Search

Tourette's syndrome (TS) is a complex inherited neuropsychiatric disorder that is characterized by multiple motor and phonic tics. Stress-related fluctuations in symptom severity and medication responsiveness are common, and patients often report that tics are worsened by fatigue, emotional trauma, and anxiety. We examined the effects of lumbar puncture (LP) stress on plasma adrenocorticotropin (ACTH) and cortisol, urinary catecholamines, and self- and clinician ratings of anxiety in 13 medication-free TS patients and 10 normal controls, ages 17 to 41 years. The TS patients secreted significantly more ACTH than the normal controls in response to the stress of the lumbar puncture. Compared to the controls the TS patients had significantly greater postLP mean and postLP peak ACTH levels. The TS patients also excreted significantly more norepinephrine in the 20 hr preceding the lumbar puncture and reported higher levels of anxiety before and during the procedure than the controls. In addition, urinary norepinephrine excretion of the TS patients was significantly correlated with clinician ratings of tic severity. The results were not related to current levels of depression and anxiety. Taken together, these findings suggest that a subset of TS patients may be characterized by heightened reactivity of the hypothalamic-pituitary-adrenal axis and related noradrenergic sympathetic systems.

We measured the midline cross-sectional area and other morphologic features of the corpus callosum (CC) from magnetic resonance (MR) images in 14 unmedicated patients with Tourette's syndrome (TS) and 14 normal control subjects matched for age, sex, handedness, and socioeconomic status. Each CC was manually circumscribed on midline images from a T1-weighted sagittal series, and the area of the entire CC and five anatomic subdivisions were measured. CC circumference, regional width, and mean callosal curvature were also measured. CC cross-sectional area correlated positively with brain size and basal ganglia volumes. The magnitude of reduction (17.7%) in total CC area in TS patients compared with control subjects was similar to the reductions seen in all CC subdivision areas. Analyses of covariance with total midsagittal cross-sectional head area as a covariate revealed the reductions to be statistically significant for the overall CC area and all subregion areas. CC width tended to be nonsignificantly thinner in all subdivisions (from 5% to 11%), and the overall length of the center line measured from rostrum to splenium was significantly reduced in the TS group (by 5.3%). Measures of mean callosal curvature suggested that CCs in TS patients are less rounded than those of normal control subjects. Worst-ever motor tic symptoms showed the strongest significant correlation with the length of the CC center line in TS patients (r = 0.88). These findings suggest that structural interhemispheric connectivity may be aberrant in the central nervous systems of TS patients, and they provide indirect supportive evidence for the presence of altered cerebral lateralization in the disorder.

Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by a changing repertoire of motor and phonic tics that typically begin in childhood and exhibit a fluctuating course. Obsessive-compulsive symptoms and problems of inattention, overactivity, and impulsiveness are present in some cases. Historically, TS has been viewed as a severe disorder. However, data from epidemiologic and family-genetic studies indicate that it shows a wide range of severity. This article, the first of two parts, examines the current notions concerning the origin, pathophysiology, and diagnosis of TS. The second article will present three cases and describe contemporary approaches to treatment.

To evaluate the role of opioids in Tourette's syndrome (TS), we performed a dose-response study of the behavioral and neuroendocrine effects of the selective kappa agonist spiradoline mesylate (U-62066E) in five TS patients and five normal control subjects, aged 20 to 47. The intramuscularly administered doses of spiradoline were 0.0, 0.8, 1.6, and 3.2 micrograms/kg. Baseline and postdrug tic frequencies were determined from "blind" videotape tic counts and bedside clinician ratings. In comparison with placebo, the lowest dose of spiradoline was associated with significant decreases in cumulative postdrug counts of total tics and phonic tics, as well as in clinician ratings of postdrug motor tic frequencies. By contrast, there was a trend for tic frequencies to increase following the intermediate dose (1.6 micrograms/kg) of spiradoline. As a group, the TS subjects also secreted significantly more growth hormone following the 1.6 micrograms/kg dose of spiradoline than did the normal control subjects. These preliminary findings provide additional evidence for the involvement of opioids in TS and suggest (1) that opioids may exert dual modulatory effects on the expression of tic symptoms and (2) that some TS patients may be characterized by increased sensitivity of kappa receptors regulating growth hormone secretion.

The search for nongenetic factors that mediate the expression of a genetic vulnerability to Tourette's syndrome (TS) is an important undertaking that may provide valuable clues concerning the pathophysiology of this disorder as well as potential treatment approaches. In a direct interview study, the perinatal experiences of 31 TS patients were compiled in an effort to identify risk factors associated with tic severity. Severity of maternal life stress during pregnancy, gender of the child, and severe nausea and/or vomiting during the first trimester were found to be significantly associated with current tic severity. Future longitudinal studies of “at-risk” children are needed to confirm these findings. Set in the context of a known chromosomal site for the TS diathesis, such studies will permit the identification and quantification of risk and protective factors in the expression of TS and further develop TS as a model neuropsychiatric disorder for the study of gene–environment interactions.

Twelve (50%) of 24 children, ages 8 to 16 years, treated with fluoxetine, 20 or 40 mg/day, for depressive or obsessive compulsive symptoms, developed behavioral side effects characterized by motor restlessness (n = 11), sleep disturbance (n = 11), social disinhibition (n = 6), or a subjective sensation of excitation (n = 3). No major changes in the neurological status of these children were observed. However, the three children with ADHD showed an exacerbation of symptoms on fluoxetine. Discontinuation (n = 5) or halving the dosage (n = 7) resulted in complete resolution of these unwanted symptoms within 1 to 2 weeks. In all 7 children whose doses were reduced, improvement of the depressive or obsessive compulsive symptoms was maintained on the lower dosage. Clinicians treating children with fluoxetine are cautioned to be aware of behavioral side effects which may be alleviated by dosage reduction or possibly by starting with lower doses. These side effects may be difficult to differentiate from ...

Fluoxetine hydrochloride is the first selective serotonin uptake inhibitor introduced commercially in the United States. This report describes preliminary clinical experience with fluoxetine in 10 children and adolescents, aged 8 to 15 years, with primary obsessive compulsive disorder (OCD) or Tourette's syndrome (TS) plus OCD. In general, fluoxetine, which was administered from 4 to 20 weeks at a dosage of 10 or 40 mg per day, was well tolerated. Adverse effects included behavioral agitation/activation in four patients and mild gastrointestinal symptoms in two patients. No abnormalities were noted in the seven children who had follow-up EKGs. Five of the 10 patients (50%) were considered responders; their obsessive-compulsive symptoms decreased substantially during treatment with fluoxetine. Responder rates were similar in the primary OCD (two of four, 50%) and TS + OCD (three of six, 50%) groups. In conclusion, short-term fluoxetine administration appears to be safe in children and adolescents. Placebo-controlled trials are needed to further assess the efficacy of fluoxetine.

To evaluate the efficacy of fluoxetine in the treatment of tics and obsessive-compulsive symptoms in patients with Tourette's syndrome (TS), 14 subjects (8-33 years old) with TS participated in a 20-week, fixed-dose (20 mg daily), double-blind, placebo-controlled crossover trial of fluoxetine monotherapy. Five subjects met criteria for obsessive-compulsive disorder (OCD), 6 additional subjects had obsessive-compulsive features, and 3 subjects had TS without obsessive-compulsive symptoms. There was no improvement in tics after 8 weeks of treatment with fluoxetine (p = 0.58). In contrast, fluoxetine treatment was associated with a significant reduction in obsessive-compulsive symptoms for the group of 6 subjects initially randomized to fluoxetine (p = 0.04). Crossover analysis showed that fluoxetine had no marked effect on tics (n = 10, p = 0.30, but produced a modest decrease in obsessive-compulsive symptoms (n = 8, p = 0.06). Order effects and carry-over effects were not significant. Withdrawal to placebo was associated with a 55% increase in obsessive-compulsive symptoms (p = 0.05), but there was no effect on tics. The most common side effect was transient behavioral activation, which occurred in about half of the subjects and was more common in children. Fluoxetine may be useful for the treatment of obsessive-compulsive symptoms in some patients with TS, but does not appear to be effective for tics.

Clinical assessment of a child with Tourette's syndrome (TS) includes a careful review of motor and phonic tics. In addition, commonly associated problems of such as obsessive-compulsive symptoms, or symptoms of attention deficit hyperactivity disorder (inattention, impulsiveness, and overactivity) should also be evaluated. Treatment almost always includes education of the child, family, and school personnel concerning the natural history and behavioral boundaries of the disorder. Other treatment interventions depend to a great extent on the primary source of impairment. This article, the second of two parts, presents three illustrative cases and revies current treatment interventions for children and adolescents with TS.

Using a 1.5-tesla GE Signa MR scanner, we imaged the brains of 14 right-handed Tourette9s syndrome (TS) patients (11 men, three women), aged 18 to 49 years, who had minimal lifetime neuroleptic exposure. We also studied an equal number of normal controls individually matched for age, sex, and handedness and group-matched for socioeconomic status. We circumscribed basal ganglia on sequential axial images from spin-echo proton density-weighted acquisitions (TR 1,700, TE 20; slice thickness, 3 mm with 1.5-mm skip) and submitted the images for three-dimensional processing at a computer graphics workstation. Our hypothesis of lenticular nucleus volume reduction in TS was confirmed for the left- but not the right-sided nucleus. Post hoc analyses revealed smaller mean volumes of the caudate, lenticular, and globus pallidus nuclei compared with controls on both the right and left. Further analyses of basal ganglia asymmetry indices suggest that TS basal ganglia do not have the volumetric asymmetry (left greater than right) seen in normal controls. These findings confirm and extend prior phenomenologic, neuropathologic, and neuroradiologic studies that implicate the basal ganglia in the pathogenesis of TS.

Rigorously designed clinical trials have demonstrated the efficacy and safety of fluoxetine in adults with major depressive disorder and obsessive-compulsive disorder (OCD) but not in patients below 18 years old. This report describes a randomized, double-blind, placebo-controlled, fixed-dose (20 mg qd) trial of fluoxetine in 14 children and adolescents with OCD, ages 8 to 15 years old; the study was 20 weeks long with crossover at 8 weeks. Obsessive-compulsive symptom severity was measured on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinician's Global Impression-Obsessive Compulsive Disorder scale (CGI-OCD). The CY-BOCS total score decreased 44% ( N = 7, p = .003) after the initial 8 weeks of fluoxetine treatment, compared with a 27% decrease ( N = 6, p = .13) after placebo. During the initial 8 weeks, the magnitude of improvement for the fluoxetine group significantly exceeded that for the placebo group as measured by the CGI-OCD ( p = .01) but not by the CY-BOCS ( p = .17). The most common drug side effects were generally well tolerated. The results suggest that fluoxetine is a generally safe and effective short-term treatment for children with OCD.

Self-injurious ideation or behavior appeared de novo or intensified during fluoxetine treatment of obsessive-compulsive disorder in six patients, age 10 to 17 years old, who were among 42 young patients receiving fluoxetine for obsessive-compulsive disorder at a university clinical research center. These symptoms required the hospitalization of four patients. Before receiving fluoxetine, four patients had major risk factors for self-destructive behavior including depression or prior suicidal ideation or self-injury. Three hypotheses concerning the apparent association between fluoxetine and these self-injurious phenomena are discussed: (1) coincidence; (2) disorganization of vulnerable individuals secondary to drug-induced activation; and (3) a specific serotonergic-mediated effect on the regulation of aggression.

The intellectual, academic, and adaptive strengths and weaknesses of 30, medication-free children (M=10.5 years) with Tourette syndrome (TS) were assessed with a battery of standardized psychoeducational measures and the Vineland Adaptive Behavior Scales. Results indicated significant relative weaknesses in mental and written arithmetic, and relative strengths in reading achievement and abstact, logical thinking. Socialization skills emerged as a signifiant weakness in adaptive functioning. Comparisons between TS children with attention deficit disorder with hyperativity (ADD-H) (n=19) and without ADD-H(n=11) pointed to similar profiles of strength and weakness in both groups in all areas assessed, but significantly lower performance IQs in TS subjects with ADD-H. These findings are discussed in relation to future research with TS children.

Phenomenology and family history in 21 clinically referred children and adolescents with obsessive compulsive disorder are described. Each child and family participated in a standard clinical psychiatric assessment. The most frequently reported symptoms were repeating rituals, washing, ordering and arranging, checking, and contamination concerns. Controlling behaviors involving other family members were seen in 57% of the patients. Associated psychopathology was common: 38% received an anxiety disorder diagnosis; 29% received a mood disorder diagnosis; tics were observed in 24%. Fifteen (71%) of the children had a parent with either obsessive compulsive disorder ( N = 4) or obsessive-compulsive symptoms ( N = 11). The clinical and research implications of these findings are discussed. J. Am. Acad. Child Adolesc. Psychiatry, 1990, 29, 5:766–772.

We report here the first use in Tourette's syndrome of the nonsteroidal androgen receptor blocking agent flutamide. One man and one woman underwent open trials of the medication, and a second man participated in a placebo-controlled, double-blind crossover trial. Improvement in tic symptoms ranged from 45 to 60%. The improvement was sustained in the woman during daily flutamide use and in one man during its intermittent use. One man's symptoms became refractory to treatment after 5 weeks of flutamide use, whereas the woman became depressed and had protracted diarrhea during her treatment.

The safety and effectiveness of clonidine hydrochloride (3 to 5 micrograms/kg per day) were evaluated in 47 subjects with Gilles de la Tourette's syndrome, aged 7 to 48 years. Twenty-four subjects were randomly assigned to clonidine treatment and 23 to placebo. Forty subjects (21 given clonidine and 19 placebo) successfully completed the 12-week, double-blind clinical trial. Clinical ratings of tic severity improved for both groups. The magnitude of response was greater in the group receiving clonidine. Clinician-rated measures of motor tic severity, the degree to which the tics are "noticeable to others," motor tic counts from videotaped interviews, and parent-rated measures of impulsivity and hyperactivity were the most responsive to clonidine treatment. These results indicate that clonidine is more effective than placebo in reducing some of the tic and other behavioral symptoms associated with Gilles de la Tourette's syndrome.

Despite the overt nature of most motor and phonic tic phenomena, the development of valid and reliable scales to rate tic severity has been an elusive goal. The Yale Global Tic Severity Scale (YGTSS) is a new clinical rating instrument that was designed for use in studies of Tourette's syndrome and other tic disorders. The YGTSS provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. Data from 105 subjects, aged 5 to 51 years, support the construct, convergent, and discriminant validity of the instrument. These results indicate that the YGTSS is a promising instrument for the assessment of tic severity in children, adolescents and adults.

Forty-six patients with Tourette's syndrome (TS), aged 7 to 45 years, were evaluated clinically and neurochemically. Patients with more severe total symptoms had lower plasma homovanillic acid (pHVA) levels. Analysis of individual items on the Tourette Syndrome Global Scale (TSGS) revealed significant inverse correlations between mean pHVA levels and motor restlessness and school/work function. There were no significant correlations between pHVA levels and individual tic items, although the correlation between mean pHVA levels and simple motor tics approached significance. Plasma 3-methyoxy-4-hydroxyphenylglycol (pMHPG) levels did not correlate significantly with TSGS scores. Pretreatment levels of pHVA or pMHPG did not predict treatment response to clonidine. These data suggest that TS patients with more severe non-tic symptomatology have lower morning pHVA levels. This relationship is of interest because earlier studies showed that TS patients have lower CSF HVA levels compared with contrast and control groups. J. Am. Acad. Child Adolesc. Psychiatry , 1988, 27, 4:409–412.

Plasma concentrations of unconjugated homovanillic acid (pHVA) reflect both central nervous system (CNS) and peripheral dopamine metabolism. Debrisoquin sulfate (DBQ) blocks peripheral, but not CNS, production of HVA from dopamine. Administration of DBQ has been used to decrease the proportion of peripherally produced HVA in pHVA measurements, making such measurements more reflective of CNS turnover of dopamine. We studied the relationships between DBQ dose, plasma DBQ (pDBQ) levels, and changes in pHVA in a group of 21 subjects (9 normal controls and 12 with Tourette's syndrome). DBQ dose was moderately correlated with pDBQ levels (r = 0.63, p = 0.002). Subjects (n = 8) with mean pDBQ levels above 60 ng/ml had a 48% to 66% decrease in mean pHVA levels; this may reflect nearly complete inhibition of peripheral HVA production. Subjects (n = 13) with mean pDBQ levels below 55 ng/ml had decreases in pHVA levels from 10% to 58%. No debrisoquin was detected in cerebrospinal fluid samples. These data suggest that pDBQ levels above 60 ng/ml are sufficient to assure substantial inhibition of peripheral HVA production and that monitoring pDBQ levels may be useful when employing this method for studying CNS metabolism.

Central dopaminergic (DA) function in children was assessed by monitoring plasma-free homovanillic acid (pHVA) levels after brief (18 hour) administration with debrisoquin sulfate, a peripherally active antihypertensive agent that blocks peripheral, but not central, HVA production. Brief debrisoquin administration resulted in marked reductions in pHVA in each of six patients studied. In five of the six patients, post-debrisoquin pHVA levels remained relatively stable over the six-hour period of observation. No significant cardiovascular or behavioral side effects of debrisoquin were observed. The brief debrisoquin administration method appears to be a safe, simple, and potentially valid peripheral technique for evaluating aspects of central dopaminergic function in children with neuropsychiatric disorders. Additional work is needed to further establish this method's validity and reliability.

Within- and across-day stability of plasma-free homovanillic acid (pHVA) was assessed in children and adults with Tourette's syndrome. A diurnal fall in pHVA was observed in 13 of 15 subjects. There was a small but significant (p less than .0001) decrease (8%) in mean morning pHVA levels obtained just 20 minutes apart (8:30 A.M. and 8:50 A.M.). A substantial and significant (p less than .001) mean decrease in pHVA (25%) was observed when samples obtained between 8:00 and 8:30 A.M. were compared with samples obtained at 12:00 noon. Changes in pHVA levels observed during the afternoon (between 12:00 noon and 4:00 P.M.) were small, nondirectional, and nonsignificant. Repeated measurement of morning pHVA in the same individual after 24 or more hours revealed marked increases or decreases in many individuals, suggesting that morning pHVA is not a stable measure. The results of this and previous studies suggest that pHVA obtained at 12:00 noon or later in the day may be a more reliable measure of centrally produced HVA. Further studies are needed regarding the stability of pHVA over time.

About 50% of children referred for clinical evaluation of Tourette's syndrome (TS) also meet criteria for attention-deficit hyperactivity disorder (ADHD). Standard treatment of ADHD with CNS stimulants results in an exacerbation of the tic symptoms in 20 to 50% of these patients. Symptoms of ADHD were treated with desipramine (DMI) in seven boys with chronic tic disorders, aged 7 to 11 years. Five patients (71%) had a moderate or marked reduction in their ADHD symptoms on a clinician's global improvement rating and on parent and teacher rating scales. There was no change in the severity of tic symptoms during DMI treatment in six patients. An intermittent eyeblink became persistent during DMI treatment in one patient. Mild tachycardia was the most common side effect. DMI appears to be safe and effective for children with ADHD and tics or a family history of TS.

Within- and across-day stability of unconjugated plasma 3-methoxy-4-hydroxyphenethyleneglycol (pMHPG, the major metabolite of norepinephrine) levels were assessed in several subgroups of 47 primarily child and adolescent subjects with Tourette's syndrome (TS). Mean morning pMHPG levels remained stable over a 20-min period from 8:30 to 8:50 AM at 3.5 +/- 0.8 ng/ml. However, the mean intraindividual fluctuation in pMHPG levels over 20 min was +/- 12%. Mean pMHPG levels remained stable in the morning from 8:00-8:30 AM to noon. However, an 11% decrease (p less than 0.01) in mean pMHPG levels was observed in the afternoon between noon and 3:00-4:00 PM. Monitored on consecutive days, mean morning pMHPG levels fell 12% (p less than 0.002). The afternoon and across-day falls in pMHPG levels observed in this study of primarily children and adolescents with TS have not been observed in studies of adult control subjects. The results suggest that the design of research protocols involving children and adolescents that use pMHPG should take into consideration the effects of time, both within- and across-day, in pMHPG levels.

A recent neuropathological study has reported decreased levels of dynorphin A immunoreactivity in striato-pallidal fibers in the brain of a patient with severe Gilles de la Tourette's syndrome (TS). This observation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS. We report on the presence of elevated concentrations of dynorphin A [1–8] in the CSF of 7 TS patients, aged 20 to 45 years. The increase in CSF dynorphin was found to be associated with the severity of the obsessive compulsive symptoms but not with tic severity in these patients. Although CSF studies lack the precision necessary to address questions of selective involvement of neuronal systems in specific CNS locations, these findings suggest that endogenous opioids are involved in the pathobiology of TS and related disorders. Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) (1). Once thought to be a rare condition, the prevalence of TS is now estimated to be on case per 1, 000 boys and one case per 10, 000 girls, and milder variants of the syndrome are likely to occur in a sizeable percentage of the population (2). Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consistent with an autosomal dominant form of inheritance (3, 4). Neurobiologic and pharmacological data have implicated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and basal ganglia structures remain the prime candidates as the neuroanatomical origin for TS and related conditions (1). Endogenous opioids, including dynorphin and met-enkephalin are concentrated in structures of the basal ganglia (5), are known to interact with central dopaminergic neurons (6, 7), and may play an important role in the control of motor functions (8). Post-mortem brain studies have directly implicated opioids in the pathophysiology of Parkinson's disease (9), Huntington's disease (10), and most recently in TS (11). The neuropathological study of Haber et al. (11) reported decreased levels of dynorphin A [1–17] immunoreactivity in striatal fibers projecting to the globus pallidus in the brain of a patient with severe TS. This observation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS. Additional evidence supporting the role of endogenous opioids comes from reports of dramatic, but poorly documented, effects of opiate antagonists in the treatment of TS patients (12, 13).

Recent discoveries in the field of molecular biology and increased attention to genetic epidemiology have stimulated renewed interest in the genetics of psychiatric disorders. Tourette's syndrome, a neuropsychiatric disorder characterized by motor and phonic tics, is used as a model to describe the research strategies employed in the genetic epidemiology of child psychiatric disorders. The relevance of genetic research findings to child psychiatric nursing is also discussed.

To the Editor.— Transient symptoms of tardive dyskinesia have been described in patients with Tourette's syndrome during and after treatment with neuroleptic agents. 1-3 To our knowledge, this is the first report of a patient with Tourette's syndrome who developed persistent tardive dyskinesia following neuroleptic withdrawal. Report of a Case.— The patient, a 32-year-old man, first exhibited repetitive head and neck jerks at the age of 6 years. By the time he was diagnosed at the age of 21 years as having Tourette's syndrome, his symptoms included severe motor and phonic tics and obsessional thoughts. Haloperidol therapy was started at 1 mg/d, and gradually was increased over a ten-year interval to 7 mg/d. Although his tics were minimal at this dosage, the patient was dissatisfied with the haloperidol because of persistent insomnia, gastrointestinal discomfort, depression, mild tremors, and muscle spasms. He sought a second opinion and a decision was