Erica Greenberg

Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: Preliminary results

Behavioral side effects related to the use of levetiracetam (LEV) in epilepsy are increasingly being recognized. Patients followed in our center have reported improvement of these side effects after starting pyridoxine (vitamin B(6)) supplements. Using mailed questionnaires, retrospective chart reviews, and phone call follow-ups, we analyzed 42 pediatric patients who had been treated with LEV and pyridoxine. Twenty-two patients started pyridoxine after being on LEV, and significant behavioral improvement was observed in nine (41%), no effect in eight (36%), deterioration in four (18%), and an uncertain effect in one. The effects of pyridoxine supplementation were observed during the first week. The remaining patients (20) were already on pyridoxine before LEV was started, started pyridoxine and LEV at the same time, or took pyridoxine intermittently. Pyridoxine is an easily available, inexpensive, and safe therapeutic option. Given these preliminary results, we plan to conduct a placebo-controlled cross-over study to better characterize these observations.

Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified

Tuberous Sclerosis Complex (TSC) is a multi‐system disorder that is highly variable in its clinical presentation. Current molecular diagnostic methods permit identification of mutations in either TSC1 or TSC2 in 75–85% of TSC patients. Here we examine the clinical characteristics of those TSC patients who have no mutation identified (NMI). A retrospective review of our patient population that had comprehensive testing for mutations in TSC1/TSC2 identified 23/157 (15%) that were NMI. NMI patients had a lower incidence of brain findings on imaging studies, neurological features, and renal findings than those with TSC2 mutations. In contrast, NMI patients had a lower incidence of seizures than TSC patients with TSC1 mutations, but had a higher incidence of both renal angiomyolipomas and pulmonary lymphangioleiomyomatosis. This distinct constellation of findings suggest that NMI patients may have a unique molecular pathogenesis, different from that seen in TSC patients with the usual mutations in TSC1 and TSC2. We suggest that the mechanisms of disease in these patients include both mosaicism for a TSC2 mutation, and unusual non‐coding region mutations in TSC2.

Social disinhibition is a heritable subphenotype of tics in Tourette syndrome

Objective: To identify heritable symptom-based subtypes of Tourette syndrome (TS). Methods: Forty-nine motor and phonic tics were examined in 3,494 individuals (1,191 TS probands and 2,303 first-degree relatives). Item-level exploratory factor and latent class analyses (LCA) were used to identify tic-based subtypes. Heritabilities of the subtypes were estimated, and associations with clinical characteristics were examined. Results: A 6-factor exploratory factor analysis model provided the best fit, which paralleled the somatotopic representation of the basal ganglia, distinguished simple from complex tics, and separated out socially disinhibited and compulsive tics. The 5-class LCA model best distinguished among the following groups: unaffected, simple tics, intermediate tics without social disinhibition, intermediate with social disinhibition, and high rates of all tic types. Across models, a phenotype characterized by high rates of social disinhibition emerged. This phenotype was associated with increased odds of comorbid psychiatric disorders, in particular, obsessive-compulsive disorder and attention-deficit/hyperactivity disorder, earlier age at TS onset, and increased tic severity. The heritability estimate for this phenotype based on the LCA was 0.53 (SE 0.08, p 1.7 × 10−18). Conclusions: Expanding on previous modeling approaches, a series of TS-related phenotypes, including one characterized by high rates of social disinhibition, were identified. These phenotypes were highly heritable and may reflect underlying biological networks more accurately than traditional diagnoses, thus potentially aiding future genetic, imaging, and treatment studies.

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome

OBJECTIVE Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts. METHOD Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated. RESULTS The authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not. CONCLUSIONS The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.

Prevalence and predictors of hair pulling disorder and excoriation disorder in Tourette syndrome

Trichotillomania/hair pulling disorder (HPD) and excoriation/skin picking disorder (SPD) are childhood-onset, body-focused repetitive behaviors that are thought to share genetic susceptibility and underlying pathophysiology with obsessive–compulsive disorder (OCD) and Tourette syndrome (TS). We sought to determine the prevalence of DSM-5 HPD and SPD in TS patients, and to identify clinical factors most associated with their co-morbidity with TS. Participants included 811 TS patients recruited from TS specialty clinics for a multi-center genetic study. Patients were assessed using standardized, validated semi-structured interviews. HPD and SPD diagnoses were determined using a validated self-report questionnaire. HPD/SPD prevalence rates were calculated, and clinical predictors were evaluated using regression modeling. 3.8 and 13.0% of TS patients met DSM-5 criteria for HPD and SPD, respectively. In univariable analyses, female sex, OCD, and both tic and obsessive–compulsive symptom severity were among those associated with HPD and/or SPD. In multivariable analyses, only lifetime worst-ever motor tic severity remained significantly associated with HPD. Female sex, co-occurring OCD, ADHD, and motor tic severity remained independently associated with SPD. This is the first study to examine HPD and SPD prevalence in a TS sample using semi-structured diagnostic instruments. The prevalence of HPD and SPD in TS patients, and their association with increased tic severity and co-occurring OCD, suggests that clinicians should screen children with TS and related disorders for HPD/SPD, particularly in females and in those with co-occurring OCD. This study also helps set a foundation for subsequent research regarding HPD/SPD risk factors, pathophysiology, and treatment models.

Tricky “Ticcy” Case: Tics/Tourette Syndrome with Co-occurring OCD

Tourette syndrome and related tic disorders are complex, neuropsychiatric conditions that likely arise from fronto-subcortical circuit dysfunction. Individuals with these disorders often have additional neuropsychiatric comorbidities such as obsessive compulsive disorder and attention deficit hyperactivity disorder. Given their presumed overlapping genetic and neurodevelopmental origins, it is common for individuals to struggle with symptoms that overlap these diagnostic categories. As a result, careful attention must be paid to complete a thorough evaluation inclusive of these and other neuropsychiatric comorbidities, the presence of which helps to guide appropriate treatment, which includes specific psychotherapeutic and pharmacotherapeutic interventions for each of these disorders. This case of a young man exemplifies the complex and evolving experience of individuals struggling with Tourette syndrome and related disorders. His and his family’s stories provide a lesson in the natural history and diagnostic process of these neuropsychiatric conditions and serve as a starting point for discussion of neuropathological correlates and an in-depth discussion of pharmaco- and psychotherapeutic management.

Assessment and treatment of trichotillomania (hair pulling disorder) and excoriation (skin picking) disorder

Recommendations are provided for the assessment and treatment of trichotillomania (hair pulling disorder, or HPD) and excoriation disorder (skin picking disorder, or SPD), two body-focused repetitive behavior (BFRB) disorders, based on their severity, comorbidities, and behavioral style. Habit reversal training (HRT) and stimulus control are first-line behavioral treatments that can be used in cases of all severity levels and may be particularly helpful when pulling or picking is performed with lowered awareness/intention. Acceptance and commitment therapy (ACT) and dialectical behavior therapy (DBT) are behavioral treatments that can be employed to augment HRT/stimulus control, especially when negative emotions trigger the pulling or picking. There are currently no FDA-approved pharmacologic treatments for HPD or SPD, though certain medications/supplements have shown varying degrees of efficacy in trials. N-acetylcysteine (NAC) should be considered for all severity levels and styles given its moderate gain/low side effect profile. Other pharmacologic interventions, including selective serotonin reuptake inhibitors (SSRIs), should be considered in cases with significant comorbidities or previous behavioral/NAC treatment failure.

Predictors of Comorbid Eating Disorders and Association with Other Obsessive-Compulsive Spectrum Disorders in Trichotillomania

Trichotillomania (TTM) and eating disorders (ED) share many phenomenological similarities, including ritualized compulsive behaviors. Given this, and that comorbid EDs may represent additional functional burden to hair pullers, we sought to identify factors that predict diagnosis of an ED in a TTM population. Subjects included 555 adult females (age range 18-65) with DSM-IV-TR TTM or chronic hair pullers recruited from multiple sites. 7.2% (N=40) of our TTM subjects met criteria for an ED in their lifetime. In univariable regression analysis, obsessive-compulsive disorder (OCD), Yale-Brown Obsessive Compulsive Scale (Y-BOCS) worst-ever compulsion and total scores, certain obsessive-compulsive spectrum disorders, anxiety disorder, attention-deficit/hyperactivity disorder (ADHD), and substance disorder all met the pre-specified criteria for inclusion in the multivariable analysis. In the final multivariable model, diagnosis of OCD (OR: 5.68, 95% CI: 2.2-15.0) and diagnosis of an additional body-focused repetitive behavior disorder (BFRB) (OR: 2.69, 95% CI: 1.1-6.8) were both associated with increased risk of ED in TTM. Overall, our results provide further support of the relatedness between ED and TTM. This finding highlights the importance of assessing for comorbid OCD and additional BFRBs in those with TTM. Future research is needed to identify additional predictors of comorbid disorders and to better understand the complex relationships between BFRBs, OCD and EDs.

896 - Genetic and Phenotypic Overlap of Specific Obsessive-Compulsive Subtypes with Tourette Syndrome

Background The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) have not been well characterized. Methods OCD and ADHD symptom patterns were identified among patients with TS and their family members (N=3494) using exploratory factor and latent class analyses; clinical associations and heritability of these factors were examined. Results Factor analyses yielded 2- and 8-factor models for ADHD and OCD, respectively. Both ADHD factors (inattention and hyperactivity/impulsiveness) were genetically related to TS, ADHD, and OCD; all OCD factors (related to symmetry/contamination, unusual thoughts, aggressive urges, and hoarding) were genetically related to OCD. The OCD aggressive urges factor was genetically associated with TS and ADHD, the symmetry/exactness and fear of harm factors were associated with TS, and the hoarding factor was associated with ADHD. Latent classes based on OCD and ADHD factor sum scores to examine the relationships between OCD and ADHD symptoms in probands and family members revealed a three-class solution: ADHD; OCD+ADHD; and asymmetry/exactness, hoarding, and ADHD. The majority of participants with TS, ADHD, mood, and anxiety disorders, as well as mothers, fathers, and probands, were classified in the ADHD class. In contrast, the largest percentage of participants with OCD and disruptive behavior disorders were classified in the asymmetry/exactness, hoarding, and ADHD class. Conclusions Symmetry/exactness, aggressive urges, fear of harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and transcend diagnostic boundaries, perhaps representing a failure of top-down cognitive control common to all three disorders.