Metabolic patterns in brain 18F-fluorodeoxyglucose PET relate to aetiology in paediatric dystonia.

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.

Fifteen-minute consultation: Management of acute dystonia exacerbation and status dystonicus.

Dystonia is a common disorder of movement and tone, characterised by sustained or intermittent muscle contractions causing abnormal movements, postures or both. Children and young people with dystonia can experience episodes of acute worsening tone, which require prompt treatment. When most severe, dystonia may become life-threatening-a state called 'status dystonicus'. This guide aims to provide a framework for how to approach the child with acutely worsening dystonia, following an 'ABCD' approach: Addressing the precipitant, Beginning supportive care, Calibrating sedation and Dystonia-specific medications.

Spastic dystonia: Still a valid term.

Hypertonia in childhood may arise because of a variable combination of neuronal and non-neuronal factors. Involuntary muscle contraction may be due to spasticity or dystonia, which represent disorders of the spinal reflex arch and of central motor output respectively. Whilst consensus definitions for dystonia have been established, definitions of spasticity vary, highlighting the lack of a single unifying nomenclature in the field of clinical movement science. The term spastic dystonia refers to involuntary tonic muscle contraction in the context of an upper motor neuron (UMN) lesion. This review considers the utility of the term spastic dystonia, exploring our understanding of the pathophysiology of dystonia and the UMN syndrome. An argument is advanced that spastic dystonia is a valid construct that warrants further exploration. WHAT THIS PAPER ADDS: There is no single universally accepted definitions for terms commonly used to describe motor disorders. Spasticity and dystonia are phenomenologically and pathophysiologically distinct entities. Spastic dystonia represents a subset of dystonia, but with pathophysiological mechanisms more in common with spasticity.

Neurodisability care in the time of COVID-19.

BACKGROUND: The COVID-19 pandemic resulted in an unprecedented societal and healthcare global crisis. Associated changes in regular healthcare provision and lifestyle through societal lockdown are likely to have affected clinical management and well-being of children/young people with neurodisability, who often require complex packages of multidisciplinary care. METHODS: We surveyed 108 families of children/young people with severe physical neurodisability and multiple comorbidities to understand how the pandemic had affected acute clinical status, routine healthcare provision, schooling and family mental and social well-being. RESULTS: A significant proportion of families reported missing hospital appointments and routine therapy, with subsequent worsening of symptoms and function. Families additionally described worsening stress and anxiety during the pandemic, regardless of their baseline level of socio-economic deprivation. CONCLUSION: This highlights the profound effect of the COVID-19 pandemic on health and function in young people with severe neurodisabilities and emphasizes the clear need to better understand how to support this vulnerable population moving forwards.

Care in COVID: A qualitative analysis of the impact of COVID-19 on the health and care of children and young people with severe physical neurodisability and their families.

AIM: To evaluate clinicians' perspectives on the impact of 'lockdown' during the COVID-19 pandemic for children and young people with severe physical neurodisability and their families. METHOD: Framework analysis of comments from families during a recent service review was used to code the themes discussed according to the World Health Organization International Classification of Functioning, Disability and Health (ICF) and interpreted into emergent themes to summarize the impact of lockdown (Stage 1). They were presented to a clinician focus group for discussion (consultants and physiotherapists working in a specialist motor disorders service, [Stage 2]). RESULTS: Three overarching themes 'Uncertainty and Anxiety', 'Exacerbation of Existing Inequalities' and 'Care Provision: Reaction, Adaptation, and Innovation' summed up the impact of the COVID-19 pandemic on health and well-being in children and young people with neurodisability and their families. All themes were influenced by time. INTERPRETATION: This study reflects clinician's perceptions of family experiences of the pandemic and lockdown. Significant impact is apparent in the entire U.K. population, but the complexity of care needs for children with physical neurodisability exacerbates this. Lobbying for government policy is vital to ensure that all children, and in particular those with significant health and social care needs, are protected and continue to access services. During the restoration and recovery phase of the pandemic, there is a need for service reconfiguration that utilizes what we have learned and is adaptive to individual family circumstances.

Deep brain stimulation reduces pain in children with dystonia, including in dyskinetic cerebral palsy.

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.

Fifteen-minute consultation: A clinical approach to the management of the child with hypertonia.

Elevated tone (hypertonia) is a common problem seen in the paediatric clinic. For most children and young people, hypertonia is just one aspect of a broader disorder of movement and posture. This paper describes a clinical approach to the management of hypertonia in children, considering the contribution of high tone to the functional problems experienced by the child, the potential adverse effects of reducing tone, side effects of the intervention and the importance of setting objectives/goals for intervention which can be measured at follow-up. We describe this as the 'MOTOR' approach and provide some examples of how it can be used in practice.

Status dystonicus in childhood.

PURPOSE OF REVIEW: Dystonia is a common paediatric neurological condition. At its most severe, dystonia may lead to life-threatening complications, a state termed status dystonicus. This review provides an update on the definition, causes, management and outcome of childhood status dystonicus. RECENT FINDINGS: High-quality studies in childhood status dystonicus are lacking, though an increasing number of case series have been published. Status dystonicus appears to occur more frequently in children compared with adults, with a clear precipitant identified in around two-thirds of cases. Although febrile illness remains the commonest trigger for status dystonicus, unplanned interruption to deep brain stimulation (DBS) is increasingly reported as a precipitant. In parallel with this, neurosurgical intervention for status dystonicus appears to have become more widely used, though optimum timing and patient selection remains unclear. In most cases, a multistaged approach is required; we propose an 'ABCD' approach - Addressing precipitants, Beginning supportive measures, Calibrating sedation and Dystonia specific medications. Outcomes following status dystonicus appear to have slightly improved in recent years, potentially as a consequence of increasing use of DBS, though mortality has remained around 10%. SUMMARY: Future work is needed to inform evidence-based guidelines for the management of status dystonicus. One of many pressing questions is the precise indication, and timing of interventions such as DBS.

Tensor and non-tensor tractography for the assessment of the corticospinal tract of children with motor disorders: a comparative study.

INTRODUCTION: Non-invasive measures of corticospinal tract (CST) integrity may help to guide clinical interventions, particularly in children and young people (CAYP) with motor disorders. We compared diffusion tensor imaging (DTI) metrics extracted from the CST generated by tensor and non-tensor based tractography algorithms. METHODS: For a group of 25 CAYP undergoing clinical evaluation, the CST was reconstructed using (1) deterministic tensor-based tractography algorithm, (2) probabilistic tensor-based, and (3) constrained spherical deconvolution (CSD)-derived tractography algorithms. RESULTS: Choice of tractography algorithm significantly altered the results of tracking. Larger tracts were consistently defined with CSD, with differences in FA but not MD values for tracts to the pre- or post-central gyrus. Differences between deterministic and probabilistic tensor-based algorithms were minimal. Non-tensor reconstructed tracts appeared to be more anatomically representative. Examining metrics along the tract, difference in FA values appeared to be greatest in voxels with predominantly single-fibre orientations. Less pronounced differences were seen outwith of these regions. CONCLUSION: With an increasing interest in the applications of tractography analysis at all stages of movement disorder surgery, it is important that clinicians remain alert to the consequences of choice of tractography algorithm on subsequently generated tracts, including differences in volumes, anatomical reconstruction, and DTI metrics, the latter of which will have global as well as more regional effects. Tract-wide analysis of DTI based metrics is of limited utility, and a more segmental approach to analysis may be appropriate, particularly if disruption to a focal region of a white matter pathway is anticipated.

Fractional anisotropy in children with dystonia or spasticity correlates with the selection for DBS or ITB movement disorder surgery.

INTRODUCTION: There is increasing interest in neurosurgical interventions for hypertonicity in children and young people (CAYP), which often presents with a mixture of dystonia and spasticity. Significant spasticity would usually be considered a contraindication for deep brain stimulation (DBS) and more suitably treated with intrathecal baclofen (ITB). We aimed to explore whether white matter microstructure, as measured by Fractional Anisotropy (FA), differed between CAYP selected for DBS compared to ITB surgery. METHODS: We retrospectively analysed Diffusion Tensor Imaging for 31 CAYP selected for DBS surgery (14 primary dystonia, 17 secondary dystonia) and 10 CAYP selected for ITB surgery. A voxel-wise comparison of FA values was performed using tract-based spatial statistics, comparing primary and secondary dystonia groups to the ITB group, and the two dystonia groups. RESULTS: Widespread areas of reduced FA were demonstrated in ITB compared to either DBS group and in CAYP with secondary compared to primary dystonia. These changes were not restricted to motor pathways. Region of interest (ROI) analysis from the corticospinal tract (CST) demonstrated groupwise differences but overlapping values at the individual level. CONCLUSIONS: DTI measures may contribute to decision making for CAYP selection for movement disorder surgery. Significant differences in CAYP with secondary dystonia selected for DBS surgery compared to CAYP selected for ITB pump implants, suggesting that more extensive white matter injury may be a feature of the spastic motor phenotype. Altered white matter microstructure could potentially explain the reduced responsiveness to interventions such as DBS in secondary compared to primary dystonia.

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.

AIM: 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. METHOD: Children with HMDs (n=161; median age 10y 3mo, range 2y 6mo-21y) were assessed using the BFM-M, GMFCS, MACS, and CFCS from 2007 to 2013. This cross-sectional study contrasts the information provided by these scales. RESULTS: All four scales were strongly associated (all Spearman's rank correlation coefficient rs >0.72, p<0.001), with worse dystonia severity implying worse function. Secondary dystonias had worse dystonia and less function than primary dystonias (p<0.001). A longer proportion of life lived with dystonia is associated with more severe dystonia (rs =0.42, p<0.001). INTERPRETATION: The BFM-M is strongly linked with the GMFCS, MACS, and CFCS, irrespective of aetiology. Each scale offers interrelated but complementary information and is applicable to all aetiologies. Movement disorders including cerebral palsy can be effectively evaluated using these scales.

Registration Accuracy of CT/MRI Fusion for Localisation of Deep Brain Stimulation Electrode Position: An Imaging Study and Systematic Review.

BACKGROUND: Postoperative imaging is essential for verifying electrode location in patients undergoing deep brain stimulation (DBS). MRI offers better visualisation of brain targets, but concerns about adverse events have limited its use. Preoperative stereotactic MRI fused with a postoperative stereotactic CT, demonstrating the electrode position, is now widely used. OBJECTIVES: The aims of this study were to: (1) evaluate the accuracy of image registration using Neuroinspire, and (2) undertake a systematic review of the literature on CT/MRI fusion techniques to ascertain the accuracy of other software packages. METHODS: Twenty patients who underwent bilateral subthalamic nucleus DBS for Parkinson's disease were selected. The postoperative CT was registered and fused with the preoperative MRI using Neuroinspire. The position of each electrode tip was determined in stereotactic coordinates both in the (unfused) postoperative CT and the fused CT/MRI. The difference in tip position was used to evaluate the registration accuracy. RESULTS: The mean error ± SD of CT/MRI fusion using Neuroinspire was 0.25 ± 0.15, 0.33 ± 0.26 and 0.46 ± 0.55 mm in lateral, anteroposterior and vertical axes. A systematic review suggested that CT/MRI registration with Neuroinspire is more accurate than that achieved with other tested CT/MRI fusion algorithms. CONCLUSION: CT/MRI fusion for localisation of electrode placement offers an accurate, reliable and safe modality for assessing electrode location.

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: Fisher's 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, χ(2) 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.

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

AIM: 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. METHOD: Clinical data from individuals with benign hereditary chorea identified through paediatric neurology services were collected in a standardized format. The NKX2.1 gene was analysed by Sanger sequencing, multiplex ligation-dependent probe amplification, and microarray analysis. RESULTS: Six of our cohort were female and four male, median age at assessment was 8 years 6 months (range 1 y 6 mo-18 y). We identified 10 probands with NKX2.1 mutations; nine of these mutations are novel (including two whole-gene deletions) and one has been previously reported. Of the 10 individuals, eight presented with muscle hypotonia and four had evidence of hypothyroidism or respiratory involvement. Only three out of the 10 individuals had the full triad of 'brain-lung-thyroid syndrome' symptoms. Additional clinical characteristics occurring in individual participants included growth hormone deficiency, pes cavus, kyphosis, duplex kidney, and obsessive-compulsive disorder. INTERPRETATION: Our data suggest that the neurological phenotype is prominent in this condition and that many patients with benign hereditary chorea do not have the classic triad of brain-lung-thyroid syndrome. The extended phenotype may include obsessive-compulsive disorder and skeletal abnormalities.

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

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.