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There is a lack of imaging markers revealing the functional characteristics of different brain regions in paediatric dystonia. In this observational study, we assessed the utility of [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET in understanding dystonia pathophysiology by revealing specific resting awake brain glucose metabolism patterns in different childhood dystonia subgroups. PET scans from 267 children with dystonia being evaluated for possible deep brain stimulation surgery between September 2007 and February 2018 at Evelina London Children's Hospital (ELCH), UK, were examined. Scans without gross anatomical abnormality (e.g. large cysts, significant ventriculomegaly; n = 240) were analysed with Statistical Parametric Mapping (SPM12). Glucose metabolism patterns were examined in the 144/240 (60%) cases with the 10 commonest childhood-onset dystonias, focusing on nine anatomical regions. A group of 39 adult controls was used for comparisons. The genetic dystonias were associated with the following genes: TOR1A, THAP1, SGCE, KMT2B, HPRT1 (Lesch Nyhan disease), PANK2 and GCDH (Glutaric Aciduria type 1). The acquired cerebral palsy (CP) cases were divided into those related to prematurity (CP-Preterm), neonatal jaundice/kernicterus (CP-Kernicterus) and hypoxic-ischaemic encephalopathy (CP-Term). Each dystonia subgroup had distinct patterns of altered FDG-PET uptake. Focal glucose hypometabolism of the pallidi, putamina or both, was the commonest finding, except in PANK2, where basal ganglia metabolism appeared normal. HPRT1 uniquely showed glucose hypometabolism across all nine cerebral regions. Temporal lobe glucose hypometabolism was found in KMT2B, HPRT1 and CP-Kernicterus. Frontal lobe hypometabolism was found in SGCE, HPRT1 and PANK2. Thalamic and brainstem hypometabolism were seen only in HPRT1, CP-Preterm and CP-term dystonia cases. The combination of frontal and parietal lobe hypermetabolism was uniquely found in CP-term cases. PANK2 cases showed a distinct combination of parietal hypermetabolism with cerebellar hypometabolism but intact putaminal-pallidal glucose metabolism. HPRT1, PANK2, CP-kernicterus and CP-preterm cases had cerebellar and insula glucose hypometabolism as well as parietal glucose hypermetabolism. The study findings offer insights into the pathophysiology of dystonia and support the network theory for dystonia pathogenesis. 'Signature' patterns for each dystonia subgroup could be a useful biomarker to guide differential diagnosis and inform personalized management strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: In adults with dystonia Probabilistic Stimulation Mapping (PSM) has identified putative "sweet spots" for stimulation. We aimed to apply PSM to a cohort of Children and Young People (CYP) following DBS surgery., Methods: Pre-operative MRI and post-operative CT images were co-registered for 52 CYP undergoing bilateral pallidal DBS (n = 31 genetic/idiopathic dystonia, and n = 21 Cerebral Palsy (CP)). DBS electrodes (n = 104) were automatically detected, and Volumes of Tissue Activation (VTA) derived from individual patient stimulation settings. VTAs were normalised to the MNI105 space, weighted by percentage improvement in Burke-Fahn-Marsden Dystonia Rating scale (BFMDRS) at one-year post surgery and mean improvement was calculated for each voxel., Results: For the genetic/idiopathic dystonia group, BFMDRS improvement was associated with stimulation across a broad volume of the GPi. A spatial clustering of the upper 25th percentile of voxels corresponded with a more delineated volume within the posterior ventrolateral GPi. The MNI coordinates of the centroid of this volume (X = -23.0, Y = -10.5 and Z = -3.5) were posterior and superior to the typical target for electrode placement. Volume of VTA overlap with a previously published "sweet spots" correlated with improvement following surgery. In contrast, there was minimal BFMDRS improvement for the CP group, no spatial clustering of efficacious clusters and a correlation between established "sweet spots" could not be established., Conclusions: PSM in CYP with genetic/idiopathic dystonia suggests the presence of a "sweet spot" for electrode placement within the GPi, consistent with previous studies. Further work is required to identify and validate putative "sweet spots" across different cohorts of patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: To establish the prevalence of dystonic pain in children and their response to deep brain stimulation (DBS)., Method: Dystonic pain was assessed in a cohort of 140 children, 71 males and 69 females, median age 11 years 11 months (range 3y-19y 1mo), undergoing DBS in our centre over a period of 10 years. The cohort was divided into aetiological dystonia groups: 1a, inherited; 1b, heredodegenerative; 2, acquired; and 3, idiopathic. Motor responses were measured with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS)., Results: Dystonic pain was identified in 63 (45%) patients, 38% of whom had a diagnosis of cerebral palsy (CP). Dystonic pain improved in 90% of children and in all aetiological subgroups 1 year after DBS, while the BFMDRS motor score improved in 70%. Statistically significant improvement (p<0.01) was noted for the whole cohort on the Numerical Pain Rating Scale (n=27), Paediatric Pain Profile (n=17), and Caregivers Priorities and Child Health Index of Life with Disabilities questionnaire (n=48). There was reduction of pain severity, frequency, and analgesia requirement. Findings were similar for the whole cohort and aetiological subgroups other than the inherited heredodegenerative group where the improvement did not reach statistical significance., Interpretation: Dystonic pain is frequent in children with dystonia, including those with CP, who undergo DBS; this can be an important, realizable goal of surgery irrespective of aetiology. We encourage the use of multimodal approach in pain research to reduce the risk of bias., (© 2020 Mac Keith Press.)

Objective: Acute dystonia in children is distressing, painful and can progress to life-threatening status dystonicus. Typical management involves benzodiazepines which can result in respiratory depression requiring PICU admission. Clonidine is less respiratory-depressant, and by facilitating sleep, switches dystonia off. It can also be administered via enteral, continuous intravenous infusion, and transdermal slow release routes. We describe the dose range and safety profile of clonidine management in a case-series of children with severe acute exacerbation of dystonia in a tertiary hospital setting., Methods: The management of 5 children (3 female, age range 8-14 years) suffering from an acute exacerbation of secondary dystonia requiring hospital admission at the Evelina London Children's Hospital was reviewed. The average and maximum dose of clonidine in mcg/kg/h and routes of administration were recorded for each day of hospital admission. Co-administration of any other medical treatments for dystonia and their route of administration were also recorded. Cardiovascular and respiratory clinical status were measured by recording the daily mean and maximum Paediatric Early Warning Scores (PEWS)., Results: Clonidine was administered via enteral, intravenous, and transdermal routes at a median dose of 2.5 mcg/kg/h (range 0.1-9 mcg/kg/h). Administration of high dose clonidine was associated with decreased use of benzodiazepines, morphine, and propofol: avoiding invasive respiratory support for ¾ cases during admission. Clonidine doses via all routes of administration did not correlate with poorer PEWS scores (p = 0.839). Both high dose intravenous and transdermal clonidine where found to be effective., Conclusions: High dose clonidine administered via different routes can be used in the acute management of severe exacerbations of dystonia. Its use in our cohort was not associated with significant cardio-respiratory depression even at doses as high as 9 mcg/kg/h., (Copyright © 2017. Published by Elsevier Ltd.)

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Background: Early onset dystonia (dyskinesia) and deafness in childhood pose significant challenges for children and carers and are the cause of multiple disability. It is particularly tragic when the child cannot make use of early cochlear implantation (CI) technology to relieve deafness and improve language and communication, because severe cervical and truncal dystonia brushes off the magnetic amplifier behind the ears. Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) neuromodulation can reduce dyskinesia, thus supporting CI neuromodulation success., Methods: We describe the importance of the order of dual neuromodulation surgery for dystonia and deafness. First with bilateral GPi DBS using a rechargeable ACTIVA-RC neurostimulator followed 5 months later by unilateral CI with a Harmony (BTE) Advanced Bionics Hi Res 90 K cochlear device. This double neuromodulation was performed in series in a 12.5 kg 5 year-old ex-24 week gestation-born twin without a cerebellum., Results: Relief of dyskinesia enabled continuous use of the CI amplifier. Language understanding and communication improved. Dystonic storms abated. Tolerance of sitting increased with emergence of manual function. Status dystonicus ensued 10 days after ACTIVA-RC removal for infection-erosion at 3 years and 10 months. He required intensive care and DBS re-implantation 3 weeks later together with 8 months of hospital care. Today he is virtually back to the level of functioning before the DBS removal in 2012 and background medication continues to be slowly weaned., Conclusion: This case illustrates that early neuromodulation with DBS for dystonic cerebral palsy followed by CI for deafness is beneficial. Both should be considered early i.e. under the age of five years. The DBS should precede the CI to maximise dystonia reduction and thus benefits from CI. This requires close working between the paediatric DBS and CI services., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Data around current prescription practices in childhood dystonia is limited. Medication use may be limited by side effects, the incidence of which is uncertain. For a large cohort assessed by our supra-regional service we aimed to: i) Review medications used at the point of referral. ii) Determine the prevalence of adverse drug responses (ADR) resulting in discontinuation of drug use. iii) Identify clinical risk factors for ADR., Methods: Case note review of 278 children with dystonia referred to our service. Data collected on medications, ADR, dystonia aetiology, Gross Motor Function Classification System (GMFCS) level and motor phenotype (pure dystonia/mixed dystonia-spasticity). Logistic regression analysis was used to identify risk factors for ADR., Results: At referral 82/278 (29.4%) children were taking no anti-dystonic medication. In the remainder the median number of anti-dystonic medications was 2 (range 1-5). Medications use increased with worsening GMFCS level. The commonest drugs used were baclofen (118/278: 42.4%), trihexyphenidyl (98/278: 35.2%), l-Dopa (57/278: 20.5%) and diazepam (53/278: 19%). Choice of medication appeared to be influenced by dystonia aetiology. ADR had been experienced by 171/278 (61.5%) of children. The commonest drugs responsible for ADR were trihexyphenidyl (90/171: 52.3%), baclofen (43/171: 25.1%) and l-Dopa (26/171: 15.2%). Binary logistic regression demonstrated no clinical risk factors for ADR., Conclusions: ADR is commonly experienced by children with dystonia, regardless of dystonia severity or aetiology. A wide variation in drug management of dystonia was identified. Collectively these findings highlight the need for a rational approach to the pharmacological management of dystonia in childhood., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Aims: This study aimed to determine the main concerns/priorities of the parents and carers of children with dystonia referred to our service and whether medical interventional studies addressed these concerns., Methods: Records of children assessed by our service from June 2005-December 2012 were reviewed and expressed parental/carer concerns at initial assessment categorized using the International Classification of Functioning (ICF) Framework. Medline, CINAHL and Embase databases were searched for outcome measures of medical and surgical interventional studies in childhood dystonia., Results: Data was collected from 273 children and young people with dystonia. The most commonly expressed concerns were: pain (104/273, 38.1%); difficulties in delivering activities of daily-living (66/273, 24.2%), difficulties with hand-use (59/273, 21.6%) and seating (41/273, 15.0%). Literature review identified 70 interventional studies, 46 neurosurgical and 24 pharmacological. The majority of neurosurgical studies (34/46) used impairment scales to measure change, with pharmacological studies typically reporting more subjective changes in motor symptoms. Only a minority of studies used assessments or scales capable of objectively addressing the concerns reported by our cohort., Interpretations: Existing interventional studies in childhood dystonia poorly address the main concerns of children with dystonia and their carers, limiting the conclusions which may be drawn as to true impact of these interventions in childhood., (Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

The methylmalonic acidemias (MMAs) are a group of inborn errors of metabolism resulting in the accumulation of methylmalonic acid in body tissues and fluids. A recognized complication of MMA is bilateral liquefaction of the globus pallidi, resulting in a fulminant total body dystonia of childhood often refractory to medical treatment. This case of total body dystonia due to MMA in a 4-year-old boy had been medically refractory for 15 months. Complete metabolic destructive liquefaction of the pallidi, that is, autopallidotomy, necessitated an alternative, bilateral subthalamic nucleus (STN) target for deep brain stimulation (DBS) with a marked improvement in dystonia and reduction in pain. The case illustrates the efficacy of STN DBS in this condition and the technical challenges in targeting the STN in a small child.

Aim: The aim of this study was to examine the impact of dystonia aetiology and duration, contracture, and age at deep brain stimulation (DBS) surgery on outcome in a cohort of children with medically refractory, disabling primary, secondary-static, or secondary-progressive dystonias, including neurodegeneration with brain iron accumulation (NBIA)., Method: Dystonia severity was assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score at baseline and 6 and 12 months postoperatively in a cohort of 70 consecutive children undergoing DBS between June 2005 and July 2011., Results: Two children (3%) received unilateral DBS for hemidystonia and were excluded and five (7%) developed infections requiring part-DBS removal within 6 months, leaving 63 children (90%) undergoing bilateral DBS for follow-up (34 males, 29 females; mean age at surgery for the whole group 10y 4mo, SD 4y 2mo, range 1-14y). Seventeen children were classified with primary dystonia: mean age 12 years 11 months, SD 4 years 6 months range 4 years 6 months to 17 years 3 months; 28 as having secondary-static dystonia: mean age 10 years 2 months, SD 4 years 9 months (range 3y 3mo-20y); five as having secondary-progressive dystonia: mean age 8 years 11 months, SD 3 years 9 months (range 5y 5mo-13y 1mo); and 13 as having NBIA dystonia: mean age 10 years 2 months, SD 3 years 11 months (range 1-14y). Children with primary dystonias demonstrated greater improvements in BFMDRS motor score than those in the other aetiological categories (Kruskal-Wallis test, p<0.001), which correlated negatively with dystonia duration and more strongly still against the ratio of dystonia duration normalized to age at surgery (DD/AS ratio) at 1 year (Spearman's rank correlation coefficient 0.4752 and -0.599 respectively). A similar significant negative correlation was found in the secondary-static dystonia group between outcome at 1 year and DD/AS ratio (-0.461). Poorer outcome in secondary dystonia coincided with the absence of a period of normal motor development in comparison with the primary dystonia group. A significant improvement in BFMDRS motor score was seen in the NBIA group at 6, but not 12 months (Wilcoxon signed rank test p=0.028, p=0.85 respectively). No reduction in efficacy was seen in children with a musculoskeletal deformity at the time of surgery., Conclusion: Response to pallidal DBS in the treatment of dystonia declines with the proportion of life lived with dystonia in primary and secondary dystonia. Other intrinsic factors reduce the median magnitude of reduction in secondary dystonia after DBS. DBS should be offered early, preferably within 5 years of onset, to maximize benefits and reduce the childhood experience of dystonia, including musculoskeletal deformity. Other multidimensional assessments are required to understand how DBS improves the lives of children with dystonia., (© The Authors. Developmental Medicine & Child Neurology © 2013 Mac Keith Press.)

Background: The finite life of non-rechargeable batteries powering implantable pulse generators (IPG) necessitates their periodic replacement. Children receiving deep brain stimulation (DBS) may require frequent battery changes over their treatment lifetime., Objectives: We aimed to determine the battery life of IPGs used in pallidal DBS for the treatment of dystonia in children and young people., Methods: We make use of a review of case notes of all children and young people undergoing DBS surgery at our institution from June 2005 to May 2010., Results: A total of 54 children and young people underwent surgery on at least one occasion, with a total of 76 IPGs implanted. Replacement IPGs due to battery failure were required in 15 out of 54 (27.8%). The average time to battery failure was 24.5 ± 2.9 months (95% confidence interval), with a range of 13-39 months. Battery life was significantly longer in primary compared to subsequent IPGs. No difference in longevity was seen between different IPG devices., Conclusions: IPG battery life may be short in children and young people receiving treatment for dystonia. These findings highlight the potential benefits of the recently introduced rechargeable neurostimulators.

Background: Deep brain stimulation (DBS) is a recognised method of treatment for primary and secondary dystonia. The size of non-rechargeable batteries has limited their use in small children. Our severe dystonia patients have required battery replacement every 20-24 months., Objectives: To evaluate reliability, care burden, patients' satisfaction and complications related to the rechargeable neurostimulator Activa® RC (launched by Medtronic in Europe in autumn 2008)., Methods: Complications were recorded prospectively, and a questionnaire on neurostimulator maintenance, care burden and parental satisfaction was applied to all patients with at least 3 months of follow-up., Results: 30 Activa RCs were implanted between December 2008 and June 2010, 25 with a follow-up of 3-17 months (mean 10); the mean patient's age at surgery was 11.1 years; 22/25 questionnaires were completed. All families achieved good standards of recharging. Caregivers were responsible for recharging in 82% of cases. With higher parameters of stimulation, recharging time was longer than initially recommended by the manufacturer. All but one family would recommend Activa RC to other patients. Transient recharging problems were the most common complication (36% of cases). Infection/skin erosion occurred in 8% of cases, self-resolving early seroma in 20%., Conclusions: Activa was found to offer reliable stimulation with a low rate of significant complications and a suitable treatment option for children with dystonia., (Copyright © 2012 S. Karger AG, Basel.)

Objective To evaluate the safety, efficacy and effective dosage of clonidine in the outpatient (OP) management of secondary dystonia. Methods A retrospective analysis of children and young people (CAYP) prescribed clonidine in an OP clinic between January 2011 and November 2013 for dystonia management. Of 224 children receiving clonidine, 149/224 did not have a movement disorder and 12/224 had no data leaving 63 movement disorder cases, 15/63 managed as in-patients, 15/48 suffered from tics leaving 33/63 for OP evaluation. Clonidine effectiveness was assessed by ‘yes/no’ criteria in improving 5 areas: seating, sleep, pain, tone and involuntary movements. Results 2/33 motor cases had insufficient data; 7/33 had concurrent therapy leaving 24/33 for analysis. Improvement in at least one area was reported by 20/24 (83%) CAYP: Improved seating tolerance 14/24, and sleep 15/24; reduced pain 15/24; improved tone 16/24 and involuntary movements 17/24. Starting doses ranged from 1 mcg/kg OD to 2 mcg/kg TDS with optimum doses reached on average at 9.5 months follow-up. Maximum dose reached was 75 mcg/kg/day given in 8 divided doses. Average maximum daily dose was 20 mcg/kg/day. The commonest frequency of administration was 8 hourly. Side effects were reported in 11/24 CAYP and discontinued in 1/24 for lack of clinical effectiveness, 1/24 for side effects and 4/24 due to both lack of effectiveness and side effects. Conclusion Clonidine was effective in secondary dystonia management in 83% of cases. A starting dose of 1 mcg/kg TDS was well tolerated and safely escalated. Prospective objective evaluation is now required to confirm the efficacy of clonidine. [ABSTRACT FROM AUTHOR]