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KCNMA1 encodes the large-conductance Ca2+- and voltage-activated K+ (BK) potassium channel α-subunit, and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize eight novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the international Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs) and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves toward positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. A phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.

Arterial ischemic strokes (AIS) are the most frequent neurologic sequela encountered in patients with cardiac myxomas. Although most of these AIS are thrombotic in nature, occasionally embolized tumor fragments may be responsible for the ischemic damage.1 Most patients with cardiac myxoma are women between the third and the sixth decade of life, who present with one or more symptoms of the classic triad (hemodynamic instability due to intracardiac obstruction, systemic embolization, and constitutional symptoms).1 Carney complex is an inherited disorder characterized by myxomas that often present earlier in life. We present a 12-year-old girl who developed a pediatric AIS (PAIS) due to the direct embolization of cardiac myxomatous tissue fragments in the setting of Carney complex. We discuss the clinical presentation, case-specific differential diagnosis, and workup, followed by epidemiology, pathophysiology, treatment, and prognosis of AIS resulting from cardiac myxomas.

Objective: The objective of this exploratory study is to describe communication between physicians and the actor parent of a standardized 8-year-old patient in respiratory distress who was nearing the end of life. Methods: Thirteen pediatric emergency medicine and pediatric critical care fellows and attendings participated in a high-fidelity simulation to assess physician communication with an actor-parent. Results: Fifteen percent of the participants decided not to initiate life-sustaining technology (intubation), and 23% of participants offered alternatives to life-sustaining care, such as comfort measures. Although 92% of the participants initiated an end-of-life conversation, the quality of that discussion varied widely. Conclusion: Findings indicate that effective physician–parent communication may not consistently occur in cases involving the treatment of pediatric patients at the end of life in emergency and critical care units. Practice Implications: The findings in this study, particularly that physician–parent end-of-life communication is often unclear and that alternatives to life-sustaining technology are often not offered, suggest that physicians need more training in both communication and end-of-life care.

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.

Objective: We report a child presenting with spinal myelopathy secondary to H3K27M mutant diffuse midline glioma. Case Report: A 4-year-old boy presented with a 3-week history of progressive gait difficulty. Examination revealed bilateral hand and lower extremity weakness, left leg hypertonia with ankle clonus, and a right hemisensory deficit. Magnetic resonance imaging of neuroaxis showed cervical and thoracic spinal cord with expansion and irregular areas of enhancement. Serum and cerebrospinal fluid studies were unremarkable for infectious, autoimmune, inflammatory, and neoplastic causes but showed mild cerebrospinal fluid pleocytosis, hypoglycorrhachia, and high protein level. A thoracic cord biopsy revealed a diffuse midline glioma (World Health Organization grade IV). Consequently, the tumor involved intracranial structures and patient died within 4 months after diagnosis. Conclusion: High-grade spinal cord gliomas are very rare but should be considered in the differential diagnosis of pediatric myelopathy. Tissue biopsy is recommended in indeterminate cases to facilitate diagnosis and to guide management.

The purpose of this article is to highlight ways in which institutional policymakers tend to insufficiently conceptualise their role as ethics practitioners. We use the case of blood product recall notification as a means of raising questions about the way in which, as we have observed it, discourse for those who make institutional ethics policies is constrained by routine balancing of simplified principles to the exclusion of reflexive practices-those that turn ethics reasoning back on itself. The latter allows ethics practitioners with comparatively little formal training to take ownership of traditional parameters, which define their discussions and ultimately ought to make them more insightful when doing ethics. Thus, in the midst of calls for more training to increase the competency of ethics committees, we suggest that an additional problem of how these lay ethicists conceive of their roles also needs to be addressed.

Objective: Subtle signs and symptoms of Huntington disease (HD) are often present before impairments reach a point where the neurologic disease is manifest and a diagnosis must be considered. The objective is to examine the prognostic significance of these early clinical signs and symptoms regarding time until unequivocal clinical HD diagnosis. Methods: We analyzed longitudinal data from 218 at-risk but healthy participants in the Huntington Study Group database who had either normal motor examination results or minimal soft motor signs at first observation. This group was followed periodically in HD clinics for up to 4.5 years. We used survival analysis to examine predictors of time until HD diagnosis. Results: Diagnostic prediction was significantly improved using specific, nonredundant items from the Unified Huntington9s Disease Rating Scale. When a movement disorder specialist initially had a global impression of “soft signs” present, cumulative relative risk of diagnosis was 4.68 times greater at 1.5 years of follow-up and 3.58 at 3 years. A neuropsychological test pattern with psychomotor speed 1 SD worse than a semantic knowledge measure increased cumulative risk by 1.99 times at 1.5 years and 1.81 at 3 years. Finally, reports of various subjective HD symptoms increased 3-year relative risk by 2.6 to 3.4. Conclusions: Findings demonstrate that neuropsychological performance and both the clinician rating and the patient subjective perception of motor difficulties contribute nonredundantly to a prediction of Huntington disease diagnosis. These findings may have implications for prognostic assessment of persons at risk and eventually assist with early interventions.

Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P .001), cognitive (P .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P .001 for all); behavioral domain scores did not diverge significantly between groups.Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

Background: Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neurodegenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic interventions Objective: To develop a clinical rating instrument to assess motor, behavioral, and functional capability in JNCL. Methods: A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted κ statistics Results: Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was 6.1 ± 1.6 years, and the mean duration of illness was 9.0 ± 4.4 years. The ICCs for the domains were as follows: motor = 0.83, behavioral = 0.68, and functional capability = 0.85. Conclusions: The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.

Mirror movements usually seen in the Klippel-Feil syndrome are most commonly appreciated in the upper extremities. Lower extremity involvement is seen rarely and when observed, is found in conjunction with upper extremity mirror movements. We report what we believe to be the first case of mirror movements found exclusively in the lower extremities in a female patient presenting with tethered cord syndrome. Our hopes are that this report will help elucidate mechanisms involved with these anomalous movements, as currently there is no commonly accepted etiology.

Paroxysmal dyskinesias are rare movement disorders. The onset of paroxysmal dyskinesias in childhood are typically idiopathic (sporadic or familial), whereas those in adulthood are usually secondary to an identifiable cause. Paroxysmal dyskinesias are classified according to precipitating factors, and these include paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, paroxysmal exertion-induced dyskinesia, and paroxysmal hypnogenic dyskinesia. The pathophysiology remains unknown; however, there is increasing evidence that channelopathies may play a role, which explains the response to anticonvulsant medications in certain kindreds. Pharmacologic treatment with anticonvulsant medications, clonazepam, tetrabenazine, trihexyphenidyl, or levodopa is reviewed herewith. Paroxysmal dyskinesias go by many names, but a rational classification does exist. Of those that respond to medications, the majority of paroxysmal dyskenesias respond to anticonvulsant medications. Channelopathies have been implemented as a cause in paroxysmal dyskinesias.

A 13-year-old girl presented with abnormal movements occurring during sleep, consisting of stiffening of the limbs bilaterally and random flailing of the arms and legs lasting less than 1 minute several times per night (video on the Neurology ® Web site at [Neurology.org][1]). Daytime episodes were reported, but rare. After workup, she was given a diagnosis of paroxysmal hypnogenic dyskinesia (PHD), was started on oxcarbazepine, and became free of episodes. PHD typically occurs during non-REM sleep1; spells are short in duration but may cause fragmented sleep. There is no established treatment and medical management is based on treatment of other more common paroxysmal dyskinesias. [1]: http://www.neurology.org/

We report a five-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2 positive inclusions were identified in brain we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations.

OBJECTIVE. We evaluated the efficacy of a comprehensive behavioral intervention for tics (CBIT) program to reduce tic severity and improve occupational performance in children with tic disorder using a one-group pretest–posttest design. METHOD. Thirty children with tic disorder completed an eight-session CBIT program. The program focused on habit reversal, relaxation training, and function-based approaches to address how the environment and social situations (antecedents and consequences) sustain or influence tic severity. RESULTS. We observed significant reduction in the number of tics and improvement in scores on the Parent Tic Questionnaire, Subjective Units of Distress Scale, and Child Occupational Self Assessment after CBIT compared with scores at baseline. CONCLUSION. Findings provided support that CBIT reduced the number of tic expressions, tic severity, and level of distress associated with tic and improved these children’s self-perception of their competence in and importance of performing everyday activities (i.e., occupational performance).

This chapter describes the experiences of a multidisciplinary clinic specializing in the diagnosis and management of Chiari 1 malformations (C1M). Data were collected regarding reasons for referral and outcomes and indicate that approximately half of referred patients were appropriately diagnosed radiographically with CIM. Moreover, of patients who actually had consistent imaging, only about one-third reported symptoms attributable to C1M. These findings illustrate pertinent issues relating to health-care resources and delivery of multidisciplinary care.

Previous work has shown that medication errors related to anticonvulsants are common during the transition into the hospital for pediatric patients. The purpose of this work was to evaluate whether children with epilepsy admitted for reasons other than epilepsy experience nonoptimal care in anticonvulsant medication management preceding the occurrence of seizures. Using a retrospective cohort of children with epilepsy admitted for reasons other than epilepsy, we created timelines from data in the medical record for the children who experienced seizures. These timelines included the timing and concentration of anticonvulsant administration and seizure occurrence. Three child neurologists independently identified whether nonoptimal care preceded the occurrence of seizures and potentially contributed to the occurrence of the seizure. Of 120 children, 18 experienced seizures and 12 experienced nonoptimal care in anticonvulsant management preceding seizure occurrence. Nonoptimal care that occurred during the transition into the hospital included missed doses of anticonvulsants, delays in administration during which seizures occurred, and patients inadvertently not receiving their home dosing of medication. Anticonvulsant medication errors are known to occur during the transition into the hospital. Here we present a case series of children who experienced nonoptimal care in anticonvulsant medication management who subsequently experienced seizures. Further work to identify how likely the outcome of seizures is following anticonvulsant medication errors, specifically focusing on timing as well as interventions to change the system issues that lead to these errors, is indicated.

Three neurodegenerative diseases, Huntington's disease (HD), Kennedy's disease (hereditary spinobulbar muscular atrophy, SBMA), and type 1 spinocerebellar ataxia (SCA-1) have been found to share a common genetic defect: an unstable region of repeated CAG trinucleotides which are thought to be translated into a polyglutamine moiety. The unstable repeat regions occur near the N-termini of the predicted proteins for HD and SBMA, but the location of the CAG repeat region is not known for SCA-1. Each disease is notable for a relatively circumscribed region of central nervous system pathology, and the lack of predicted similarity of the abnormal proteins makes a common mechanism related to the function of each protein unlikely. In order to reconcile the similar genetic abnormalities with the disparities in phenotypes, we suggest a common thread with regard to the pathogenesis of neuronal death. We hypothesize that the mechanism of neurotoxicity in these diseases occurs not through the production of abnormal proteins, but by the generation of abnormal posttranslational cleavage products. These products, in part consisting of abnormally large polyglutamine moieties, act to disturb the cellular and mitochondrial milieu such that energy metabolism is impaired, rendering specific regions of the nervous system vulnerable, and resulting in the clinical phenotypes of HD, SBMA, and SCA-1. We offer this interpretation of recent genetic findings from a neurobiologic perspective, in addition to suggesting testable hypotheses concerning potential disease mechanisms.

Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood. Symptoms typically present at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. Studies on sex differences in JNCL have yielded mixed results, but parent anecdotes suggest that females experience a more precipitous disease course. Therefore, we sought to determine if sex-based differences exist in JNCL. We used data from the Unified Batten Disease Rating Scale (UBDRS), the Batten Disease Support and Research Association (BDSRA) database, and the PedsQL quality of life (QoL) survey to evaluate sex-based differences in functional independence and time from symptom onset to death. On average, females had JNCL symptom onset one year later and death one year earlier than did males. Despite a later age at onset, females had lower functional capability, earlier loss of independent function, and lower physical QoL. Future research in sex differences in JNCL may help to further understand the biological mechanisms underpinning the disease course and may point to targeted therapies.

One in 20 essential tremor (ET) cases arises during childhood. We report 19 pediatric ET cases (mean age = 12.7 years). The majority (68.4%) were male, and only one had head tremor. Childhood and adult forms of ET may differ in several important respects, providing information about the underlying biology of ET. A possible male preponderance in childhood ET cases could reflect a modification of disease expression by gender, such that males manifest the disease at an earlier age than females. A paucity of childhood cases with head tremor suggests that the neuropathological changes in ET may evolve somatotopically. Head tremor may require midline or more extensive bilateral pathology which may only occur later in the disease.

Objective The objective of this blinded, prospective, longitudinal study was to determine whether new group A β hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (non-PANDAS) group. Method Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. Results No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group. Conclusions This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.

Tremor in childhood is not commonly described in the literature; but it is also likely underappreciated. The etiology of childhood tremor encompasses a wide variety of pathologic processes. Tremor may occur in isolation, or in association with other neurologic findings or systemic disorders. This article aims to provide an overview of tremorogenic mechanisms with respect to neuroanatomy and neurophysiology, particularly as they relate to children. Classification of tremors, diagnostic entities in childhood, and treatment will also be discussed. With improved recognition and characterization of childhood tremors, we may gain a better understanding of the pathophysiology of the disease and determine more age-appropriate treatment strategies.

Excitatory amino acid (EAA) receptor-mediated events have recently been implicated in dopaminergic mechanisms of neurotoxicity. 2,4,5-Trihydroxyphenylalanine (6-hydroxy-DOPA, TOPA), the ortho-hydroxylated derivative of the dopamine precursor 2,4-dihydroxyphenylalanine (L-DOPA), has recently been reported to have neurotoxic properties which are blocked by CNQX, a specific antagonist of the AMPA class of non-N-methyl-D-aspartate (non-NMDA) EAA receptors. We report here that 6-hydroxy-DOPA is a selective displacer of [3H]AMPA binding in rodent brain. 6-Hydroxy-DOPA was as potent as kainate in displacing [3H]AMPA binding, with an IC50 value of 32 microM. Ineffective displacers of [3H]AMPA binding included dopamine, 6-hydroxydopamine, L-DOPA, D-DOPA, carbidopa, DOPAC, beta-methylamino-L-alanine, 2,4-dihydroxyphenylacetyl-L-asparagine, homogentisic acid, 2,4-dihydroxyphenylacetic acid, amantadine, and threo-DOPS. 6-Hydroxy-DOPA (100 microM) also displaced 20% of [3H]kainate binding, but did not displace binding to NMDA, phencyclidine (PCP), or dopaminergic (D1 and D2) receptors. These data raise the possibility that 6-hydroxy-DOPA or another abnormal metabolite of L-DOPA could act as an excitotoxic agent via action at AMPA receptors. Given that non-NMDA receptors are postulated to play a role in neurotoxic events, these data provide an additional mechanism via which EAA receptor-mediated events could produce neurodegeneration in areas of brain with dopaminergic innervation.

We used receptor autoradiography to determine the distribution of excitatory amino acid (EAA) binding site subtypes in the periaqueductal gray (PAG) of the rat. N-Methyl-o-aspartate (NMDA), kainate, quisqualate-ionotropic, and quisqualate-metabotropic binding sites were all present in the PAG. Distribution was inhomogeneous with greatest density of all binding site subtypes in the dorsolateral subdivision and lowest density in the ventrolateral subdivision. Relative to regions of brain with high densities of EAA binding site subtypes, quisqualate-metabotropic binding sites had the highest relative density and NMDA binding sites the least. The presence of all subtypes of EAA binding sites in the PAG suggests that EAA action within the PAG is likely to be complex. The periaqueductal gray (PAG) is a mesencephalic nucleus implicated in the control of nociception, vocalization and defensive behaviors [2, 8, 9, 13-16]. Physiological, immunocytochemical, biochemical, and [3H]Daspartate transport studies suggest that excitatory amino acids (EAAs) are important neurotransmitters within the PAG [1, 2, 4, 7-10, 13-16, 23]. EAAs act via multiple receptors named after their prototype agonists [24]. The so-called N-methyl-D-aspartate (NMDA), quisqualate (QA), and kainate (KA) receptors all act by control of ion channels. In addition, a second QA preferring recep

Although trihexyphenidyl is used clinically to treat both primary and secondary dystonia in children, limited evidence exists to support its effectiveness, particularly in dystonia secondary to disorders such as cerebral palsy. A prospective, open-label, multicenter pilot trial of high-dose trihexyphenidyl was conducted in 23 children aged 4 to 15 years with cerebral palsy judged to have secondary dystonia impairing function in the dominant upper extremity. All children were given trihexyphenidyl at increasing doses over a 9-week period up to a maximum of 0.75 mg/kg/d. Trihexyphenidyl was subsequently tapered off over the next 5 weeks. Objective motor assessments were performed at baseline, 9 weeks, and 15 weeks. The primary outcome measure was the Melbourne Assessment of Unilateral Upper Limb Function, tested in the dominant arm. Tolerability and safety were monitored closely throughout the trial. Of the 31 children who agreed to participate in the study, 5 failed to meet entry criteria and 3 withdrew due to nonserious adverse events (chorea, drug rash, and hyperactivity). Three children required a dosage reduction because of nonserious adverse events but continued to participate. The 23 children who completed the study showed a significant improvement in arm function at 15 weeks ( P = .045) but not at 9 weeks ( P = .985). Post hoc analysis showed that a subgroup (n = 10) with hyperkinetic dystonia (excess involuntary movements) worsened at 9 weeks ( P = .04) but subsequently returned to baseline following taper of the medicine. The authors conclude that scientific evidence for the clinical use of trihexyphenidyl in cerebral palsy remains equivocal. Trihexyphenidyl may be a safe and effective for treatment for arm dystonia in some children with cerebral palsy if given sufficient time to respond to the medication. Post hoc analyses based on the type of movement disorder suggested that children with hyperkinetic forms of dystonia may worsen. A larger, randomized prospective trial stratified by the presence or absence of hyperkinetic movements is needed to confirm these results.

The authors describe a pediatric patient with repaired hypoplastic left heart syndrome developing protein-losing enteropathy, hypocalcemia, vitamin D deficiency, and hemichorea. After correction of nutritional vitamin D deficiency with calcium and vitamin D supplementation, the chorea resolved. Hypoalbuminemia also improved after the correction of vitamin D deficiency without requiring albumin infusions. This report also raises the possible role of calcium or vitamin D in the intestinal loss of albumin in protein-losing enteropathy.

MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.

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.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.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, p0.001) 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.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.

Tourette's syndrome (TS) is a genetically influenced developmental neuropsychiatric disorder characterized by chronic vocal and motor tics. We studied Slit and Trk-like 1 ( SLITRK1 ) as a candidate gene on chromosome 13q31.1 because of its proximity to a de novo chromosomal inversion in a child with TS. Among 174 unrelated probands, we identified a frameshift mutation and two independent occurrences of the identical variant in the binding site for microRNA hsa-miR-189. These variants were absent from 3600 control chromosomes. SLITRK1 mRNA and hsa-miR-189 showed an overlapping expression pattern in brain regions previously implicated in TS. Wild-type SLITRK1, but not the frameshift mutant, enhanced dendritic growth in primary neuronal cultures. Collectively, these findings support the association of rare SLITRK1 sequence variants with TS.

We obtained information about the behavioral, psychiatric, and functional status of 26 children (13 males, 13 females) with juvenile neuronal ceroid lipofuscinosis (JNCL; mean age 12y 3mo [SD 3y 4mo]; range 6y 9mo to 18y 8mo). Twenty-five children had visual impairment and 18 were known to have a positive seizure history before enrollment. Parents completed the Child Behavior Checklist, Scales of Independent Behavior - Revised, and a structured interview to assess obsessive-compulsive symptoms. Participants exhibited a broad range of behavioral and psychiatric problems, rated as occurring frequently and/or as severe in more than half of the sample. Males and females did not differ with regard to the number of behavioral and psychiatric problems. Children were also limited in their ability to perform activities of daily living, including self-care, hygiene, socialization, and other age-appropriate tasks. Results provide a quantitative baseline for behavioral and psychiatric problems and functional level in JNCL, against which further decline can be measured. Longitudinal assessment of behavioral and psychiatric symptoms and functional abilities is continuing and will provide much-needed data on the natural history of JNCL.

Approximately 5% of new essential tremor (ET) cases arise during childhood. The goal of the current report was to examine the possible association between male gender and pediatric ET, using data from 95 pediatric ET cases seen at three medical centers (two in the United States and one in Spain). The odds of ET in our sample of cases were threefold higher in boys compared to girls. Whether this association between male gender and pediatric ET represents a selection bias or a true gender-mediated biological difference in disease expression is not known, although some data support the latter possibility.

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntington's disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy-five clinicians experienced in the evaluation of patients with early HD and six non-clinicians were shown a videotape compiled from the film archives of the United States–Venezuela Collaborative HD Research Project. Observers were asked to rate a 2–3-minute segment of the motor examination for each of 17 at-risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted κ statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted κ = 0.67; standard error (SE) = 0.09). Agreement among the non-clinicians was only fair (weighted κ = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients. © 2005 Movement Disorder Society

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation ± SE) were estimated for sibling (0.40 ± 0.09), parent-offspring (0.10 ± 0.11), avuncular (0.07 ± 0.11), and cousin (0.15 ± 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental., link_to_subscribed_fulltext

The authors present a case of a child with epilepsy who developed choreoathetotic movements coinciding with the development of epilepsia partialis continua. His abnormal movements and seizures resolved after successful management of his epilepsia partialis continua with intravenous immunoglobulin and steroid therapy. The authors propose that the chorea was an unusual manifestation of epilepsia partialis continua.

To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement.Subjects were participants in the Huntington Study Group's Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using chi2 and Student's t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used.Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents' average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement.Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

Objective: To determine whether pergolide, a mixed D1/D2/D3 dopamine agonist, is efficacious and safe in the treatment of children with chronic tic disorders and Tourette syndrome.Background: Neuroleptics, which block dopamine transmission, are currently used to treat children with severe tics, but major side effects and limited efficacy reduce clinical utility. Prior open-label and crossover studies of pergolide suggest potential benefit.Methods: The authors enrolled 57 children and adolescents, ages 7 to 17 years, randomizing them in a 2:1 ratio to either pergolide (0.15 to 0.45 mg per day) or placebo. Tic symptoms had to be >30 on the Yale Global Tic Severity Scale (YGTSS). The primary outcome measure was change in tic severity assessed by YGTSS.Results: Compared to placebo treatment, pergolide treatment was associated with lower tic severity scores (treatment effect 8.8, pergolide vs placebo; 95% CI 0.1 to 17.6; p = 0.05) and attention-deficit hyperactivity disorder symptoms scores (treatment effect 3.8; 95% CI 0.7 to 6.8; p = 0.02). No patient had a serious adverse event and pergolide was well tolerated.Conclusions: In this randomized, placebo-controlled trial, pergolide appeared to be an efficacious and safe medication for tic reduction in children, and may also improve attention-deficit hyperactivity disorder symptoms.

Purpose To emphasize that papilledema and other ophthalmic manifestations may occur in the syndrome of headache, neurologic deficits, and cerebrospinal fluid lymphocytosis (HaNDL). Design Two interventional case reports. Methods Two patients were seen with ophthalmologic findings, including decreased vision, papilledema, sixth nerve palsy, and a variety of neurologic deficits. Each underwent cerebrospinal fluid analysis and intracranial pressure measurement by spinal tap and neuroimaging studies to confirm the diagnosis of HaNDL. Results Both patients received acetazolamide to lower intracranial pressure. The first patient had complete resolution of signs and symptoms. The second, who was also given systemic corticosteroids, was left with diminished visual acuity in the right eye with nasal visual field loss and optic atrophy. Conclusions The diagnosis of HaNDL is one of exclusion, which must be made in conjunction with a neurologist. HaNDL may be accompanied by elevated intracranial pressure and papilledema. As in other disorders causing papilledema, these patients may have permanent visual sequelae. Recognition by the ophthalmologist of this rarely reported syndrome will facilitate prompt patient diagnosis and treatment.

Item does not contain fulltext BACKGROUND: Benign hereditary chorea (BHC) is an autosomal dominant disorder that can be distinguished from Huntington disease by its early onset, stable or only slightly progressive course, and absence of mental deterioration. The variation in clinical features is such that its very existence has been doubted. The authors recently described the localization of a gene responsible for BHC on chromosome 14q in a large Dutch family. OBJECTIVE: To report results of extensive clinical and linkage analyses for this Dutch family and six other families with BHC. RESULTS: Three of the seven families had linkage to a region on chromosome 14q13.1-q21.1. HOMOG analysis showed odds of 10 x 10(11) in favor of locus heterogeneity. Haplotype analyses for the linked families resulted in a reduction of the critical interval for the BHC gene to 8.4 cM between marker D14S49 and marker D14S278. Clinically, these three families had a homogeneous picture with early-onset chorea, sometimes accompanied by slight ataxia in walking, but without dystonia, myoclonic jerks, or dysarthria. The severity of the choreatic movements tended to abate in adolescence or early adulthood. In the unlinked families, symptoms and signs were more heterogeneous as to age at onset and the occurrence of myoclonic jerks or dystonia. CONCLUSIONS: BHC is a clinically and genetically heterogeneous disorder, with one well-defined clinical syndrome mapping to chromosome 14q.

We report medullary injury during adenoidectomy in two children who received injections of local anesthetic agents into the operative bed. Initial manifestations included hemiparesis, nystagmus, and ataxia. Magnetic resonance imaging showed hemorrhagic, paramedian medullary lesions in both patients. The mechanism of injury is likely to be injection of fluid into the medulla.