strategy for stereotypies. Habit reversal combined with diff erential reinforcement of other behaviors in a cohort of 10 non-autistic children aged 6 \200\22312 years with stereotypies resulted in improvements in stereotypy severity. Improvement corre lated with the number of treatment sessions completed and motivation (38). Additional behav ioral strategies include response interruption and redirection (39 \200\22341). Complex motor tics represent more intricate co-ordinated patterns of movement involving mor e than one muscle group. Bending, jumping, kicking, spitting, smelling, obscene gestures (c opro- praxia), and elaborate repertoires of movement are examples. Some patients manifest b locking \200\224sudden cessation of all motor activity. Th e separation of complex tics fro m compulsions or habit disorders can be quite challenging. Complex phonic tics are more involved utterances, including words, phrases, profanity, or r acial slurs (coprolalia), repetition of others \200\231 words (echolalia), or repetition of one \200\231s own words (palila- lia). Th e latter two symptoms may also be a manifestatio n of com- pulsive behavior. Pharmacological benefi t from benzodiazepines, SSRIs (42, 43), neuroleptics (44), opiate an tagonists, alpha-adrenergic agents, beta-blockers, and antiepileptic medications have been reported (12, 45). Th ree randomized controlled trials demonstrated benefi t of risperidone over placebo for treatment of autistic children with stereotypy; one randomized trial show ed no diff erence from pla- cebo (46). Tics wax and wane and vary in anatomical distribution. Children with mild tics are typicall y free of functional impairment. Very young children may even be unaware of the movements. However, more frequent and intricate tics can result in social embarrassment, speech interr uption, and diffi culty with everyday tasks. Less com- monly, tics result in pain or frank injury (49). Tics Tics are sudden, repetitive, stereotyped, and non-rhythmic move- ments that can be a m anifestation of childhood-onset neuro- behavioral disorders. Tics are categorized as motor or phonic if laryngeal, pharyngeal, nasal, or respiratory muscles are involved. In 74 \200 \22392% of children, these involuntary movements are preceded by a premonitory urge, descri bed as a general tightening, discomfort, sensation of internal build-up, or localizable pai n, itching, burn- ing, or pressure (47). Th e premonitory urge is relieved at least tem- po rarily by the tic in the majority of patients. Th ere is oft en a lag between tic onset and the onset of recognized premonitory urges (up to 3 years in one series). Tics can persist in all stages of sleep and are suppressible which, in addition to the premonitory urge, are features that help to diff erentiate tics from other movement dis- orders. Tics are sugges tible, may demonstrate rebound phenomena aft er suppression, and may be exacerbated by posi tive or negative stress or relaxation aft er stress, such as return to home aft er school. Work by Conelea and colleagues (48) suggests that, when examined objectively, tic frequency does not actually increase in the setting of stress; rather, successful tic suppression is disrupted. Tics fl uctuate in frequency and severity, and evolve in type and anatomical di stri- bution over time such that the constellation of tics present in a child in early chil dhood may be quite diff erent from those demonstrated years later. Neurobiology Th ere has been signifi cant focus on the role of the basal ganglia in tic dis orders, given its involvement in other movement disor- ders as well as the development or e xacerbation of tics in the set- ting of acquired basal ganglia lesions (50 \200\22352). Ana tomical studies have demonstrated decreased caudate nucleus volumes in children and adults with Tourette \200\231s syndrome (TS) compared with controls, and inverse correlation betwe en childhood caudate volume and tic severity in early adulthood (53 \200\22355). Th inning of the sensorimo- tor cortex compared with controls was positively correlated with tic seve rity in a cohort of 25 children with TS (56). A study of tic suppression using functional M RI found changes in signal inten- sity in the basal ganglia, thalamus, and related cortical regions (57). Decreased parvalbumin positive GABAergic and choline acetyl- transferase pos itive cholinergic interneurons in the caudate and putamen suggest impaired regulation of st riatal neuronal fi ring (58). Tics may be a consequence of abnormal corticothalamic acti- v ation of specifi c groups of striatal neurons, resulting in increased focal inhibition of g lobus pallidus internus (GPi) or substantia nigra pars reticulata (SNr) output neurons. Clinically, response to dopamine-receptor antagonists and potential exacerbation of tics by dopamine and dopamine receptor agonists suggest involvement of the dopaminergic neurotrans mit- ter system. PET and SPECT studies demonstrate confl icting results, but there is evide nce for increased dopamine activity in the stria- tum (59). Post-mortem pathology supports functional imaging fi ndings, with evidence of increased dopamine uptake sites in the cauda te and putamen (60). Simple motor tics are brief, purposeless, and typically involve only one muscle group. Exam ples include blinking, eye rolling, head nodding, and shoulder shrugging. Tics may be cloni c (sud- den jerks), tonic (sustained muscle contractions), or dystonic (sustained abnormal postures). Abdominal tightening is a com- mon tonic tic, while sustained mouth opening, ocu logyric move- ments, blepharospasm, and torticollis are examples of dystonic tics. In contr ast with stereotypies that mainly occur in the upper limbs or entire body, simple motor tic s predominate in the head and neck. An enhanced immune response and post-streptococcal autoim- munity are among numerous propos ed aetiological factors. Tics are described as part of pediatric autoimmune neuropsychiatri c disorders associated with streptococcal infections (PANDAS) in which there is abrupt onse t of multiple neuropsychiatric symptoms Oxford Textbook of Movement Disorders 250 Tourette \200\231s syndrome Clinical course Tic onset is in early childhood, on average at age 5 \200\2237 years, with signifi cant improvement in symptoms, if not resolution, by age 18 years. Th e mean age at onset of phonic tics is later than that of motor tics, 10 \200 \22311 years versus 7 years, respectively (64, 65). Th e age of greatest tic severity is ty pically 10 years, and tics tend to improve in adolescence. In a cohort of 42 children with TS, almost 50% were tic free by age 18 years. Early tic severity may not be a predictor of later tic severity (66). Although tics generally demonstrate a favor- able course over time , the same may not be true for co-morbid dis- orders, which can exhibit lifelong manifestat ions. Despite common association with psychopathology, TS was not common in assess- ment of adults in an adult inpatient psychiatry setting with major psychiatric disorders (67). Whe n tics do persist into adulthood, facial and truncal tics tend to predominate over other ti cs, and there may be an increased risk of mood disorders and substance abuse (68). following pharyngeal streptococcal infection. Symptoms may sub- sequently fl are in associa tion with repeated streptococcal infection. Although recent studies show elevations in anti -streptolysin (ASO) titres and frequency of streptococcal infections in children with TS co mpared with controls, these same studies fail to show a clear relationship between streptoc occal infection and neuropsychiatric symptom exacerbations (61). Th us, PANDAS remains a co ntrover- sial entity. Tic disorders Primary tic disorders are categorized based on type of tic (motor, phonic, or both) and duration of symptoms (less or greater than 1 year). TS is a clinical diagnosis b ased on the presence of at least one phonic and multiple motor tics that have been present on a near daily basis for at least a year based on history and/or observation. See Table 24 .2 for distinctions between transient tic disorder, chronic motor and chronic phonic tic di sorders, Tourette \200\231s syndrome, and tic disorder not otherwise specified (NOS). Despite portrayal in the media of coprolalia and copropraxia as common in TS, relatively fe w patients exhibit this symptom. In an evaluation of lifetime occurrence of coprophenomena in 597 individuals with TS, coprolalia occurred in 19.3% of males and 14.6% of females, con sistent with other reports (65, 69). Copropraxia occurred at a lower frequency, in 5.9% of males and 4.9% of females. It is an unusual presenting symptom; the mean age at onset is 10 .5 \200\22311 years (64, 69). Coprophenomena may be associated with more severe TS, as mani fested by a broader array of co- morbidities including associations with aggression, earlie r onset of tics, greater number of tics, spitting, inappropriate sexual behav- iour, and se lf-injury (65, 69). Epidemiology of tics and Tourette \200\231s syndrome Estimates of the prevalence of tic dis orders in childhood vary widely, from 0.9 to 28%. In contrast, estimated adult prevalence i s approximately 1%, emphasizing that tics are predominantly, although not completely, an is sue of childhood. Challenges in establishing accurate estimates include changing criteria a nd defi - nitions of tics, assessment using existing diagnoses versus observa- tion, and id entifi cation of mild cases. Although tic phenomenology is similar across diff erent cultur es, there is a question of lower tic prevalence in African Americans and sub-Saharan black Africans (62, 63). Co-morbid disorders Th ere is a high co-occurrence of neuropsychological disorders with tic s, including problems of attention, mood, anxiety, socialization, learning, impulse control , oppositionality, and obsessions and com- pulsions (70). Tics occur with higher frequency in special education popula- tions, at a frequency of 27% compared with 19.7% in a general edu- cation sample (63); TS similarly occurs at higher fre quency in this population. For TS, prevalence estimates similarly vary based on popula- tion and methodology, 0.4 \200 \2233.8% in general pediatric populations. An overall estimate of 1% was generated by Rober tson et al. in a meta-analysis of 14 studies including 420,312 subjects (62). Males are aff ected more than females, 3 \200\2234:1 (64). ADHD is a common comorbidity which may present 2 \200\2233 years prior to the onset of tics . In the Tourette Syndrome International Database Consortium (TIC) database of over 6000 su bjects, the frequency of ADHD was 61% in children and 39% Table 24.2 DSM-IV TR criteria for tic disorders (2) Transient tic disorder Chronic motor tic disorder Motor Chronic vocal tic disorder Phonic Tourette \200\231s syndrome Tic disorder not otherwise speci \201 ed Motor or phonic Tic types Motor or phonic Motor ( \211 2) and phonic ( \211 1) Many times daily or near daily Frequency Many times daily or near daily Many times daily or near daily Many times daily or near daily No frequency criterion Duration 4 weeks \200\22312 months \211 12 months \211 12 months \211 12 months <4 weeks or ongoing but <12 months Tic-free intervals <3 months <3 months <3 months <3 months No criterion Age of onset <18 years <18 years <18 years <18 years No age criterion Other factors Not due to e \200 ects of a substance or general medical condition Not due to e \200 ects of a substance or general medical condition Not due to e \200 ects of a substance or general medical condition Not due to e \200 ects of a substance or general medical condition Tics that do not meet criteria for a speci \201 c disorder CHAPTER 24 Tic Disorders and Stereotypies 251 injuries, self-biting, cervical myelopathy, fractures, and subdural haematoma (76). Individ uals with malignant TS may benefi t from a higher level of therapeutic intervention such as botulinum toxin for cervical tics or deep brain stimulation (DBS). in adults, with males having a slightly higher occurrence of ADHD than females. Earlier ons et of tics (64) and greater burden of co-morbid disorders, including anger, mood disorder, obses- sive \200\223compulsive disorder (OCD), oppositional \200\223defi ant disorder (ODD) , anxiety, specifi c learning disability, and sleep disturbance have all been associated wi th the presence of ADHD. Although ADHD correlates with greater overall functional impairmen t, there is no evidence that it has a direct impact on tic severity. In TS subjects with AD HD, 82% had one or more additional co-morbid disorders (71). ADHD is one of many factors as soci- ated with coprophenomena and social skills defi cits. Other stud- ies have found a si milar frequency of ADHD occurrence (64). Tourettism and secondary tic disorders Although primary tic disorders, including TS, are th e most com- mon cause of tics, insults to the basal ganglia from tumor (77), stroke, enceph alitis, and head trauma may result in secondary tic disorders or \200\230tourettism \200 \231. Less oft en, tics occur in association with neurodegenerative disorders, and genetic syndromes such as Down \200\231s syndrome. Finally, medications (levodopa, SSRIs, neurolep- tics, anticonvulsants), drugs of abuse (amphetamines, opiates), and toxins (carbon monoxid e) may induce or exacerbate tics. Taken as a group, individuals with secondary tics demonst rate a lesser burden of neuropsychiatric co-morbidities of ADHD, behavioral prob- lems, and sleep disorders when compared with individuals with TS (78). Primary tic disorders uniform ly begin in childhood. Th e new onset of tics in late adolescence or adulthood should promp t evalu- ation for secondary causes of tics. Approximately 30% of children with TS suff er from OCD, although a much higher frequency of low-impairment non-specifi c obsessive \200\223compulsive (OC) symptoms may exist (sub-syn dromal OC behaviors). Common compulsive symptoms include smelling, checking, counting, and touching. Obsessions in TS are less likely to be related to cleanliness, contamination, ill ness, or washing. Some compulsions, such as symmetry, evening up, and repeating activities may be related to \200\230just-right \200\231 phenomena, where patients with TS repeat, re arrange, or adjust items, speech, or actions until things feel \200\230just right \200\231 . OCD peaks in severity approximately 2 years aft er tic peak severity (64). Evaluation In a typically developing child with tics and an otherwise normal neurological e xamination, ancillary studies such as EEG, nerve conduction studies (NCS) and EMG, and brai n MRI are usually normal, and thus are not recommended unless there is some doubt about the diagnosis, there are atypical features, or the onset is later in childhood than would be e xpected for primary tic disorders. However, given the high burden of co-morbid psychopathol ogy, particularly in TS, identifi cation of the presence of tics is an oppor- tunity to exp lore and address other diagnoses. Careful evaluation of academic performance, socialization , and mood is warranted. Patients with TS are at increased risk for non-OCD generalized anxiety disorder, panic diso rder, specifi c phobias, and mood dis- orders, including depression (72). Separation anxiet y is common among children with TS and may be exacerbated by use of neu- roleptic agents wh ich can cause a specifi c school phobia (73). Episodic rage is oft en provoked by unmet expectation or a change in plan, is out of propor tion to the inciting incident, is directed, is brief in duration (<30 min), and is followed by remorse and regret. Parents or siblings are the most common targets, and rage attacks o ccur almost exclusively at home (74). Many children feel out of control during attacks, but some are able to sense when a rage attack is impending, which may be a tool for behavioral thera- pies. Parents oft en describe the spells as being incongruent with the child \200 \231s personality and temperament between attacks. Stephens and Sandor (73) evaluated 33 co nsecutive medication-free children with TS and found that children with TS plus ADHD or OCD were at increased risk for aggressive behaviors compared with children with TS only. Child ren with TS alone were similar to controls in aggressive behavior profi le. ADHD and OCD, b ut not tic sever- ity, best correlate with aggression in TS. Similarly, children with TS on ly are comparable to controls in the occurrence of disrup- tive behaviors, which are more f requent in children with TS plus ADHD or ADHD alone (75). Treatment For many children with tics, identifi cation of the problem and education regardi ng tics, low likelihood of impairment, and nat- ural history are suffi cient. If tics are n ot functionally impairing, do not cause signifi cant social embarrassment or school dysfunc - tion, and are not bothersome to the patient, treatment may not be warranted. Treatment is symptomatic only; it is not clear that treatment of tics alters the natural history of the disorder. When symptomatic treatment is required, the most troublesome symp- tom should be established and targeted fi rst, which may be a symp- tom other than tics. Given the waxing and waning nature of tics, it may be challen- ging to decide when to initi ate treatment. If a patient presents with worsening tics at a time consistent with prior fl ares, such as at the beginning of the school year, a period of waiting and supportive mana gement may be appropriate. It is unlikely that tics will be com- pletely eliminated by a pa rticular treatment regimen, but signifi cant improvement can occur, with return to premorbi d functioning. Tics are oft en non-impairing, and certainly life-threatening tics are rare. When tics or a ssociated disorders and behaviors result in emergency room visits or hospitalizations, the syndrome may be categorized as malignant TS. In a review of 333 individuals with TS, 5.1% w ere considered to have malignant TS. Emergency visits typically relate to anger, violence, self-injurious behavior, or sui- cidality. Malignant TS, oft en refractory to standard trea tments, has been associated with more complex tic symptomatology, suicidal ideation, and a greater burden of co-morbid disorders, especially OCD (76). Self-abusive tics were reported to be present in 13% of one sample of 250 children with TS (64). Serious TS-related seque- lae reported in the literature include third-degree burns, pica, eye For children with problematic tics, alpha-2-adrenergic agonists, which are typically well t olerated, are reasonable fi rst-line agents, even though they demonstrate only moderate eff i cacy. Guanfacine may be preferred to clonidine because of its longer half-life, and thus fewer daily doses and lesser sedative eff ects. Both tics and ADHD may respond to intervent ion with alpha-2-adrenergic Oxford Textbook of Movement Disorders 252 agents. Guanfacine and clonidine should be tapered aft er prolonged use to avoid rebound hy pertension. for tics (CBIT) consists of habit reversal training with tic aware- ness and competing resp onse components, relaxation training, and functional interventions to target environments a nd situations where tics worsen (92). Although benefi cial for targeting specifi c problema tic tics, barriers to implementation of CBIT include lack of access to trained providers an d commitment to practice on the part of the patient. Very young and/or highly inattentive c hildren may not be appropriate candidates for this behavioral intervention. Dopamine receptor antagonists demonstrate greater effi cacy, but use may be limited by side -eff ect profi le. If fi rst-line therapy is insuffi cient, addition or substitution of a d opamine receptor blocker is an appropriate next step. Haloperidol and pimozide are the only two neuroleptics approved by the FDA for treatment of TS. Th ree trials have demonstrated superiority of pimozide to placebo in the treatment of tics. Two studies found no signifi c ant diff er- ence between haloperidol and pimozide, while one study showed inferiority of p imozide. Pimozide may demonstrate better overall tolerability and fewer extrapyramidal side eff ects than haloperidol (79). Risperidone has also shown effi cacy in the management of tics (80). Tic suppression correlates with D2 receptor binding affi n- ity, and thus some a typical antipsychotics such as quetiapine show limited benefi t. No signifi cant diff erenc e was observed between ris- peridone and pimozide in a randomized clinical trial (81). Treatment with botulinum toxin can be a very eff ective therapy for specifi c tics that are confi ned to a focal anatomical region, such as cervical tics or very loud vocalizations. Botulinum toxin may reduce the frequency and severity of tic as well as diminishing the pre monitory urge (49, 93, 94). Consideration of an invasive or surgical approach for pediatric TS is a complex decision, g iven the natural history of improvement in tics in late adolescence or adulthood. However, some patients with severe TS fail to demonstrate such a trajectory of improve- ment and hav e life-threatening tics that are refractory to treatment. Another consideration is that qua lity of life may be determined to a greater degree by other factors than tics, even when th ey are severe. Th ere are reports of effi cacy with use of tetrabenazine (82 \200\22384), baclofen (85), a nd topiramate (86, 87), and in open-label trials of levetiracetam (88, 89). Of note, in bli nded randomized trials ver- sus placebo or clonidine, levetiracetam did not demonstrate ben efi t (90, 91). Tetrabenazine, in contrast with dopamine receptor antag- onists, does not c arry the risk of development of tardive dyskinesia. However, its use may be limited by the side eff ect of depression.