Gerald Erenberg

Contemporary Assessment and Pharmacotherapy of Tourette Syndrome

SummaryTo develop a guide to clinical assessment and pharmacotherapy for children and adults with Tourette syndrome (TS), we reviewed published literature over the past 25 years to identify original articles and reviews on the assessment and pharmacological treatment of Tourette syndrome, attention—deficit/hyperactivity disorder (ADHD) and obsessive—compulsive disorder (OCD). The literature search also included a survey of reviews published in book chapters. The assessment section was compiled from several reviews. Pharmacological treatments were classified into those with strong empirical support (as evidenced by two positive placebo-controlled studies for tics, OCD, or ADHD in TS samples); modest empirical support (one positive placebo-controlled study), or minimal support (open-label data only). We conclude that accurate diagnosis, including identification of comorbid conditions, is an essential step toward appropriate treatment for patients with TS. In many patients with TS, symptom management requires pharmacotherapy for tics or coexisting conditions. The evidence supporting efficacy and safety for medications used in patients with TS varies. But this evidence offers the best guide to clinical practice.

Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome

In response to recent publicity regarding the potential use of deep brain stimulation (DBS) for reducing tic severity in Tourettes syndrome (TS), the Tourette Syndrome Association convened a group of TS and DBS experts to develop recommendations to guide the early use and potential clinical trials of DBS for TS and other tic disorders. The goals of these recommendations are to ensure that all surgical candidates are (1) fully informed about the risks, benefits, and alternative treatments available; (2) receive a comprehensive evaluation before surgery to ensure that DBS is clearly the appropriate clinical treatment choice; and (3) that early clinical experience will be documented publicly to facilitate rational decision‐making for both clinical care and future clinical trials.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders

Objective: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. Methods: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders–IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. Results: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (–5.5 ± 6.9 vs –3.0 ± 8.7, p = 0.063) and Tic Symptom Self-Report total score (–4.7 ± 6.5 vs –2.9 ± 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (–0.7 ± 1.2 vs –0.1 ± 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (–10.9 ± 10.9 vs –4.9 ± 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (–0.8 ± 1.1 vs –0.3 ± 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. Conclusions: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

Clinical outcome after complete or partial cortical resection for intractable epilepsy

This is the first epilepsy surgery series to analyze the definition of “completeness” of resection, based solely on results of chronic scalp and subdural EEG recording. When patients had complete removal of all cortical areas with ictal and interictal epileptiform discharges, the clinical outcome was usually good. When areas with epileptiform discharges were left behind, good outcome was significantly less frequent. This correlation between complete resection and good outcome was independent of the presence or absence of CT-detected structural lesions or sharp waves on post-resection electrocorticography. These results support completeness of resection, defined by prolonged extraoperative EEG, as an important factor in seizure surgery.

Hypothermia and barbiturate coma for refractory status epilepticus

Three pediatric patients with generalized status epilepticus unresponsive to therapy with conventional anticonvulsants were successfully treated with moderate hypothermia (30± to 31±C) and barbiturate coma with thiopental. All 3 patients were treated with thiopental at doses producing burst suppression or an isoelectric tracing on the EEG and thiopental and barbiturate levels were followed sequentially in the plasma. Continuous thiopental infusion rates of 5 to 55 mg/kg ± h maintained burst suppression and correlated with plasma thiopental levels of 25 to 40 mg/dl. Total doses of thiopental used to obtain and maintain burst suppression ranged from 15 to 50 g over 48 to 120 h. In all 3 patients, control of the status epilepticus was obtained. Moderate hypothermia and thiopental barbiturate coma are indicated in patients with generalized tonic-clonic status epilepticus which cannot be controlled with standard anticonvulsant drug therapy. This regimen has the advantage that the patient can be managed in an ICU without the need for general anesthesia with volatile anesthetic agents.

Genome-wide association study of Tourette's syndrome

Tourettes syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Gilles de la Tourette's syndrome Effects of stimulant drugs

We reviewed the medication histories in 200 children with Gilles de la Tourettes syndrome to investigate how frequently CNS stimulants may unmask a latent syndrome or worsen existing tics. Forty-eight patients had received stimulant drugs. Nine were treated before the onset of tics, but only four were still receiving stimulants when tics began. In 39 patients with preexisting tics, stimulants increased tics in 11, caused no change in 26, and decreased tics in 2. Behavior improved in 22 patients. Thirteen of these 22 had no increase in tics when stimulants were used. Cautious trials of stimulant therapy may benefit some patients with this syndrome.

Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control

Background: Self injurious behaviour (SIB), the deliberate, repetitive infliction of self harm, is present in a wide variety of neuropsychiatric disorders, including Tourette syndrome (TS). Although SIB occurs in up to 60% of individuals with TS, and can cause significant clinical impairment and distress, little is known about its aetiology. Objective: This study examined the relationship between SIB and other behavioural features that commonly co-occur with TS in nearly 300 subjects with TS participating in three genetic studies. SIB, obsessions, compulsions, tic severity, attention deficit hyperactivity disorder related impulsivity, risk taking behaviours, and rages were systematically assessed in all subjects. Methods: Using logistic regression, a best fit model was determined for both mild to moderate SIB and severe SIB. Results: Mild/moderate SIB in TS was correlated with the presence of obsessive and compulsive symptoms such as the presence of aggressive obsessions or violent or aggressive compulsions, and with the presence of obsessive−compulsive disorder and overall number of obsessions. Severe SIB in TS was correlated with variables related to affect or impulse dysregulation; in particular, with the presence of episodic rages and risk taking behaviours. Both mild/moderate and severe SIB were also correlated with tic severity. Conclusions: This study suggests that mild/moderate and severe SIB in TS may represent different phenomena, which has implications for clinical management of these symptoms.

Benign focal epileptiform discharges in childhood migraine (BFEDC)

Interictal EEGs were studied in 100 children, ages 3 to 15 years. Records were interpreted independent of history; 89% were normal, 9% had benign focal epilepti form discharges (BFEDC), one had temporal spikes, and one had background slowing. The nine patients with BFEDC did not differ from the others. None had epilepsy. This incidence of 9% is higher (p < 0.0001) than the incidence of BFEDC in the normal population (1.9%). The significance of this finding is not clear, but migraine and benign focal epilepsy of childhood may be genetically linked, or the vascular abnormality of migraine may cause brain injury to produce sharp waves of low epileptogenicity. These results do not suggest that headaches are epileptic.

Tic Symptom Profiles in Subjects with Tourette Syndrome from two Genetically Isolated Populations

BACKGROUND Tourette Syndrome (TS) has a complex etiology and wide variability in phenotypic expression. Identifying underlying symptom patterns may be useful for etiological and outcome studies of TS. METHODS Lifetime tic and related symptom data were collected between 1996 and 2001 in 121 TS subjects from the Central Valley of Costa Rica and 133 TS subjects from the Ashkenazi Jewish (AS) population in the US. Subjects were grouped by tic symptoms using an agglomerative hierarchical cluster analysis. Cluster membership was tested for association with available ancillary information (age of onset, tic severity, comorbid disorders, medication treatment and family history). RESULTS Cluster analysis identified two distinct groups in each sample, those with predominantly simple tics (cluster 1), and those with multiple complex tics (cluster 2). Membership in cluster 2 was correlated with increased tic severity, global impairment, medication treatment, and presence of comorbid obsessive-compulsive symptoms in both samples, and with family history of tics, lower verbal IQ, earlier age of onset, and comorbid obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in the AS sample. CONCLUSIONS This study provides evidence for consistent and reproducible symptom profiles in two independent TS study samples. These findings have implications for etiological studies of TS.