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.

Structure and clinical correlates of obsessive-compulsive symptoms in a large sample of children and adolescents: a factor analytic study across five nations.

The underlying structure of obsessive-compulsive disorder (OCD) remains to be confirmed in child and adolescent populations. In this paper we report the first factor analytic study of individual OCD items from Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). OCD symptoms were assessed using the CY-BOCS symptom checklist in a sample of 854 patients with OCD (7-18 years of age) recruited from clinics in five countries. Pooled data were subjected to exploratory and confirmatory factor analysis (CFA) to identify the optimal factor structure. Various models were tested for age and gender subgroups. Also, the invariance of the solution across age and gender was tested and associations with demographic and clinical factors were explored. A three-factor model provided the best-fit solution. It consisted of the following factors: (1) harm/sexual, (2) symmetry/hoarding, (3) contamination/cleaning. The factor structure was invariant for age and gender across subgroups. Factor one was significantly correlated with anxiety, and factor two with depression and anxiety. Factor three was negatively correlated with tic disorder and attention-deficit/hyperactivity disorder (ADHD). Females had higher scores on factor two than males. The OCD symptom structure in children and adolescents is consistent across age and gender and similar to results from recent child and adolescents although hoarding may not be a separate factor. Our three-factor structure is almost identical to that seen in early studies on adults. Common mental disorders had specific patterns of associations with the different factors.

Maternal history of autoimmune disease in children presenting with tics and/or obsessive-compulsive disorder.

OBJECTIVES: A commonality across a number of pediatric neuropsychiatric disorders is a higher than typical rate of familial - and especially maternal - autoimmune disease. Of recent interest, a subtype of obsessive-compulsive disorder (OCD) and tic disorders known collectively as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is believed to be secondary to central nervous system (CNS) autoimmunity that occurs in relation to group A streptococcal infection. Thus, we hypothesized that a sample of children with OCD and/or tics would have an increased maternal risk for an autoimmune response relative to population norms. We also expected maternal prevalence of various autoimmune diseases to be higher among those participants that met the putative criteria for PANDAS. METHODS: We examined, via structured interview, the medical history of the biological mothers of 107 children with OCD and/or tics. RESULTS: Autoimmune disorders were reported in 17.8% of study mothers, which is significantly greater than the general prevalence among women in the United States (approximately 5%). Further, study mothers were more likely to report having an autoimmune disease if their children were considered "likely PANDAS" cases versus "unlikely PANDAS" cases. CONCLUSIONS: The results offer preliminary support for hypothesized links between maternal autoimmune disease and both OCD/tics and PANDAS in youth. Further research is necessary to clarify these general associations; links to specific autoimmune disease; and relevance of autoimmune disease in other family members (e.g., fathers).

Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind trial.

BACKGROUND: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post-traumatic peripheral neuropathic pain (including post-surgical). METHODS: Patients with a pain score >or=4 (0-10 scale) were randomized and treated with either flexible-dose pregabalin 150-600 mg/day (n = 127) or placebo (n = 127) in an 8-week double-blind treatment period preceded by a 2-week placebo run-in. RESULTS: Pregabalin was associated with a significantly greater improvement in the mean end-point pain score vs. placebo; mean treatment difference was -0.62 (95% CI -1.09 to -0.15) (P = 0.01). The average pregabalin dose at end-point was approximately 326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain-related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all-patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end-point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. CONCLUSION: Flexible-dose pregabalin 150-600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post-traumatic peripheral neuropathic pain.

Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Pregabalin is effective in several neuropathic pain syndromes. This trial evaluated its efficacy, safety, and tolerability for treatment of painful HIV-associated neuropathy. METHODS: This randomized, double-blind, placebo-controlled, parallel-group trial included a 2-week double-blind dose-adjustment (150-600 mg/day BID) phase, a 12-week double-blind maintenance phase, and an optional 3-month open label extension phase. The primary efficacy measure was the mean Numeric Pain Rating Scale (NPRS) score, an 11-point numeric rating scale. Secondary measures included Patient Global Impression of Change (PGIC) and sleep measurements. RESULTS: Baseline mean NPRS score was 6.93 for patients randomized to pregabalin (n = 151) and 6.72 for those to placebo (n = 151). Pregabalin average daily dosage (SD) was 385.7 (160.3) mg/d. At endpoint, pregabalin and placebo showed substantial reductions in mean NPRS score from baseline: -2.88 vs -2.63, p = 0.3941. Pregabalin had greater improvements in NPRS score relative to placebo at weeks 1 (-1.14 vs -0.69, p = 0.0131) and 2 (-1.92 vs -1.43, p = 0.0393), and at weeks 7 (-3.22 vs -2.53 p = 0.0307) and 8 (-3.33 vs -2.53, p = 0.0156). At all other time points, differences between groups were not significant. Sleep measurements and 7-item PGIC did not differ among treatment groups; however, collapsed PGIC scores showed 82.8% of pregabalin and 66.7% of placebo patients rated themselves in 1 of the 3 "improved" categories (p = 0.0077). Somnolence and dizziness were the most common adverse events with pregabalin. CONCLUSIONS: Pregabalin was well-tolerated, but not superior to placebo in the treatment of painful HIV neuropathy. Factors predicting analgesic response in HIV neuropathy warrant additional research. CLASSIFICATION OF EVIDENCE: This Class II trial showed that pregabalin is not more effective than placebo in treatment of painful HIV neuropathy.

Symptom dimensions and cognitive-behavioural therapy outcome for pediatric obsessive-compulsive disorder.

OBJECTIVE: To examine whether obsessive-compulsive disorder (OCD) symptom subtypes are associated with response rates to cognitive-behavioural therapy (CBT) among pediatric patients. METHOD: Ninety-two children and adolescents with OCD (range = 7-19 years) received 14 sessions of weekly or intensive (daily psychotherapy sessions) family-based CBT. Assessments were conducted at baseline and post-treatment. Primary outcomes included scores on the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), remission status, and ratings on the Clinical Global Improvement (CGI) and Clinical Global Impression - Severity (CGI-Severity) scales. RESULTS: Seventy-six per cent of study participants (n = 70) were classified as treatment responders. Patients with aggressive/checking symptoms at baseline showed a trend (P = 0.06) toward improved treatment response and exhibited greater pre/post-treatment CGI-Severity change than those who endorsed only non-aggressive/checking symptoms. Step-wise linear regression analysis indicated higher scores on the aggressive/checking dimension were predictive of treatment-related change in the CGI-Severity index. Regression analysis with CY-BOCS score as the dependent variable showed no difference between OCD subtypes. CONCLUSION: Response to CBT in pediatric OCD patients does not differ substantially across subtypes.

Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial.

OBJECTIVE: To evaluate pregabalin in central neuropathic pain associated with spinal cord injury. METHODS: A 12-week, multicenter study of patients randomized to either flexible-dose pregabalin 150 to 600 mg/day (n = 70) or placebo (n = 67), administered BID. Patients were allowed to remain on existing, stable pain therapy. The primary efficacy variable was the endpoint mean pain score, derived from patients' last 7 days daily pain diary entries. Key secondary endpoints included pain responder rates, the SF-MPQ, sleep interference, mood, and the patient global measure of change. RESULTS: The mean baseline pain score was 6.54 in the pregabalin group and 6.73 in the placebo group. The mean endpoint pain score was lower in the pregabalin group (4.62) than the placebo group (6.27; p < 0.001), with efficacy observed as early as week 1 and maintained for the duration of the study. The average pregabalin dose after the 3-week stabilization phase was 460 mg/day. Pregabalin was significantly superior to placebo in endpoint assessments on the SF-MPQ. The > or =30% and > or =50% pain responder rates were higher with pregabalin than placebo (p < 0.05). Pregabalin was associated with improvements in disturbed sleep (p < 0.001) and anxiety (p < 0.05), and more patients reported global improvement at endpoint in the pregabalin group (p < 0.001). Mild or moderate, typically transient, somnolence and dizziness were the most common adverse events. CONCLUSIONS: Pregabalin 150 to 600 mg/day was effective in relieving central neuropathic pain, improving sleep, anxiety, and overall patient status in patients with spinal cord injury.

Progress toward analysis of D8/17 binding to B cells in children with obsessive compulsive disorder and/or chronic tic disorder.

BACKGROUND: Previous research has suggested that a subgroup of children with obsessive compulsive disorder (OCD) have neuropsychiatric sequelae of streptococcal pharyngitis, similar to that seen in the neurological manifestation of rheumatic fever (RF). Monoclonal antibody D8/17 demonstrates increased binding to B cells in patients with RF and in patients with neuropsychiatric disorders using immunofluorescent microscopy. OBJECTIVE: The aim of this study was to determine if an earlier immunofluorescent microscopy study of monoclonal antibody D8/17 in childhood-onset OCD and/or chronic tic disorder (CTD) could be replicated using the more objective method of flow cytometric analysis. METHOD: D8/17 binding to B cells was determined in patients with OCD and or CTD (N=32), and healthy controls (N=12) by flow cytometric analysis. RESULTS: Subjects with OCD/CTD showed increased mean cell binding (26.0%) of monoclonal antibody compared with healthy controls (9.1%) (p<0.001). When using the threshold of greater than 19% binding (95% upper confidence interval) as a measure of positivity, 65.6% of patients compared with 8.3% of controls showed increased antibody binding to B cells (p=0.01). CONCLUSIONS: Although this study reports positive results, many methodological issues will need to be addressed before generalized use of assay for diagnostic purposes.

Obsessive compulsive disorder: is there an association with childhood streptococcal infections and altered immune function?

During the last few years, an increased interest in the possibility of immune mediated pathophysiology of obsessive compulsive disorder (OCD) and related disorders has been seen. In the late 1980s, the National Institute of Mental Health reported an increase of obsessive compulsive symptoms in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal infection in children with sudden onset of OCD symptoms but no chorea led to the coining of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus). This association has furthered interest in studying immune parameters in non-PANDAS OCD as well. This article will review the neuropsychiatric findings in OCD and Tourette syndrome (TS) with emphasis placed on PANDAS, and its association with SC, and a review of the existing studies that have assessed immunologic measures in patients with OCD and TS.

Selective serotonin reuptake inhibitors in the treatment of paediatric anxiety disorders: a review.

Anxiety disorders (obsessive-compulsive disorder, social phobia/selective mutism, panic disorder, separation anxiety, generalized anxiety disorder, simple phobia and post-traumatic stress disorder) are the most prevalent psychiatric disorders in children and adolescents. The selective serotonin reuptake inhibitors (SSRIs)--citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline--have demonstrated efficacy in treating anxiety disorders in adults. Although less information is available on the use of these agents in the paediatric population, research into the SSRIs for childhood anxiety disorders is increasing. This article reviews current literature, including case reports as well as open and controlled trials, on the effectiveness and tolerability of the SSRIs in the paediatric population. It also discusses developmental differences in children that should be considered in the utilisation of the SSRIs in paediatric patients.

Body mass index and colon cancer mortality in a large prospective study.

Obesity has been reported to increase the risk of colon cancer, especially in men. The authors examined this relation in the American Cancer Society's Cancer Prevention Study II, a nationwide mortality study of US adults. After 12 years of follow-up, 1,616 deaths from colon cancer in women and 1,792 in men were observed among 496,239 women and 379,167 men who were cancer free at enrollment in 1982. The authors used Cox proportional hazards analyses to control for effects of age, race, education, smoking, exercise, alcohol, parental history of colon cancer, fat intake, vegetable and grain intake, aspirin use and, in women, estrogen replacement therapy. In men, death rates from colon cancer increased across the entire range of body mass index (BMI). The rate ratio was highest for men with BMI > or =32.5 (rate ratio (RR) = 1.90, 95% confidence interval (CI): 1.46, 2.47) compared with men with BMI between 22.00 and 23.49. In women, a weaker association was seen in the three BMI categories of 27.5-29.9 (RR = 1.26, 95% CI: 1.03, 1.53), 30.0-32.4 (RR = 1.37, 95% CI: 1.09, 1.72), and > or =32.5 (RR = 1.23, 95% CI: 0.96, 1.59). These prospective data support the hypothesis that obesity increases the risk of colon cancer death and that the relation is stronger and more linear in men than in women.

On defining Sydenham's chorea: where do we draw the line?

Sydenham's chorea (SC) is a major manifestation of rheumatic fever characterized by an array of neuropsychiatric symptoms that vary in severity, timing, and character. Some of the same symptoms are seen in Tourette's syndrome and childhood-onset obsessive-compulsive disorder. Genetic vulnerability appears to play a role in all three conditions. The term PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus) has been introduced to describe a putative subset of obsessive-compulsive disorder and Tourette's syndrome that bears some resemblance to Sydenham's chorea. This article discusses whether PANDAS should be subsumed under Sydenham's chorea, thus expanding the diagnostic boundaries of Sydenham's chorea to include primarily neuropsychiatric presentations now classified as cases of obsessive-compulsive disorder or Tourette's syndrome. We conclude that PANDAS is a useful construct, but that it would be premature to view it as a subset of Sydenham's chorea-whether defined narrowly or broadly.

Diabetes mellitus and pancreatic cancer mortality in a prospective cohort of United States adults.

OBJECTIVES: Diabetes mellitus and pancreatic cancer are known to be associated, but it is not known whether diabetes is a true risk factor, preceding development of the cancer, or if it is an early manifestation of the cancer. To address this uncertainty, we examined the association of pancreatic cancer mortality and reported diabetes of at least one year's duration in a large, prospective study of United States adults. The vast majority of diabetes in this cohort is likely to be non-insulin-dependent diabetes. METHODS: After 12 years of follow-up, 2,953 deaths from pancreatic cancer were observed in a cohort of 1,089,586 men and women who were cancer-free at study entry in 1982. Cox proportional hazards models, adjusted for age, race, smoking, family history of pancreatic cancer, body mass index (wt/ht2), and education, were used to assess associations. RESULTS: A history of diabetes was significantly related to pancreatic cancer mortality in both men (rate ratio [RR] = 1.49, 95 percent confidence interval [CI] = 1.25-1.77) and women (RR = 1.51, CI = 1.24-1.85). However, the strength of the association varied over the follow-up period. The death rate from pancreatic cancer was twice as high in diabetics as in non-diabetics during the second and third years of follow-up (adjusted RR = 2.05, CI = 1.56-2.69) but only about 40 percent higher in years nine to 12 (adjusted RR = 1.38, CI = 1.08-1.77). CONCLUSIONS: The small but persistent increased risk of death from pancreatic cancer, seen even when the diagnosis of diabetes preceded death by many years, supports the hypothesis that diabetes may be a true, albeit modest, risk factor for pancreatic cancer.

Occupation and breast cancer mortality in a prospective cohort of US women.

The authors examined the association between main lifetime occupation and subsequent breast cancer mortality in a large prospective study of US adults. After 9 years of follow-up, 1,780 cases of fatal breast cancer were observed among 563,395 women who were cancer-free at interview in 1982. Main lifetime occupation was derived based on self-reports of current and former occupational titles and was classified into 14 broad occupational groups and 16 more narrowly defined occupational titles. Results from Cox proportional hazards models, adjusted for breast cancer risk factors, revealed little variability in breast cancer mortality by occupation. Two significant associations were observed: In comparison with housewives, women in "administrative support, including clerical" occupations were at a small increased risk (rate ratio (RR) = 1.14, 95% confidence interval (CI) 1.01-1.31), and an increased risk was seen for "executives" (RR = 1.93, 95% CI 1.03-3.62), based on 10 breast cancer deaths. No significant increases in risk were observed for teachers and librarians (RR = 0.89), nurses (RR = 0.84), managers (RR = 0.89), or women employed in sales (RR = 0.88) or service (RR = 0.84) occupations. When analyses were limited to women who had worked in their occupation for 10 or more years, the results for each occupational title were virtually unchanged. These results offer little support for an association between occupation and breast cancer mortality in general or for particular occupational titles, including teachers and nurses.

Special considerations: use of lithium in children, adolescents, and elderly populations.

Certain populations of patients require special considerations when lithium is prescribed. Children and adolescents have higher volumes of body water and more active renal glomerular filtration rates than adults. Their central nervous system is developing and therefore is vulnerable to the impact of substances, including medications such as lithium, that can cause side effects or adverse events. Elderly patients have less body water, slower metabolism, and often comorbid illnesses, so they also require close evaluation and monitoring when prescribed lithium. This paper examines the indications for, pharmacokinetics of, clinical uses of, and side effects of lithium in children, adolescents, and the elderly. Use of alternate mood stabilizers is also addressed briefly.

B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette's syndrome?

OBJECTIVE: It has been hypothesized that Sydenham's chorea, a major manifestation of rheumatic fever, may provide a medical model for obsessive-compulsive disorder and associated conditions, such as Tourette's syndrome. Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in nearly all patients with rheumatic fever and is thought to be a trait marker for susceptibility to this complication of group A streptococcal infection. The authors investigated whether D8/17 expression is greater than normal in some forms of obsessive-compulsive disorder and Tourette's syndrome. METHOD: By immunofluorescence techniques, 31 patients with childhood-onset obsessive-compulsive disorder and/or Tourette's syndrome or chronic tic disorder and 21 healthy comparison subjects were evaluated for percentage of D8/17-positive B cells. None had rheumatic fever or Sydenham's chorea. Levels of antineuronal antibodies and streptococcal antibodies were also determined. RESULTS: The average percentage of B cells expressing the D8/17 antigen was significantly higher in the patients (mean = 22%, SD = 5%) than in the comparison subjects (mean = 9%, SD = 2%). When classified categorically, all patients but only one comparison subject were D8/17 positive. No difference between groups in the presence of antineuronal antibodies or high streptococcal titers was found. CONCLUSIONS: Patients with childhood-onset obsessive-compulsive disorder or Tourette's syndrome had significantly greater B cell D8/17 expression than comparison subjects despite the absence of documented Sydenham's chorea or rheumatic fever. These findings suggest that D8/17 may serve as a marker for susceptibility among some forms of childhood-onset obsessive-compulsive disorder and Tourette's syndrome, as well as rheumatic fever or Sydenham's chorea.

Radiation response of mouse lymphoid and myeloid cell lines. Part II. Apoptotic death is shown by all lines examined.

The mode of death induced by gamma-irradiation in a panel of 10 mouse lymphoid or myeloid cell lines was examined. Four of these lines were known to lose viability (membrane integrity) rapidly after irradiation, whilst the others were known to lose viability considerably more slowly. However, based on the criteria of morphology and DNA degradation pattern, all 10 lines showed apoptotic death. The occurrence of apoptosis after irradiation in rapid-dying lymphoid cell lines was consistent with published results, whilst the demonstration of apoptosis in slow-dying lines was unexpected. Cells of the slow-dying lymphoid lines underwent one or more mitoses prior to death, a feature also reported for fibroblastoid cell lines. However, the occurrence of radiation-induced necrosis in fibroblasts suggests that the pathways leading to 'mitotic death' differ between fibroblastoid and lymphoid cell lines.