Harvey S. Singer

Volumetric MRI changes in basal ganglia of children with Tourette's syndrome

To define the site of pathology in Tourettes syndrome (TS), we performed a volumetric MRI study of basal ganglia structures and lateral ventricles on 37 children with this disorder and 18 controls. There were no statistically significant differences in the size of the right or left caudate, putamen, globus pallidus, or ventricles in these populations. In contrast, there were significant differences for measures of symmetry in the putamen and the lenticular region. Virtually all controls (17 right- and one left-handed) had a left-sided predominance of the putamen, whereas in 13 of 37 TS subjects, a right predominance exceeded that of any control. Statistical comparisons among TS patients, with (n = 18) or without (n = 19) attention-deficit hyperactivity disorder (ADHD), and controls showed significant differences for the volume of the left globus pallidus and for lenticular asymmetry. Post hoc evaluations showed that in the TS + ADHD group, the volume of the left globus pallidus was significantly smaller than the volume of the right and that lenticular asymmetry was due to a greater right-sided predominance in the TS + ADHD group. This study lends further support to proposals that claim the basal ganglia is involved in the pathogenesis of TS and also suggests that the comorbid problem of ADHD is related to regional changes that differ from those primarily associated with tics.

Ziprasidone treatment of children and adolescents with Tourette's syndrome : A pilot study

OBJECTIVE To evaluate the efficacy and tolerability of ziprasidone in children and adolescents with Tourettes syndrome and chronic tic disorders. METHOD Twenty-eight patients aged 7 to 17 years were randomly assigned to ziprasidone or placebo for 56 days. Ziprasidone was initiated at a dose of 5 mg/day and flexibly titrated to a maximum of 40 mg/day. RESULTS Ziprasidone was significantly more effective than placebo in reducing the Global Severity (p = .016) and Total Tic (p = .008) scores on the Yale Global Tic Severity Scale. Compared with placebo, ziprasidone significantly reduced tic frequencies as determined by blind videotape tic counts (p = .039). The mean (+/- SD) daily dose of ziprasidone during the last 4 weeks of the trial was 28.2 +/- 9.6 mg. Mild transient somnolence was the most common adverse event. No clinically significant effects were observed on specific ratings of extrapyramidal symptoms, akathisia, or tardive dyskinesia. CONCLUSIONS In this limited sample, ziprasidone (5-40 mg/day) appears to be effective and well tolerated in the treatment of Tourettes syndrome. Ziprasidone may be associated with a lower risk of extrapyramidal side effects in children. However, additional studies are necessary to evaluate more fully its safety and efficacy in children with tic disorders.

Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder

The aim of this study was to investigate the morphology of the corpus callosum (CC) in Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD) to determine whether these conditions affect distinct regional differences.Seventy-seven children and adolescents, aged 6 to 16 years, comprised the four research groups--16 patients with TS, 21 patients with TS plus ADHD, 13 patients with ADHD, and 27 unaffected control subjects. A semiautomated, computer-assisted procedure was used to measure the total area, five subregions, centerline length, perimeter, and bending angle of the CC. MRI data were analyzed using several statistical methods, primarily two-tailed analysis of variance to test the effects of TS and ADHD status, while controlling for the influence of age, gender, and total intracranial area (an estimate of brain size). TS was associated with significant increases in the area of four of five subdivisions, the total area, and the perimeter of the CC. ADHD was associated with a significant decrease in the area of the rostral body. There were no interactions between TS and ADHD factors. These findings suggest that the area of the CC is larger in children with TS, and that this difference is independent of age, handedness, intracranial area, and the diagnosis of ADHD. Our findings support hypotheses that the neurobiologic mechanisms in TS and ADHD involve frontal/subcortical circuits. NEUROLOGY 1996;47: 477-482

Validity of the behavior rating inventory of executive function in children with ADHD and/or Tourette syndrome

The dynamic, multidimensional nature of executive function (EF), thought to be characteristically impaired in those with attention deficit hyperactivity disorder (ADHD), has been challenging to operationalize and assess in a clinical setting [Barkley, R. A. (1997). ADHD and the nature of self-control. New York: Guilford Press.]. Gioia, Isquith, Guy, and Kenworthy [Gioia, G. A., Isquith, P. K., Guy, S. C., & Kenworthy, L. (2000) Behavior Rating Inventory of Executive Function. Odessa, FL: Psychological Assessment Resources.] developed the Behavior Rating Inventory of Executive Function (BRIEF) to address these concerns. In order to provide concurrent validity information on the BRIEF, parents of 76 children (ADHD=18; Tourette syndrome (TS)=21; TS+ADHD=17; controls=20) completed the BRIEF, additional behavior rating scales and interviews, measures of psychoeducational (PE) competence, and performance-based measures of EF. Both ADHD and TS+ADHD groups were rated as more impaired (P<.0001) than the other groups on the five primary BRIEF indices. BRIEF index scores showed no significant correlation with performance-based EF or PE measures, with the exception of math achievement; however, the BRIEF showed a strong relationship with interviews and other parent rating measures of behaviors seen in ADHD. Future attempts to validate the BRIEF should focus on differences within subtypes of ADHD (e.g., inattentive, combined subtypes), and separating ADHD from other clinical groups in which EF is reported to be a problem.

L-Histidine Decarboxylase and Tourette's Syndrome

Tourettes syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourettes syndrome and tics.

Basal Ganglia Volumes in Children With Attention-Deficit Hyperactivity Disorder:

Previous research has demonstrated volume reduction of the left globus pallidus in children with the codiagnoses of Tourette syndrome and attention-deficit hyperactivity disorder (ADHD), in comparison with children who have Tourette syndrome alone and with normal controls. The purpose of this study was to determine whether children with ADHD alone also had volume reduction of the globus pallidus or other basal ganglia structures. Subjects were 10 boys with ADHD, 16 boys with Tourette syndrome and ADHD, and 11 normal control boys. Groups were matched for age. Boys with ADHD were individually matched for age, handedness, and IQ to 10 of the 16 boys with Tourette syndrome and ADHD. Volumes of caudate, putamen, and globus pallidus were measured and corrected for brain volume. The boys with ADHD had significantly smaller left globus pallidus volume and total globus pallidus volume (corrected for brain volume) than the normal controls. The Tourette syndrome plus ADHD group did not differ from the ADHD group on any of the measures. We conclude that small globus pallidus volume, particularly on the left side, is associated with ADHD. (J Child Neurol 1996; 11: 112-115).

Tourette's syndrome: from behaviour to biology

Tourettes syndrome (TS) is a chronic neuropsychiatric disorder characterised by motor and vocal tics. Diagnosis is based solely on clinical criteria. The prevalence of this syndrome is estimated to be between one and ten per 1000 children and adolescents and the outcome is generally favourable; most patients improve by their late teens or early adulthood. Affected individuals are at increased risk of various comorbid neurobehavioural problems, the negative effects of which commonly exceed those of tics. Despite evidence that TS is an inherited disorder, the exact genetic abnormality is unknown. Environmental factors might have an important role in the expression of tics, and a poststreptococcal autoimmune cause has been proposed but is unproven. Brain imaging, neurophysiological, and post-mortem studies support involvement of cortical-striatal-thalamocortical pathways, but the definitive pathophysiological mechanism or neurotransmitter abnormality is unknown. Recent evidence, however, suggests a prefrontal dopaminergic abnormality. Traditional neuroleptics are the standard treatment for TS, but there is increasing interest in non-neuroleptic drugs, behavioural therapies, and surgical approaches.

Antibodies against human putamen in children with Tourette syndrome

Background Similar to the model for Sydenhams chorea, antineuronal antibodies, which develop in response to a preceding streptococcal infection, have been speculated to have a role in the development of Tourette syndrome (TS). Methods Serum antibodies against human caudate, putamen, and globus pallidus (interna and externa) were assayed by enzyme-linked immunosorbent assay (ELISA) and Western blot techniques and results were correlated with clinical characteristics and markers of streptococcal infection. Subjects A total of 41 children with TS (mean age, 11.3 years) and 39 controls (mean age, 12.1 years) were included. Results Compared with controls, TS subjects had a significant increase in the mean (p = 0.006) and median (p = 0.002) ELISA optical density (OD) levels of serum antibodies against putamen, but not caudate or globus pallidus. Western blots on 20 control and 20 TS serum samples showed that specific antibodies to caudatelputamen occurred more frequently in TS subjects at 83, 67, and 60 kDa; antigens were present in a synaptosomal fraction. TS subjects with a positive family history of tics had higher OD values (p ≤ 0.04), but no association was shown with age of tic onset, tic severity, sudden onset of tics, or presence of attention-deficit hyperactivity disorder or obsessive-compulsive disorder. Risk ratio calculations in TS and control groups and in study subjects dichotomized for high and low putamen OD values were similar for titers of antistreptolysin O ≥166 or antideoxyribonuclease B ≥ 170. A subgroup analysis limited to subjects with elevated streptococcal titers, however, showed a significantly (p ≥ 0.004) larger number of TS subjects with elevated OD levels. Conclusion Children and adolescents with TS had significantly higher serum levels of antineuronal antibodies against putamen than did controls, but their relation to clinical characteristics and markers for streptococcal infection remains equivocal.

Saccades in Huntington's disease: Initiation defects and distractibility

We recorded saccadic eye movements in patients mildly affected with Huntingtons disease. Most showed an increase in saccade latencies that was greater for saccades made on command than to the sudden appearance of a visual target. All patients showed excessive distractibility during attempted fixation. They had particular difficulty suppressing a saccade to a suddenly appearing visual target when simultaneously trying to initiate a saccade in the opposite direction. Our results are compatible with a posited role of the basal ganglia in both the initiation of volitional saccades and in the maintenance of fixation. Saccade abnormalitie—especially distractibility—are sensitive but probably not specific indicators of Huntingtons disease.

Neurobiology of Tourette's syndrome: concepts of neuroanatomic localization and neurochemical abnormalities

Despite a preponderance of evidence suggesting an organic rather than psychogenic origin for Tourette syndrome, the precise neurobiological abnormality remains speculative. Neuroanatomically, there is expanding confirmation that cortico-striato-thalamo-cortical pathways represent the site of origin for tics and accompanying neuropsychiatric problems. Pathophysiological hypothesis are generally defined based on involvement of (1) a specific anatomical site (striato-thalamic circuits, striatal compartments), (2) physiologic abnormality (excess thalamic excitation, impaired intracortical inhibition), or (3) involvement of a specific neurotransmitter or synaptic component. This review provides information essential for understanding current and future proposals pertaining to the neurobiology of this intriguing disorder.