A double blind randomized placebo control trial of levetiracetam in Tourette syndrome.

The objective of this study was to investigate the effectiveness of levetiracetam for the treatment of tics in children with Tourette syndrome (TS). Levetiracetam, an atypical anticonvulsant, has been suggested in open-label protocols to be an effective tic-suppressing agent in individuals with TS. A double blind, randomized, placebo-controlled, cross-over trial was performed to investigate this medication in children with moderate to moderately-severe tics. Subjects received, in a randomized sequence, 4-weeks of levetiracetam (maximum dose 30 mg/kg/day) or placebo, with a 2-week intervening washout period between cycles. Primary outcome measures included two separate scales from the Yale Global Tic Severity Scale; the Total Tic score and the Total overall score. Measures were assessed at baseline, prior to randomization, on Day 28 (end of Phase 1), on Day 42 (baseline for second phase) and on Day 70 (end of Phase 2). Twenty-two subjects (21 boys and 1 girl) with TS, mean age 12.2 +/- 2.3 years, range 8 to 16 years, participated. A mild reduction in tics occurred during both the levetiracetam and placebo treatment phases. There was no significant difference between treatments and no evidence of sequence or cross-over effects. In conclusion, Levetiracetam is not more beneficial than placebo in suppressing tics in children with TS.

Dopaminergic polymorphisms in Tourette syndrome: association with the DAT gene (SLC6A3).

Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by involuntary motor and phonic tics. The pattern of inheritance and associated genetic abnormality has yet to be fully characterized. A dopaminergic abnormality in this disorder is supported by response to specific therapies, nuclear imaging, and postmortem studies. In this protocol, dopaminergic polymorphisms were examined for associations with TS and attention-deficit hyperactivity disorder (ADHD). Polymorphisms investigated included the dopamine transporter (DAT1 DdeI and DAT1 VNTR), dopamine receptor (D4 Upstream Repeat and D4 VNTR), dopamine converting enzyme (dopamine beta-hydroxylase), and the acid phosphatase locus 1 (ACP1) gene. DNA was obtained from 266 TS individuals +/- ADHD and 236 controls that were ethnicity-matched. A significant association, using a genotype-based association analysis, was identified for the TS-total and TS-only versus control groups for the DAT1 DdeI polymorphism (AG vs. AA, P = 0.004 and P = 0.01, respectively). Population structure, estimated by the genotyping of 27 informative SNP markers, identified 3 subgroups. A statistical re-evaluation of the DAT1 DdeI polymorphism following population stratification confirmed the association for the TS-total and TS-only groups, but the degree of significance was reduced (P = 0.017 and P = 0.016, respectively). This study has identified a significant association between the presence of TS and a DAT polymorphism. Since abnormalities of the dopamine transporter have been hypothesized in the pathophysiology of TS, it is possible that this could be a functional allele associated with clinical expression.

Norepinephrine transporter polymorphisms in Tourette syndrome with and without attention deficit hyperactivity disorder: no evidence for significant association.

Noradrenergic abnormalities have been proposed in the pathophysiology of Tourette syndrome and attention-deficit hyperactivity disorder. Patients with Tourette syndrome with (n=115) and without (n=110) attention-deficit hyperactivity disorder were evaluated for association with two single nucleotide polymorphisms of the norepinephrine transporter gene (SLC6A2); a T-182C single nucleotide polymorphism located in the 5' flanking promoter region and a silent mutation (G1287A) occurring in exon 9. A polymerase chain reaction restriction enzyme assay was developed for the T-182C single nucleotide polymorphism based on a prior sequencing methodology. In this case-control study, no association was identified between either polymorphism and Tourette syndrome or attention-deficit hyperactivity disorder. In a small subset, these NET polymorphisms did not predict therapeutic response to the noradrenergic transporter inhibitor atomoxetine. Further research with additional NET polymorphisms and larger sample sizes are indicated in the pursuit of biomarkers for therapeutic responders.

Behavioral therapy for treatment of stereotypic movements in nonautistic children.

Although typically described in autistic, mentally retarded, and sensory-deprived individuals, motor stereotypies also occur in normal children. In this preliminary report, the behavior modification techniques of habit reversal and differential reinforcement of other behavior were evaluated as a therapeutic modality for the suppression of stereotypic movements in nonautistic subjects. Twelve children, ages 6 to 14 years, with physiologic stereotypies were treated using a standardized treatment protocol. Clinical outcomes were based on differences between assessments obtained at baseline and on telephone follow-up. Evaluation scales included measures of the frequency, intensity, interference, and number of stereotypies (Stereotypy Severity Scale motor portion and Stereotypy Linear Analog Scale) and assessment of global function (Child Global Assessment Scale and Stereotypy Severity Scale global portion). The results were correlated with the child's level of motivation and the number of treatment sessions. After a mean follow-up of 12.1 months, motor stereotypies showed significant improvement on the Stereotypy Linear Analog Scale and Stereotypy Severity Scale total score, P = .009 and P = .046, respectively. Both scales showed a relationship between the number of treatment sessions attended and a reduction in movements. The Child Global Assessment Scale also improved with therapy, but there was no correlation with the number of treatment sessions. Highly motivated patients had greater improvement on the Stereotypy Linear Analog Scale and Stereotypy Severity Scale scales compared with less motivated patients, but motivation had no impact on the Child Global Assessment Scale. The combined use of habit reversal and differential reinforcement of other behavior is beneficial in reducing motor stereotypies in nonautistic children.