Design of a Multisite Study Assessing the Impact of Tic Disorders on Individuals, Families, and Communities.

BACKGROUND: Tic disorders, including Tourette syndrome, are complex, multisymptom diseases, yet the impact of these disorders on affected children, families, and communities is not well understood. METHODS: To improve the understanding of the impacts of Tourette syndrome, two research groups conducted independent cross-sectional studies using qualitative and quantitative measures. They focused on similar themes, but distinct scientific objectives, and the sites collaborated to align methods of independent research proposals with the aim of increasing the analyzable sample size. RESULTS: Site 1 (University of Rochester) was a Pediatric Neurology referral center. Site 2 (University of South Florida) was a Child Psychiatry referral center. A total of 205 children with tic disorders were enrolled from both studies. The University of Rochester also enrolled 100 control children in order to clearly isolate impacts of Tourette syndrome distinct from those occurring in the general population. The majority of children with tic disorders (n = 191, 93.1%) had Tourette syndrome, the primary population targeted for these studies. Children with Tourette syndrome were similar across sites in terms of tic severity and the occurrence of comorbid conditions. The occurrence of psychiatric comorbidities in the control group was comparable with that in the general pediatric population of the United States, making this a well-justified comparison group. CONCLUSIONS: Through collaboration, two sites conducting independent research developed convergent research methods to enable pooling of data, and by extension increased power, for future analyses. This method of collaboration is a novel model for future epidemiological research of tic disorders.

A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease.

OBJECTIVE: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). METHODS: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. RESULTS: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. CONCLUSIONS: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Myoclonus-dystonia, obsessive-compulsive disorder, and alcohol dependence in SGCE mutation carriers.

Although myoclonus and dystonia are the hallmarks of myoclonus-dystonia (M-D), psychiatric features, particularly obsessive-compulsive disorder and alcohol dependence, have been reported in three families linked to chromosome 7q21. As the epsilon sarcoglycan (SGCE) gene for M-D was subsequently identified, we evaluated the relationship between psychiatric features and SGCE mutations in these original and two additional families and confirm that OCD and alcohol dependence are associated with manifesting mutated SGCE.

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.

Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples: 17q25 is a putative susceptibility region.

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 contributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P=.002). The original families, as well as two additional pedigrees, were genotyped for 25 single-nucleotide polymorphisms (SNPs), with a focus on three genes in the indicated region that could play a role in the development of GTS, on the basis of their function and expression profile. Multiple three-marker haplotypes spanning all three genes studied provided highly significant association results (P<.001). An independent sample of 96 small families with one or two children affected with GTS was also studied. Of the 25 SNPs, 3 were associated with GTS at a statistically significant level. The transmission/disequilibrium test for a three-site haplotype moving window again provided multiple positive results. The background linkage disequilibrium (LD) of the region was studied in eight populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. In conclusion, our findings warrant the further investigation of 17q25 as a candidate susceptibility region for GTS.

Longitudinal outcome of Parkinson's disease patients with psychosis.

OBJECTIVES: To examine the long-term outcome of PD patients with psychosis requiring antipsychotic therapy; to explore predictors of mortality, nursing home placement, dementia, and persistent psychosis; and to compare outcomes of those with persistent psychosis vs those whose psychosis resolved. METHODS: Baseline data available from 59 patients enrolled in the PSYCLOPS (PSychosis and CLOzapine in PD Study) trial included age, age at onset of PD, duration of PD and psychosis, character of psychosis, medications, living setting, and scores for Mini-Mental State Examination (MMSE), Unified Parkinson's Disease Rating Scale, Hoehn and Yahr Scale, and Clinical Global Impression Scale. Longitudinal data were collected 26 months later regarding four outcomes: death, nursing home placement, diagnosis of dementia, and persistence of psychosis. Logistic regression was used to explore whether any baseline characteristics were associated with an increased likelihood of one of these outcomes. RESULTS: At baseline, 56% of patients had an MMSE score of <25, 12% were in a nursing home, 95% had hallucinations, and 60% had paranoia. On follow-up, 25% were dead, nursing home placement occurred in 42%, psychosis was persistent in 69%, and dementia was diagnosed in 68%. Select baseline characteristics predicted individual outcomes: Nursing home placement was associated with the presence of paranoia and older age; persistent psychosis was associated with younger age at onset of PD and longer disease duration; dementia was associated with older age at PD onset and lower initial MMSE score; no characteristics predicted death. Whether psychosis persisted or not had no significant effect on the development of the other three outcomes. The prevalence of hallucinations at follow-up was not different between groups currently receiving antipsychotics vs those on no treatment. CONCLUSIONS: Psychosis in PD requiring antipsychotic therapy is frequently associated with death, nursing home placement, development and progression of dementia, and persistence of psychosis. Still, it appears the prognosis has improved with atypical antipsychotic therapy based on the finding that 28% of NH patients died within 2 years compared with 100% in a previous study done prior to availability of this treatment.

The behavioral spectrum of tic disorders: a community-based study.

BACKGROUND: Tourette syndrome (TS) and related tic disorders are commonly associated with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). It has been argued, however, that any observed association between TS and these and other psychopathologies may be due to ascertainment bias in that individuals with multiple problems are more likely to be referred for medical evaluation. METHODS: In order to overcome the potential confounding by ascertainment bias, the authors conducted a community-based study of school children using direct interviews to determine the prevalence of tic disorders and any comorbid psychopathology. A standard psychiatric interview and standardized rating scales were utilized to diagnose childhood behavioral disorders. RESULTS: Of the 1,596 children interviewed, 339 were identified as having tics. The following psychopathologies were found more commonly (p < 0.05) in the children with tics: OCD, ADHD, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, mania, major depression, and oppositional defiant behavior. CONCLUSION: The behavioral spectrum of tic disorders includes OCD, other anxiety disorders, a mood disorder, and attention-deficit and disruptive behavior disorders.

Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence.

BACKGROUND: Inherited myoclonus-dystonia (M-D) is a disorder that is characterized primarily by myoclonic jerks and is often accompanied by dystonia. In addition to motor features, psychiatric disease is reported in some families. METHODS: To determine whether the same genetic etiology underlies both neurologic and psychiatric signs, the authors studied psychiatric symptoms in nonmanifesting carriers (NMC), noncarriers (NC), and manifesting carriers (MC) in three families demonstrating linkage of M-D to the 7q21 locus. Interviewers administered the computerized version of the Composite International Diagnostic Interview. Algorithms for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of obsessive-compulsive disorder (OCD), generalized anxiety disorder, major affective disorder, alcohol abuse, alcohol dependence, drug abuse, and drug dependence were used. Rates of disorders among the MC, NMC, and NC were compared. RESULTS: Of 55 participating individuals, 16 were MC, 11 were NMC, and 28 were NC. The rate of OCD was greater in carriers (5/27) compared with NC (0/28) (p = 0.023). It was also greater in the symptomatic gene carriers (4/16) compared with the asymptomatic group (1/11) (p = 0.022). Alcohol dependence was increased in the symptomatic carriers (7/16) (p = 0.027), but not in the carrier group overall (7/27). CONCLUSION: OCD may be associated with the DYT11 M-D gene; however, a larger sample is necessary to confirm this finding. Alcohol dependence is highly associated with expressing symptoms of M-D. This may be explained by self-medication with alcohol to improve motor symptoms of M-D.

Prevalence of tics in schoolchildren and association with placement in special education.

BACKGROUND: Based on the knowledge that Tourette's syndrome (TS) is associated with several clinical features that can impair school function and growing evidence that the disorder is much more common than previously thought, the authors hypothesized that TS and related tic disorders would be associated with school problems in the childhood population at large. METHODS: Direct, blinded (to educational placement) interviews of 1,596 schoolchildren in Monroe County, Rochester, NY, were conducted. RESULTS: Twenty-seven percent of 341 students classified as receiving special education (SpEd) had tics compared with 19.7% (p = 0.008) of 1,255 students in regular classroom programs (RegEd). The weighted prevalence estimates for tics were 23.4% in SpEd and 18.5% in RegEd. A higher percentage of students in SpEd (7.0%) met diagnostic criteria for TS than students in RegEd (3.8%; p = 0.01). CONCLUSIONS: Although possibly influenced by selection bias, our results indicate that tic disorders are common in children and are highly associated with school dysfunction. Tics may represent an identifiable sign of an underlying brain developmental disorder that contributes to academic difficulties.

Tics and its disorders.

Tourette syndrome (TS) is familial neuropsychiatric disorder that is characterized by motor and phonic tics that begin in childhood. Once thought of as a rare and debilitating disorder, in the last decade new scientific knowledge suggests that TS and related tic disorders are more common and less debilitating for the majority of individuals. Evidence points toward a spectrum of TS symptomatology that extends beyond the tics disorder to probably include obsessive-compulsive disorder, attention deficit hyperactivity disorder, and mood disorders. Tourette syndrome and its differential diagnosis are discussed in this article with a focus on new developments in classification, etiology, epidemiology, genetics, pathophysiology, and clinical management.

Relationship between mood and motor fluctuations in Parkinson's disease.

Mood fluctuations have been reported in up to two-thirds of patients with Parkinson's disease who experience motor fluctuations. Most researchers indicate that mood fluctuations tend to be associated with motor fluctuations in that patients experience decreased mood when "off" (immobile) and elevated mood when "on" (mobile). Sixteen patients with Parkinson's disease and motor fluctuations completed hourly diaries for 7 consecutive days documenting their mood, anxiety, and motor states using visual analogue scales. Mood and anxiety fluctuations were frequently documented. Motor and emotional states were not, however, consistently correlated. When they were correlated, the most frequent pattern was the common occurrence of decreased mood, increased anxiety, and reduced motor function.

A major locus for myoclonus-dystonia maps to chromosome 7q in eight families.

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.

MR volumetric analysis of the human basal ganglia: normative data.

RATIONALE AND OBJECTIVES: The authors undertook this study to identify a precise, semiautomated, reproducible magnetic resonance (MR) imaging technique for measuring the basal ganglia, to establish normative volumetric data, and to verify the presence of previously reported asymmetries. MATERIALS AND METHODS: Twenty-eight healthy adults underwent cranial MR examination. The volumes of the various components of the basal ganglia were measured by means of a combination of thresholding and manual tracing techniques performed with specialized software. The validity of these measurements was assessed by fashioning, imaging, and measuring a practical basal ganglia phantom. Measurement accuracy was also established by means of inter- and intrarater reliability indexes. Normalized volumes were statistically analyzed with analysis of variance and paired t tests. RESULTS: The absolute values of the various components of the basal ganglia varied widely even though the volumes were normalized to differences in intracranial volume. The right caudate nucleus volume was significantly (P < .000001) larger than the left in both men and women and in both right-handed and non-right-handed subjects. This asymmetry led to an increase in the overall volume of the basal ganglia on the right. CONCLUSION: The authors have defined a precise, reproducible technique for measuring various components of the basal ganglia and have established normative data. The basal ganglia, similar to other brain structures, exhibit hemispheric lateralization.

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 Tourette's 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 Tourette's 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.

Movement disorders in Alzheimer's disease: more rigidity of definitions is needed.

Rigidity, slowness, gait impairment, and other disorders of movement accompany Alzheimer's disease (AD) at various stages of the illness. The presence of these so-called extrapyramidal features have been reported to predict disease prognosis and pathologic localization. Unfortunately, failure to accurately characterize the movement disorder, particularly to distinguish parkinsonism from cortically based motor disturbances (that is, paratonia, apraxia), makes the results of many published studies difficult to interpret. There is an important need to precisely characterize movement disorders in studies of AD to clarify the clinical phenomenology and neurobiology of the condition and to accurately distinguish AD from other degenerative dementias, such as dementia with Lewy bodies.

The Tourette syndrome diagnostic confidence index: development and clinical associations.

BACKGROUND: The clinical characteristics of Tourette syndrome (TS) present challenges for the systematic determination of whether individuals are affected and severity. Vocal and motor tics wax and wane, decrease over time, and may be voluntarily suppressible, and therefore may be absent at interview. Current instruments measure symptoms at interview or rate symptom severity only. METHOD: To minimize error in case ascertainment and produce an instrument measuring lifetime likelihood of having had TS, clinical members of the American Tourette Syndrome Association International Genetic Collaboration developed the Diagnostic Confidence Index (DCI). The expert group worked collaboratively with progressive revision in consensus workshops using existing diagnostic criteria as guidelines. The DCI produces a score from 0 to 100 that is a measure of the likelihood of having or ever having had TS. RESULTS: The DCI was administered to 280 consecutive patients with TS attending a TS clinic; 264 (94%) completed it, indicating high feasibility and acceptability. Its correlation with other instruments and associations with psychopathology provide support for its being a lifetime measure of TS. CONCLUSIONS: The DCI is a useful, practicable instrument in the clinic or research practice allowing an assessment of lifetime likelihood of TS. Further work is needed to test the DCI's psychometric properties, such as its validity and reliability in populations of interest.

Genome scan for linkage to Gilles de la Tourette syndrome.

Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics. Despite clear evidence for a genetic predisposition to TS from family, twin, and adoption studies, there have been no confirmed linkage findings. In this article we test for linkage to TS in multigenerational families segregating TS using a panel of 386 markers with the largest interval between any two markers being 28 cM and an average distance between markers of 10 cM. We tested for linkage using an autosomal dominant model with reduced penetrance and using nonparametric methods. No significant evidence for linkage was found with parametric analysis. A logarithm of the odds (LOD) score of greater or equal to one under the autosomal dominant model was observed in 24 of these markers in at least one of the families tested. No LOD scores greater than two were observed with any of the markers. For the nonparametric analysis, eight markers were observed with a P-value less than 0.00005 for significance evidence of linkage in at least one family. However caution should be used in the interpretation of the nonparametric analyses as this statistic (the affected-pedigree-member method) is know to have a high false-positive rate. Further support for linkage in these regions is required before linkage can be assumed.