Daniel E. Lumsden

Proportion of life lived with dystonia inversely correlates with response to pallidal deep brain stimulation in both primary and secondary childhood dystonia

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).

The impact and prognosis for dystonia in childhood including dystonic cerebral palsy: a clinical and demographic tertiary cohort study

Introduction and methods The impact of dystonia in childhood is poorly understood. We report our experience of referrals between 2005 and 2012. Results Of 294/315 assessable children, 15/294 had pure spasticity, leaving 279/294 with dystonia classified as primary (30/279: 10.7%); primary-plus (19/279: 6.8%) and secondary (230/279: 82.4%) dystonia, including heredodegenerative dystonia (29/279: 10.3%); 150/279 (53.7%) with cerebral palsy and 51/279 (18.2%) acquired brain injury. Definitive diagnoses were available in 222/294 (79.6%), but lower in primary/primary-plus compared with secondary groups (11/49 vs 211/230: Fishers exact test p<0.0001). Spasticity comorbidity was present in 79/230 (34.3%) children. Median age (interquartile years) at referral was 9.75 (6.58–13), not significantly differing by aetiology (Kruskal–Wallis test p>0.05); dystonia-onset age was 3 (0.5–7.0) for primary/primary-plus and 0.25 (0.08–0.8) in the secondary/CP groups. Dystonia duration at referral was 4.75 years (3.0–10.33) for primary/primary-plus groups and 7.83 (5.4–11) in the secondary group. The mean (interquartile range) proportion of life lived with dystonia, derived as dystonia duration normalised to age was 0.68 (0.31–0.96); 0.59 (0.35–0.8); 0.75 (0.62–0.95)and 0.9 (0.92–0.99) for primary, primary-plus, heredodegenerative and secondary-static dystonias respectively. Only 91/279 (32.6%) experienced a period of normal motor development. Carers perceived dystonia deterioration in 168/279 (60.2%), stabilisation in 88/279 (31.5%) and improvement in 23/279 (8.2%). Dystonia occurred in 26/225 (11.6%) siblings: 14/26 secondary and 5/26 heredodegenerative dystonia. Comorbidities were identified in 176/279 (63.1%) cases. Gross Motor Function Classification System (GMFCS) levels I–III were commoner in primary/primary-plus (37/49: 75%) compared with secondary/CP (29/230: 13%) cases, χ2 p<0.0001). Discussion In this selective cohort, childhood dystonia is severe, presenting early before worsening without remission. Secondary dystonias spend a higher proportion of life living with dystonia and lower functional capacity. Despite referral bias, services offering neurosurgical interventions and health service planning agencies should understand the context and predicament of life with childhood dystonia.

Interventional studies in childhood dystonia do not address the concerns of children and their carers

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.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

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.

Evaluation of functional goal outcomes using the Canadian Occupational Performance Measure (COPM) following Deep Brain Stimulation (DBS) in childhood dystonia

PURPOSE To evaluate the functional goal-directed outcomes of Deep Brain Stimulation (DBS) in childhood dystonia according to aetiology and to explore relationship with a traditional impairment-based measure. METHOD This is a prospective case series study involving thirty children with dystonia with a 1-year follow-up post-DBS. The Canadian Occupational Performance Measure (COPM) and Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) were used as primary outcome measures. Results were analysed based on aetiology in 3 groups: 1. primary/primary plus dystonia; 2. secondary dystonia-cerebral palsy (CP); 3. secondary dystonia-non-CP group. Correlation between functional outcome using COPM and dystonia improvement as captured by BFMDRS was measured. RESULTS All groups demonstrated significant improvement in individualised goal attainment, measured with the COPM, at 1-year post-DBS. The secondary dystonia-CP group also achieved significant improvement at 6 months for performance and satisfaction scores. In the majority of secondary dystonias, the BFMDRS failed to demonstrate significant improvement. A linear correlation between change in BFMDRS and COPM scores was observed when the entire cohort was analysed. INTERPRETATION/CONCLUSIONS DBS improved functional performance, independently of the dystonic phenotype. Improvements in individualized COPM functional goal areas were seen in the absence of significant changes in BFMDRS scores, highlighting the relative insensitivity of impairment scales in this patient group.

Medication use in childhood dystonia

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.

Burke–Fahn–Marsden dystonia severity, Gross Motor, Manual Ability, and Communication Function Classification scales in childhood hyperkinetic movement disorders including cerebral palsy: a ‘Rosetta Stone’ study

Hyperkinetic movement disorders (HMDs) can be assessed using impairment‐based scales or functional classifications. The Burke–Fahn–Marsden Dystonia Rating Scale‐movement (BFM‐M) evaluates dystonia impairment, but may not reflect functional ability. The Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) are widely used in the literature on cerebral palsy to classify functional ability, but not in childhood movement disorders. We explore the concordance of these three functional scales in a large sample of paediatric HMDs and the impact of dystonia severity on these scales.

Dystonia Severity Action Plan: a simple grading system for medical severity of status dystonicus and life-threatening dystonia

SIR–Dystonia is the most common movement disorder seen in childhood and may be defined as ‘a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both.’ Dystonia may arise from a range of pathologies, and impairs quality of life, participation, and function, in addition to causing pain and progressive deformity. Children and young people with dystonia may experience acute deterioration in their dyskinesia, variously termed ‘status dystonicus’ or ‘dystonic storm’, which has been broadly defined as ‘generalized, intense and potentially fatal exacerbation of muscle contractions.’ This definition is not universally used though, and the precise delineation of the point at which status dystonicus is reached is far less objective than, for example, in status epilepticus. It is important to remember that these acute episodes actually represent the severest end of a continuum of worsening dystonia. Early recognition may potentially facilitate intervention and prevent progression. In a recently reported large retrospective case series of 89 episodes of status dystonicus (58.8% occurring in children <15y) first-line pharmacological treatments of established status dystonicus (most commonly anticholinergics and tetrabenazine) were effective in ~10% of cases. Treatment in this case series frequently necessitated deep sedation in intensive care and there carried a mortality rate of 10.3%. Numerous scales exist to measure the severity of dystonia (e.g. the Burke Fahn Marsden Dystonia Rating Scale, Barry-Albright Dystonia scale). The limitation of these scales include their time-consuming nature, need for considerable training for use, a plateau affect which limits their utility in the most severely affected cases, and also concerns about reliability and smallest detectable difference, particularly in the secondary dystonias which are most commonly seen in childhood. The recently described Dyskinesia Impairment Scale holds great promise, but the length of time taken to record and score video assessments may restrict its use to the research setting. The need exists for a pragmatic criterion-referenced clinical scoring system which can be rapidly and reliably applied and which may be understood by parents and all healthcare providers, not just those professionals with an expertise in movement disorders. It is important that such a scale includes graduations up to the point at which a child or young person can be said to have entered status dystonicus, to alert clinicians to a gradual worsening of dystonia and the need for effective intervention. A common agreed nomenclature when describing exacerbations of dystonia is also necessary if clinical trials are to be developed to best guide treatment methodologies. Between our centres we have devised a simple scoring system (shown in Table I) in an effort to meet this need. The system has been devised to provide simple objective clinical criteria against which the severity of a child’s dystonia may be rated and action taken. This system has been specifically designed to be used as a tool by all health care professionals involved in the clinical care of children with dystonia, and not just the movement disorder specialist. To determine the utility of our scoring system, 10 clinical vignettes (Appendix S1; online supporting information) based on real cases managed at our centre, were provided to a mixed group of 30 health care professionals, including nursing staff, allied health professionals, and paediatricians of different grades and specialities. Each participant could score all 10 cases, with average intraclass correlation scores of 0.993 (p<0.001) indicating a high level of intrarater reliability. Furthermore, all 30 participants thought that the system would be of use during their routine clinical practice. Carers, health professionals, paediatricians, neurologists, and neurodisability consultants need to communicate effectively when managing children with worsening dystonia. This simple scale based on commonly seen clinical indicators could help plan treatment and guide where care should be delivered, for example in the ward, high-dependency, or intensive care setting. It may help focus targeted intervention and develop a picture of the child’s overall disease trajectory over time while allowing measurement of the health costs of brittle, unstable dystonia, and status dystonicus.

Rechargeable deep brain stimulators in the management of paediatric dystonia: well tolerated with a low complication rate.

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.

Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum

Benign hereditary chorea is a dominantly inherited, childhood‐onset hyperkinetic movement disorder characterized by non‐progressive chorea and variable degrees of thyroid and respiratory involvement. Loss‐of‐function mutations in NKX2.1, a gene vital to the normal development and function of the brain, lungs, and thyroid, have been identified in a number of individuals.