Lawrence W. Brown

A randomised, double-blind, placebo-controlled study of topiramate in the treatment of Tourette syndrome

Objective: To investigate the effects of topiramate on Tourette syndrome (TS). Background: Dopamine-receptor-blocking drugs have been traditionally used to control tics in patients with TS, but these neuroleptics are associated with potentially limiting side effects. Methods: This is a randomised, double-blind, placebo-controlled, parallel group study. To be included in the study, subjects required a DSM-IV diagnosis of TS, were 7–65 years of age, had moderate to severe symptoms (Yale Global Tic Severity Scale (YGTSS) ⩾19), were markedly impaired as determined by the Clinical Global Impression (CGI) scale severity score of ⩾4 and were taking no more than one drug each for tics or TS comorbidities. Results: There were 29 patients (26 males), mean age 16.5 (SD 9.89) years, randomised, and 20 (69%) completed the double-blind phase of the study. The primary endpoint was Total Tic Score, which improved by 14.29 (10.47) points from baseline to visit 5 (day 70) with topiramate (mean dose 118 mg) compared with a 5.00 (9.88) point change in the placebo group (p = 0.0259). There were statistically significant improvements also in the other components of the YGTSS as well as improvements in various secondary measures, including the CGI and premonitory urge CGI. No differences were observed in the frequency of adverse events between the two treatment groups. Conclusion: This double-blind, placebo-controlled trial provides evidence that topiramate may have utility in the treatment of moderately severe TS.

Periodic limb movement in sleep in children with Williams syndrome

OBJECTIVE Williams syndrome (WS) is associated with neurobehavioral abnormalities that include irritability and attention-deficit/hyperactivity disorder. Parents often report children having difficulties initiating and maintaining sleep because of restlessness and arousals. Therefore we evaluated a group of children with WS for the presence of a movement arousal sleep disorder. METHODS Twenty-eight families of children with WS participated in a telephone survey aimed to screen for a movement arousal disorder. Of the 16 children identified as having such a disorder, 7 (mean age, 3.9 +/- 2.2 years) underwent polysomnography. Their studies were compared with those of 10 matched control subjects (mean age, 5.3 +/- 2.0 years). RESULTS The 7 subjects with WS who were screened by the survey had sleep latency, total sleep time, arousals, and awakenings that were similar to those of control subjects. However, they presented with a disorder of periodic limb movement in sleep (PLMS). The PLMS index in the subjects with WS was 14.9 +/- 6.2 versus 2.8 +/- 1.9 in control subjects (P < .0001). In addition, arousal and awakening in subjects with WS were strongly associated with PLMS. Moreover, children with WS spend more time awake during sleep periods than control subjects (10.0% +/- 7.0% vs 4.4% +/- 4.7%; P < .05). Five children were treated with clonazepam, and in 4 a significant clinical response was noted. CONCLUSION We report an association between WS and PLMS. Clonazepam may reduce the clinical symptoms of PLMS in some of these children.

Nocturnal enuresis: a suggestive endophenotype marker for a subgroup of inattentive attention-deficit/hyperactivity disorder.

OBJECTIVE Attention-deficit/hyperactivity disorder (ADHD) and enuresis co-occur at a higher rate than expected; the cause for this is unclear. STUDY DESIGN Diagnostic and demographic variables were compared in 344 children ages 6 to 12 years, with and without enuresis, recruited in an ADHD genetic study. Sleep variables were investigated in a subgroup of 44 enuretic children with age- and sex-matched nonenuretic controls. The association of enuresis with single nucleotide polymorphisms located in regions reported in linkage with enuresis was explored. RESULTS The prevalence rate of nocturnal enuresis was 16.9% for the entire cohort. There were no differences in sex, age, socioeconomic status, intelligence quotient, medication treatment, or comorbidities. The enuresis group had a higher likelihood of inattentive symptoms than the nonenuretic group. Night wakings and ability of children to wake themselves in the morning were both significantly decreased in children with enuresis compared with control children in the Child Sleep Habits Questionnaire Night Wakings subscale. No significant association was found with chromosomal regions previously reported in linkage with enuresis. CONCLUSIONS Deficits in arousal may contribute to both enuresis and inattentive ADHD. Nocturnal enuresis may be a useful clinical marker in identifying a subgroup of the inattentive phenotype in ADHD genetic studies.

Ring chromosome 20.

Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to severe cognitive impairment. Facial dysmorphism or other congenital malformations are rarely reported making it difficult to diagnose the syndrome based on clinical findings alone. Therefore, diagnosis requires cytogenetic testing. More than 100 cases have been published since the initial report in 1972. In some patients, the ring (20) is found in all cells analyzed and in these cases, the ring is almost always accompanied by deletions of 20pter and/or 20qter. However, in the majority of cases the ring is present in only a proportion of cells, with two normal 20s in the remaining cells (mosaicism), and in these cases, no deletions of chromosome 20 have been observed. Patients with supernumerary r(20) chromosomes have also been identified, but these individuals do not generally have seizures and are not discussed in this review. Characterization by fluorescence in situ hybridization and array-based analysis has shed insight into the molecular composition and possible mechanisms of ring formation, in both the mosaic and non-mosaic patients. The age of onset of seizures correlates with the percentage of cells with the ring in mosaic patients. While the underlying etiology of the phenotype is still not understood, evidence is accumulating which suggests the deletion of candidate genes on chromosome 20 is not responsible. Cytogenetic analysis, rather than chromosomal microarray analysis is recommended for diagnosis of this syndrome, as the mosaic cases do not have copy number alterations and are therefore not identified by array-based analysis.

The neurologist's role in supporting transition to adult health care A consensus statement

The child neurologist has a critical role in planning and coordinating the successful transition from the pediatric to adult health care system for youth with neurologic conditions. Leadership in appropriately planning a youths transition and in care coordination among health care, educational, vocational, and community services providers may assist in preventing gaps in care, delayed entry into the adult care system, and/or health crises for their adolescent patients. Youth whose neurologic conditions result in cognitive or physical disability and their families may need additional support during this transition, given the legal and financial considerations that may be required. Eight common principles that define the child neurologists role in a successful transition process have been outlined by a multidisciplinary panel convened by the Child Neurology Foundation are introduced and described. The authors of this consensus statement recognize the current paucity of evidence for successful transition models and outline areas for future consideration.

The long-term outcomes of ocular tics in a pediatric neuro-ophthalmology practice

PURPOSE To describe the outcome and comorbidities of ocular tics in children evaluated by a pediatric neuro-ophthalmologist. METHODS The medical records of all consecutive patients in a pediatric neuro-ophthalmology practice diagnosed with ocular tics (eye rolling, blinking, and widening) were retrospectively reviewed. Children with known secondary causes for tics were excluded. Patients, parents, and/or guardians were contacted by telephone to obtain follow-up information. RESULTS A total of 43 patients were included in the retrospective cohort, with a mean age of 7.8 ± 4.8 years at diagnosis. Thirty-two patients participated in the follow-up survey, with an average follow-up of 6.1 ± 3.9 years. None of the 43 children carried a diagnosis of Tourette syndrome or obsessive-compulsive disorder (OCD) at presentation; 1 child had attention deficit hyperactivity disorder (ADHD). At follow-up, 14 of the 32 children (44%) had persistent ocular tics, 3 (9%) reported new nonocular motor tics, 5 (16%) reported new vocal tics, and 4 (13%) developed both nonocular motor and vocal tics. One patient (3%) was formally diagnosed with Tourette syndrome during the follow-up interval, and 3 (9%) were diagnosed with ADHD. CONCLUSIONS Almost half of the children with ocular tics at presentation had persistent ocular tics on follow-up. New nonocular motor and vocal tics occurred in several patients.

Hypoxemia and hemodynamic changes during the hypercarbia stimulation test.

The hypercarbia stimulation test is a valuable technique to document the absence of brainstem responsiveness to elevated levels of carbon dioxide (PCO2); however, its application has been limited by concern that hypoxemia may induce cardiovascular instability. We investigated hemodynamic and oxygen (PO2) changes in 19 patients: group 1 (17 patients) had no spontaneous ventilations at PCO2 values ranging from 37-129 torr; group 2 (2 patients) had spontaneous ventilations at less than 38 torr. Group 1 was separated into 2 subgroups: A (10 patients) with PO2 greater than 153 torr and B (7 patients) with PO2 less than 80 torr. Hemodynamic changes (less than 10% variation in baseline pulse and blood pressure) occurred in 9 of 10 patients in group 1A and all patients in Group 1B. Mean differences in pulse and blood pressure changes between these groups were not significant; therefore, pulse and blood pressure changes are not predictive of hypoxemia and hypercarbia is not necessary to induce spontaneous ventilation in patients with intact medullary function.

Outgrowing the Child Neurologist: Facing the Challenges of Transition

H uman apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4. APOE4 is a major genetic risk factor for Alzheimer disease and is associated with dementia in Down syndrome and poor neurological outcome after traumatic brain injury, cerebral hemorrhage, and other neuropathological disorders. While apoE4 can induce neuropathology by participating in various cellular and molecular pathways, herein I review data supporting the hypothesis that apoE4 has direct toxic effects on the cerebrovascular system that in turn can lead to secondary neuronal dysfunction and degeneration as well as accumulation of neurotoxins in brain such as -amyloid (A ) in Alzheimer disease. I review A -independent cerebrovascular effects of apoE, particularly activation of a proinflammatory cyclophilin A–mediated pathway in brain vascular pericytes by apoE4 that has recently been shown to lead to a loss of cerebrovascular integrity and blood-brain barrier breakdown causing neuronal injury. I also review A -dependent cerebrovascular effects of apoE such as faulty A clearance from brain to circulation by apoE4. Finally, I discuss isoform-specific interactions of apoE with low-density lipoprotein receptor-related protein 1 on brain vascular cells (ie, endothelial cells, pericytes), which play an important role in A -independent and A -dependent effects of apoE on cerebral vasculature. JAMA Neurol. 2013;70(4):440-444. Published online February 11, 2013. doi:10.1001/jamaneurol.2013.2152

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent–child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case–control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive–compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.