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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

Tourette's 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

OBJECTIVE: Substantial evidence suggests that both environmental and genetic factors contribute to the development and clinical expression of Tourette's syndrome. Although genetic studies of Tourette's syndrome are common, studies of environmental factors are relatively few and have not identified consistent risk factors across studies. This study examines in a large cohort of subjects (N=180) the relationship between prenatal/perinatal adverse events with Tourette's syndrome severity as determined by tic severity and rates of commonly comorbid disorders such as obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and self-injurious behavior. METHOD: Tic severity, OCD, ADHD, self-injurious behavior, and exposure to a variety of prenatal/perinatal events were systematically assessed in all subjects enrolled in three genetic studies of Tourette's syndrome. Using linear and logistic regression, a best-fit model was determined for each outcome of interest. RESULTS: Prenatal maternal smoking was strongly correlated with increased tic severity and with the presence of comorbid OCD in these Tourette's syndrome subjects. Other variables, such as paternal age and subject's birth weight, were significantly but less strongly associated with increased symptom severity. The authors found no association between symptom severity and hypoxia, forceps delivery, or hyperemesis during pregnancy, which have been previously identified as risk factors. CONCLUSIONS: This study identifies prenatal maternal smoking as a strong risk factor for increased symptom severity in Tourette's syndrome. [ABSTRACT FROM AUTHOR]

Spontaneous cerebellar haematomas in previously well children are most often caused by haemorrhage from small angiomas. Eight such cases in children 12 years of age or younger have been reported previously. Their clinical course was usually not as acute as the course most commonly seen in adults, and four of the children survived after evacuation of the haematoma. Two additional cases are presented. Both children were admitted in a comatose state, but survived after surgical intervention. Cerebellar haematomas in children seem to have a better prognosis than in adults and should be considered in the evaluation of children with subarachnoid haemorrhage or the rapid onset of coma. Even if admitted in extremis, recovery is possible after prompt diagnosis and surgical evacuation of the haematoma. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to characterize the clinical features, course, and treatment of essential tremor (ET) in children., Methods: A retrospective chart review was conducted over 25 years (1984-2011). Inclusion criteria were age <21 years and satisfying the core diagnostic criteria for ET. Primary exclusion criteria included other neurological findings, tremorogenic medications, sudden onset/stepwise progression, primary orthostatic tremor, and isolated task specificity; and secondary exclusion criteria were abnormal neuroimaging or metabolic/thyroid studies. Cases were reviewed for age, sex, family history, tremor characteristics, functional impairment, treatment, and follow-up., Results: In total, 211 children had ET, including 130 males and 81 females. The mean ± standard deviation age was at diagnosis was 14.09 ± 5.0 years, the age of onset was 9.71 ± 5.62 years, and the age of onset was birth in 7 children. One hundred ninety-nine children had bilateral hand tremor, 34 had asymmetry, 9 had unilateral onset but later became bilateral. Twelve children had voice tremors, 13 had leg tremors, 5 had head tremors, and 7 had trunk tremors. Tremor at rest was present in 20 children. Thirty-five percent of the children had a family history of ET, including in a father (n = 21), mother (n = 13), brother (n = 6), sister (n = 3), and other family member (n = 28). Fifty-five percent of patients had functional disabilities, including writing (n = 66), eating (n = 28) drinking from a cup (n = 13), typing (n = 4), playing instruments (n = 6), buttoning (n = 6), and playing (n = 3). For treatment, 33 patients received propranolol, 1 received atenolol, 13 received primidone, 3 received metoprolol, and 1 received nadolol. In total, 99 patients were followed for a mean ± standard deviation of 1.82 ± 2.21 years.If left untreated, tremor remained unchanged in 33 patients, and 7 had an apparent short-term improvement. On propranolol, 15 of 20 patients significantly improved., Conclusions: This is the largest series to date of ET in children. The current findings indicate that onset at birth is possible, family history is less common in children than in adults, and tremor at rest is possible. Functional disability was noted in 55% of children, and 29.4% required medication.

Background: The objective of this study was to determine the frequency, nature, and impact of sleep disorders in children and adolescents with Tourette syndrome and to raise awareness about their possible inclusion as a Tourette syndrome comorbidity., Methods: Using a prospective questionnaire, we interviewed 123 patients of age ≤21 years with a confirmed diagnosis of Tourette syndrome. Each completed questionnaire was then reviewed in accordance with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for categorization to a form of sleep disorder., Results: Of the 123 patients with Tourette syndrome, 75 (61%) had comorbid attention deficit hyperactivity disorder and 48 (39%) had Tourette without attention deficit hyperactivity disorder. The sleep problems observed included problems in the nature of sleep, abnormal behaviors during sleep, and impact of sleep disturbances on quality of life. Within these cohorts, 31 (65%) of the 48 Tourette-only patients and 48 (64%) of the 75 Tourette + attention deficit hyperactivity disorder patients could fit into some form of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, coded sleep disorders. Of the 48 Tourette + attention deficit hyperactivity disorder patients with sleep disorders, 36 (75%) had insomnia signs, which could be explained by the co-occurrence of attention deficit hyperactivity disorder and high stimulant use. However, 10 (32%) of the 31 Tourette-only patients with sleep disorders had insomnia irrespective of attention deficit hyperactivity disorder or medication use., Conclusions: Sleep problems are common in children with Tourette syndrome irrespective of comorbid attention deficit hyperactivity disorder, justifying their inclusion as a comorbidity of Tourette syndrome., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study compares primary stereotypies (repetitive, self-stimulating, and seemingly nonsensical movements that can occur within typically developing children) and secondary stereotypies (those occurring within autistic or mentally retarded children). Utilizing a retrospective chart review from 1995 to 2010, the current study compares primary and secondary stereotypies by the application of a classification system that organizes the movement by its type (motor only, phonic only, mixed) and complexity. In addition, it investigates other parameters associated with the movements such as duration, frequency, age, functional impairment, and progression. The sample group consisted of 28 primary and 28 secondary cases. Primary stereotypies were predominantly motor, simple, of shorter duration, and of less frequency, whereas secondary stereotypies had more vocalization, complexity, longer durations, and higher frequencies. Moreover, functional impairment due to stereotypies was noted in 3 primary and 7 secondary cases, and worsening of stereotypies was noted in 70% of primary versus 44% of secondary cases.

Objective: The authors analyzed the frequency of occurrence of headaches in children and adolescents with Tourette syndrome (TS) to address their possible inclusion as a comorbidity., Study Design: Using a prospective questionnaire, administered directly, we interviewed a total sample size of 109 patients with TS ≤ 21 years of age. The questionnaires were then analyzed according to the International Headache Society's diagnostic criteria., Results: We found headaches to be present in 55% of the patients, with the 2 most common headache types being migraine headaches and tension-type headaches. The rate of migraine headache within the TS group was found to be 4 times greater than that of the general pediatric population, as reported in the literature. In addition, the rate of tension-type headache was found to be more than 5 times greater than that of the general pediatric population., Conclusions: Overall, the high rates of migraine and tension-type headache within this population support the proposition that headaches are a comorbidity of TS., (Copyright © 2012 Mosby, Inc. All rights reserved.)

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.

Rare sequence variants may be important in understanding the biology of common diseases, but clearly establishing their association with disease is often difficult. Association studies of such variants are becoming increasingly common as large-scale sequence analysis of candidate genes has become feasible. A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS). The statistical evidence for this suggestion came from association analyses of a rare 3'-UTR variant, var321, which was observed in two patients but not observed in more than 2000 controls. We genotyped 307 Costa Rican and 515 Ashkenazi individuals (TS probands and their parents) and observed var321 in five independent Ashkenazi parents, two of whom did not transmit this variant to their affected child. Furthermore, we identified var321 in one subject from an Ashkenazi control sample. Our findings do not support the previously reported association and suggest that var321 is overrepresented among Ashkenazi Jews compared with other populations of European origin. The results further suggest that overrepresentation of rare variants in a specific ethnic group may complicate the interpretation of association analyses of such variants, highlighting the particular importance of precisely matching case and control populations for association analyses of rare variants.

In response to recent publicity regarding the potential use of deep brain stimulation (DBS) for reducing tic severity in Tourette's 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.

To 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.

The relationship between tic disorders and attention deficit hyperactivity disorder (ADHD) is of great clinical importance because both disorders can lead to emotional, social, and academic difficulties. To further complicate this interrelationship is the concern that the use of psychostimulant medication to treat ADHD will help the hyperactivity and attention problems but will lead to the onset of tics or will worsen preexisting tics. The first part of this review investigates how often Tourette syndrome (TS) is associated with ADHD and finds that ADHD has been reported in 35% to 90% of children with TS. The second part of the review looks at whether the ADHD seen in TS is the same as in children who do not have tics. Recent studies lead to the conclusion that the ADHD seen in TS is the same, although the attentional difficulties seen in TS are influenced also by the distraction of the tics themselves as well as by internal distractions such as is seen in comorbid anxiety or obsessive-compulsive behavior. The final part of the review investigates the question of whether psychostimulants worsen or cause tics. Twenty-two studies were found that investigated this possible relationship. Earlier studies were confounded by the natural pattern seen in TS in which tics spontaneously wax and wane in occurrence, intensity, and frequency. More recent double-blind, placebo-controlled studies have shown that psychostimulants are equally effective in improving ADHD symptoms whether the disorder is associated with tics or not. When group data are analyzed, there is no significant increase in tics when psychostimulants are used in patients with tics compared with controls. Individual patients, however, may experience an increase in tics. This increase is not appreciated in analysis of group data. In conclusion, it is medically appropriate to provide treatment with psychostimulant medication in persons with tics where the ADHD symptoms are significantly disturbing their quality of life.

This study reports on the seizure and psychosocial outcome of 29 patients with electroclinically well-defined childhood-onset symptomatogenic or cryptogenic partial epilepsy with complex partial seizures who were followed prospectively over 14 years. Many were refractory at the time of enrollment. At 14-year follow-up, we acquired information on seizure type and frequency, psychiatric history, substance abuse, criminal activity, in addition to educational, vocational, and marital status through chart reviews and/or structured telephone interviews. Sixteen patients were only treated medically. They were divided by their following responses to medications: eight patients with less than one seizure per month were in the medically responsive group and eight patients with at least one seizure per month constituted the medically refractory group. Thirteen patients underwent focal resection for medically refractory epilepsy. Medically refractory patients displayed worse educational, vocational, social, and behavioral outcomes than medically responsive patients. Behavioral abnormalities persisted or evolved in five medically refractory patients when they became seizure free. Other studies have indicated that patients with medically refractory complex partial seizures have poor psychosocial outcomes. Although behavioral problems can occur even when seizures are well controlled, their early detection and treatment may be essential to the improvement of psychosocial outcomes.

Children with learning disabilities form a large pool of patients seen by neurologists for help in understanding the disability and deciding which forms of remediation are appropriate. Learning disabilities may accompany a large variety of other neurologic disabilities, but the usual child with such a problem is in excellent health. A thorough office evaluation for possible medical problems is always necessary, but most children do not require laboratory testing. All children with learning disabilities, whether or not they have accompanying neurologic problems, should be seen for psychological and/or educational evaluation. Some children may also benefit from an evaluation by a speech and language pathologist, occupational therapist, or ophthalmologist. The neurologist, alone or in association with a child psychologist, should also investigate the possible association of learning disabilities with attention deficit hyperactivity disorder. It is only for children with this component of learning problems that the possibility of medication arises. Working closely with the family, the child's school system, and other involved professionals becomes an important aspect of providing full and necessary help to children with learning disabilities. A caring physician can be a major help to the child and his family in understanding this disorder and supporting them during a difficult time.

Psychogenic seizures in 21 nonepileptic children and adolescents, aged 8 to 18 (mean 14.5) years, were recorded by means of video recording and electroencephalography. The episodes included thrashing movements, limb jerking, or staring, with unresponsiveness. Ictal and interictal electroencephalograms showed no abnormalities after antiepileptic medication was discontinued. Fifteen patients had psychogenic seizures spontaneously during recording, and six had seizures in response to suggestion and intravenous saline injection. After the video-electroencephalographic evaluation, patients and families were told that the episodes were emotional in origin. All patients but 1 agreed to remain without antiepileptic medication, and 16 patients (76%) agreed to begin psychiatric treatment. At 6 to 66 (mean 30) months' follow-up, 14 of 18 (78%) were free of episodes. These data indicate that the majority of young patients with psychogenic seizures have a good outcome. A firm diagnosis is critical so that the episodes can be classified and emphasized as medically not worrisome, permitting a shift away from antiepileptic medication and toward psychiatric treatment.

Paroxysmal choreoathetosis is a rare, involuntary movement disorder. Attacks occur spontaneously or may be induced by movement, startle, or anxiety. The movements are tonic, dystonic, or choreoathetotic. Sporadic and, more commonly, familial cases have been reported. Onset occurs most often during childhood, and the course is nonprogressive. Response to anticonvulsant therapy is usually excellent. Five cases of the sporadic form of paroxysmal choreoathetosis are reported. Three of the five patients had attacks after initiation of movements such as rising from a chair. Results of physical examination were normal in four patients. One child had mild hemiatrophy and unilateral hyper-reflexia. Results of laboratory studies, including determinations of serum calcium and ceruloplasmin levels, EEGs and CAT scans of the head, were normal. The attacks ceased in all patients after treatment with either phenytoin or carbamazepine.

A 33-month-old girl presented with acute subarachnoid hemorrhage from a ruptured multilobulated fusiform aneurysm of the midbasilar artery. This rare lesion was treated surgically by occluding the basilar artery. Intraoperative brain stem auditory evoked potential and somatosensory evoked potential monitoring results did not change with basilar artery occlusion, suggesting that the occlusion would be tolerated. However, the amplitudes of brain stem auditory evoked potential Waves III-V to right ear stimulation were transiently reduced during left pontine retraction during the aneurysm exposure. The patient made a complete clinical recovery.

A 12-week single-blind study used valproic acid in the treatment of refractory, simple and complex absence (petit mal) seizures in 17 children. The clinical seizure control was compared with the number and duration of electrical discharges on six-hour EEG recordings before and during therapy. Sixteen patients showed clinical improvement. Fourteen had greater than 75% clinical improvement and ten patients became free of absence seizures. Side effects were mild, but two patients experienced transient, asymptomatic thrombocytopenia. Good correlation between clinical response and decreasing seizure activity on the EEG occurred in the seizure-free patients.

Few detailed studies have examined the long-term outcome of complex partial seizures (CPS) in children and adolescents. Previous studies have selected patients on clinical criteria only or have included those with benign focal epileptiform discharges of childhood, nonepileptiform sharp transients, and generalized epileptiform discharges. We have followed up 29 patients with clinically and electroencephalographically defined CPS of childhood onset for five years or more. Twelve patients are seizure free, eight of them after having epilepsy surgery. Of the remaining, eight patients have intractable seizures. Only one patient was able to discontinue anticonvulsant therapy after epilepsy surgery. No patient had spontaneous remission of seizures without anticonvulsant medications. School difficulties, behavior problems, and unemployment were seen in half the group. We believe CPS in this age group are difficult to control and need aggressive management. In selected patients, epilepsy surgery offers a good chance of seizure control and improvement of educational, social, and vocational potential.

Initial reports described Tourette syndrome as a lifelong disorder. Since then, others have noted that some patients experience remissions during late adolescence. To examine this issue, we sent questionnaires to 99 patients with Tourette syndrome who were 15 to 25 years old. The majority of the 58 respondents indicated that they had fewer tics as they reached late adolescence or young adulthood. Although most reported associated behavior or learning problems, the majority felt they were coping well. The long-term outcome in many patients with Tourette syndrome may be more optimistic than previously reported.