Unilateral deep brain stimulation (DBS) of nucleus ventralis intermedius thalami (Vim) for the treatment of post-traumatic tremor in children: a multicentre experience.

PURPOSE: Deep brain stimulation (DBS) of nucleus ventralis intermedius thalami (Vim) is a validated technique for the treatment of essential tremor (ET) in adults. Conversely, its use for post traumatic tremor (PTT) and in paediatric patients is still debated. We evaluated the efficacy of Vim-DBS for lesional tremor in three paediatric patients with drug-resistant post-traumatic unilateral tremor. METHODS: We retrospectively collected data regarding three patients with unilateral tremor due to severe head injury, with no MRI evidence of basal ganglia lesions. The three patients underwent stereotactic frame-based robot-assisted DBS of Vim contralateral to the tremor side. RESULTS: Mean follow-up was 48 months (range: 36-60 months). Tremor was reduced in all patients with a better control of voluntary movements and improvement of functional status (mean FIM scale improvement + 7 points). No surgical complications occurred. CONCLUSION: Unilateral contralateral DBS of Vim could be efficacious in post-traumatic tremor, even in paediatric patients and should be offered in PTT drug-resistant patients.

Assessment of Postural Control in Children with Movement Disorders by Means of a New Technological Tool: A Pilot Study.

Considering the variability and heterogeneity of motor impairment in children with Movement Disorders (MDs), the assessment of postural control becomes essential. For its assessment, only a few tools objectively quantify and recognize the difference among children with MDs. In this study, we use the Virtual Reality Rehabilitation System (VRRS) for assessing the postural control in children with MD. Furthermore, 16 children (mean age 10.68 ± 3.62 years, range 4.29-18.22 years) were tested with VRRS by using a stabilometric balance platform. Postural parameters, related to the movements of the Centre of Pressure (COP), were collected and analyzed. Three different MD groups were identified according to the prevalent MD: dystonia, chorea and chorea-dystonia. Statistical analyses tested the differences among MD groups in the VRRS-derived COP variables. The mean distance, root mean square, excursion, velocity and frequency values of the dystonia group showed significant differences (p < 0.05) between the chorea group and the chorea-dystonia group. Technology provides quantitative data to support clinical assessment: in this case, the VRRS detected differences among the MD patterns, identifying specific group features. This tool could be useful also for monitoring the longitudinal trajectories and detecting post-treatment changes.

Patient and caregiver experiences with pantothenate kinase-associated neurodegeneration (PKAN): results from a patient community survey.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive genetic disorder of PANK2, which enables mitochondrial synthesis of coenzyme A. Its loss causes neurodegeneration with iron accumulation primarily in motor-related brain areas. Symptoms include dystonia, parkinsonism, and other disabilities. PKAN has been categorized as classic PKAN, with an age of onset ≤ 10 years, rapid progression, and early disability or death; and atypical PKAN, with later onset, slower progression, generally milder, and more diverse symptom manifestations. Available treatments are mostly palliative. Information on the lived experience of patients with PKAN and their caregivers or on community-level disease burden is limited. It is necessary to engage patients as partners to expand our understanding and improve clinical outcomes. This patient-oriented research study used multiple-choice and free-form question surveys distributed by patient organizations to collect information on the manifestations and disease burden of PKAN. It also assessed respondents' experiences and preferences with clinical research to inform future clinical trials. RESULTS: The analysis included 166 surveys. Most respondents (87%) were parents of a patient with PKAN and 7% were patients, with 80% from Europe and North America. The study cohort included 85 patients with classic PKAN (mean ± SD age of onset 4.4 ± 2.79 years), 65 with atypical PKAN (13.8 ± 4.79 years), and 16 identified as "not sure". Respondents reported gait disturbances and dystonia most often in both groups, with 44% unable to walk. The classic PKAN group reported more speech, swallowing, and visual difficulties and more severe motor problems than the atypical PKAN group. Dystonia and speech/swallowing difficulties were reported as the most challenging symptoms. Most respondents reported using multiple medications, primarily anticonvulsants and antiparkinsonian drugs, and about half had participated in a clinical research study. Study participants reported the most difficulties with the physical exertion associated with imaging assessments and travel to assessment sites. CONCLUSIONS: The survey results support the dichotomy between classic and atypical PKAN that extends beyond the age of onset. Inclusion of patients as clinical research partners shows promise as a pathway to improving clinical trials and providing more efficacious PKAN therapies.

Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome.

The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNA sequencing showed clear expression of the truncated transcript and no differences were found between mutant and wild-type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique paediatric syndrome. Because enzymatic activity was preserved, the observed mislocalization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.

17q12 Recurrent Deletions and Duplications: Description of a Case Series with Neuropsychiatric Phenotype.

Syndromic neurodevelopmental disorders are usually investigated through genetics technologies, within which array comparative genomic hybridization (Array-CGH) is still considered the first-tier clinical diagnostic test. Among recurrent syndromic imbalances, 17q12 deletions and duplications are characterized by neurodevelopmental disorders associated with visceral developmental disorders, although expressive variability is common. Here we describe a case series of 12 patients with 17q12 chromosomal imbalances, in order to expand the phenotypic characterization of these recurrent syndromes whose diagnosis is often underestimated, especially if only mild traits are present. Gene content and genotype-phenotype correlations have been discussed, with special regard to neuropsychiatric features, whose impact often requires etiologic analysis.

Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases.

Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.

De Novo 1q21.3q22 Duplication Revaluation in a "Cold" Complex Neuropsychiatric Case with Syndromic Intellectual Disability.

Syndromic intellectual disability often obtains a genetic diagnosis due to the combination of first and next generation sequencing techniques, although their interpretation may require revaluation over the years. Here we report on a composite neuropsychiatric case whose phenotype includes moderate intellectual disability, spastic paraparesis, movement disorder, and bipolar disorder, harboring a 1.802 Mb de novo 1q21.3q22 duplication. The role of this duplication has been reconsidered in the light of negativity of many other genetic exams, and of the possible pathogenic role of many genes included in this duplication, potentially configuring a contiguous gene-duplication syndrome.

A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.

Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.

Spinal cord demyelination in children: A diagnostic challenge in neuropaediatrics for a good outcome.

BACKGROUND: Biotinidase deficiency (BTD) is an autosomal recessive inborn error of metabolism provoking progressive biotin depletion, which causes, in turn, multiple carboxylase deficiency. Its infantile onset is characterized by intractable seizures associated with lethargy, psychomotor regression, hypotonia, feeding and respiratory problems, and cutaneous abnormalities. CASE DESCRIPTION: We describe a 52-month-old female whose clinical and neuroradiological pictures were consistent with myelopathy, which is generally more frequent in older patients, as well as with symptoms of an infantile onset of biotinidase deficiency, revealed at 17 months. RESULTS: A biochemical biotinidase test revealed a profound deficiency of biotinidase detecting a 10% residual enzymatic activity, which led to the diagnosis of BTD. Gene sequencing revealed a compound heterozigous mutation (c.454A > C/c.1612C > T). CONCLUSION: Our findings suggest that even if myelopathy is uncommonly reported in BTD, and generally occurs in older children, its presence in childhood-onset floppiness should always be considered as a possible marker for an atypical presentation of BTD. Although, until recently, BTD myelopathy was believed to be prevalent in older children, a spinal cord involvement has also been described in at least nine cases in early infancy. Thus, another early diagnosis suggests that myelopathy may be more frequent than previously thought, and it is probably underdiagnosed because spinal MRI is not always routinely performed on these children. Early recognition of BTD disease is important as it would lead to prompt treatment, preventing irreversible brain damage and increasing the chances of complete recovery.

Pediatric Motor Inflammatory Neuropathy: The Role of Antiphospholipid Antibodies.

We report the clinical case of a nine-year-old girl who presented with progressive motor neuropathy, revealed via the detection of a higher delay in F-wave recording using digitalized nerve conduction/electromyography. Since the lupus anticoagulant (LAC) positivity, detected using diluted Russell viper venom time (dRVVT), switched to persistent serological anticardiolipin immunoglobulin G (IgG) positivity, a possible non-thrombotic antiphospholipid antibody (aPL)-related clinical manifestation was suspected, and intravenous immunoglobulin treatment (IVIG) was started. The IVIG treatment was well tolerated and the complete resolution of motor impairment was obtained after the third IVIG infusion. Our findings suggest that it could be useful to check for antiphospholipid antibodies in children with a rapid onset of progressive neurological signs in order to provide the beneficial use of IVIG in the treatment of pediatric aPL neurological conditions.

Movement Disorders - Childhood Rating Scale 4-18 revised in children with dyskinetic cerebral palsy.

BACKGROUND: Movement Disorders - Childhood Rating Scale for age 4-18 (MD-CRS 4-18) is a tool aimed to evaluate movement disorders in developmental age, validated since 2008 and applied in the literature. Psychometric properties, including inter- and intra-reliability and construct validity have been evaluated over time on children and adolescents with different types of movement disorders. AIM: The aim of the study is to revise the Movement Disorders - Childhood Rating Scale 4-18 (MD-CRS 4-18 R) and evaluate its psychometric properties, compared to previous version of the scale, in dyskinetic cerebral palsy. DESIGN: This is a measurement-focused study of video recorder sessions. SETTING: Video session carried out inpatient and outpatient. POPULATION: This measurement-focused study was carried out on a cohort of 57 participants with DCP (37 males; mean age 9 years and 6 months ±3 years and 8 months) evaluated through video-recorded sessions by experienced scorers using MD-CRS 4-18 and MR-CRS 4-18 R. METHODS: Inter-rater reliability, intra-rater reliability of MD-CRS 4-18 and MD-CRS 4-18 R were performed. RESULTS: This study supports the relevant contribution of MD-CRS 4-18 R to identify the severity of movement disorders in dyskinetic cerebral palsy, as indicated by the higher ICC values on Index II compared to previous MD-CRS 4-18 results. Standard Error Measurement (SEM) and Minimally Detectable Difference (MDD) of MD-CRS 4-18 R in DCP were all very low, with SEMs ranging from 0.01 to 0.02 and MDD from 0.03 to 0.06. CONCLUSIONS: Data obtained with MD-CRS 4-18 R are in accordance with previous scale on individuals with movement disorders due to different etiologies, tested with MD-CRS 4-18. CLINICAL REHABILITATION IMPACT: MD-CRS 4-18 R is able to verify natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP. Also MD-CRS 4-18 Revised form is a feasible tool, now easier to understand than the previous one, more available for incoming clinical trials.

Integrated care of muscular dystrophies in Italy. Part 2. Psychological treatments, social and welfare support, and financial costs.

This paper describes the psycho-social treatments received by 502 patients with MDs and their relatives, and the costs for care sustained by the families in the previous six month period. Data were collected by the MD-Care Schedule (MD-CS) and the Family Problems Questionnaire (FPQ). Psycho-educational interventions were provided to 72 patients (14.3%), and social/welfare support to 331 patients (65.9%). Social/welfare support was higher in patients with DMD or LGMD, in those showing more severe disability, and in patients who were in contact with centres located in Northern Italy. Psycho-educational interventions were received by 156 (31%) relatives, and social/welfare support by 55 (10.9%) and mainly provided by Family/Patients Associations (83.6%). Relatives with higher educational levels, who spent more daily hours in the assistance of patients with DMD, and in contact with centres in Central Italy more frequently benefited from psycho-educational interventions. In the previous year, costs for care were sustained by 314 (63.9%) relatives. Financial difficulties related to patient's condition, were higher in families of patients who needed more intensive rehabilitation and daily hours of caregiving, and in families who lived further away from the reference's centre. These results showed that psycho-social aspects of MDs care are only partially met in Italy, and that ad hoc supportive interventions for these patients and their families should be potentiated.

Integrated care of muscular dystrophies in Italy. Part 1. Pharmacological treatment and rehabilitative interventions.

This paper describes the pharmacological therapies and rehabilitative interventions received by 502 patients with Muscular Dystrophies, evaluated in relation to patient's socio-demographic and clinical variables, and geographical areas. Data were collected by the MD-Socio-Demographic and Clinical Schedule (MD-SC-CS) and by the Family Problems Questionnaire (FPQ). The most part of the enrolled patients were in drug treatment. The number of the medications increased in relation to patient's age, disability degree and duration of illness and was higher among patients with Duchenne Muscular Dystrophy (DMD) compared with Becker (BMD) or Limb-Girdle Muscular Dystrophies (LGMD). Steroids (deflazacort or prednisone) were the drug most frequently used, followed by cardiologic and bone metabolism drugs. In general, patients using steroids were younger and had a shorter duration of illness; patients using cardiac drugs and dietary supplements were older and had a longer duration of illness. Rehabilitative interventions were provided to about 70% (351/502) of patients, mainly DMD. Of these, physiotherapy was the more frequent treatment (96.6%) and was prevalently performed in rehabilitative centres (about 70% of patients) and at home in only 30%. Hydrokinetic-therapy was practiced by 6.8% of patients. Respiratory rehabilitation was provided to 47.0% of patients (165/351) and assisted mechanical ventilaventilation to 13.1% (46). The amount of rehabilitative interventions increased in relation to the patient's age, level of disability and duration of illness. Compared to Central and Northern Italy, in Southern Italy there was a higher attention to cardiological impairment as shown by a higher number of patients receiving heart drugs. No statistically significant differences concerning the possibility to have access to rehabilitative interventions were noted among the three geographical areas. However, patient living in Southern Italy tend to receive rehabilitation more often at home.

Suitability of North Star Ambulatory Assessment in young boys with Duchenne muscular dystrophy.

The aim of this study was to establish the suitability of the North Star Ambulatory Assessment for use in young boys with Duchenne muscular dystrophy. We studied 147 typically developing and 144 boys affected by Duchenne muscular dystrophy between the ages of 3 and 5 years. More than 85% of the typically developing boys by the age of 4 years had full scores on all the items with total scores ≥33/34. Before the age of 4 years more than 15% of the typically developing boys did not achieve full scores on all the items. Some items, such as standing on one leg, showed significant improvement with age. In contrast, other activities were rarely achieved even in the older boys. Even if there was a progressive increase in scores with age, both total and individual item scores in Duchenne were still far from those obtained in the typically developing children of the same age. Our findings suggest that the North Star Ambulatory Assessment can be reliably used at least from the age of 4 years. Longitudinal natural history data studies are needed to assess possible changes over time and the possible effect of early steroids.

Burden, professional support, and social network in families of children and young adults with muscular dystrophies.

INTRODUCTION: This study explores burden and social and professional support in families of young patients with muscular dystrophies (MDs) in Italy. METHODS: The study was carried out on 502 key relatives of 4- to 25-year-old patients suffering from Duchenne, Becker, or Limb-Girdle MD who were living with at least 1 adult relative. RESULTS: A total of 77.1% of relatives reported feelings of loss, 74.0% had feelings of sadness, and 59.1% had constraints in leisure activities. Burden was higher among relatives of patients with higher disability and who spent more daily hours in caregiving. Practical difficulties were higher among relatives who perceived lower help in patient emergencies and less practical support by their social network. Psychological burden was higher in those relatives who were unemployed, those with poorer support in emergencies, and those with lower social contacts. CONCLUSIONS: Caring for patients with MDs may be demanding for relatives even in the early stages of these disorders, especially when social support is poor and the patient's disability increases.

Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes.

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of -15.8 (SD 77.3) m at 12 months, of -58.9 (SD 125.7) m at 24 months and -104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.

6 Minute walk test in Duchenne MD patients with different mutations: 12 month changes.

OBJECTIVE: In the last few years some of the therapeutical approaches for Duchenne muscular dystrophy (DMD) are specifically targeting distinct groups of mutations, such as deletions eligible for skipping of individual exons. The aim of this observational study was to establish whether patients with distinct groups of mutations have different profiles of changes on the 6 minute walk test (6MWT) over a 12 month period. METHODS: The 6MWT was performed in 191 ambulant DMD boys at baseline and 12 months later. The results were analysed using a test for heterogeneity in order to establish possible differences among different types of mutations (deletions, duplications, point mutations) and among subgroups of deletions eligible to skip individual exons. RESULTS: At baseline the 6MWD ranged between 180 and 560,80 metres (mean 378,06, SD 74,13). The 12 month changes ranged between -325 and 175 (mean -10.8 meters, SD 69.2). Although boys with duplications had better results than those with the other types of mutations, the difference was not significant. Similarly, boys eligible for skipping of the exon 44 had better baseline results and less drastic changes than those eligible for skipping exon 45 or 53, but the difference was not significant. CONCLUSIONS: even if there are some differences among subgroups, the mean 12 month changes in each subgroup were all within a narrow Range: from the mean of the whole DMD cohort. This information will be of help at the time of designing clinical trials with small numbers of eligible patients.

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy.

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25years old. A full score was consistently achieved by the age of 5years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials.

"I have got something positive out of this situation": psychological benefits of caregiving in relatives of young people with muscular dystrophy.

This paper focuses on the psychological benefits of caregiving in key relatives of patients with muscular dystrophies (MD), a group of rare diseases characterized by progressive weakness and restriction of the patient's functional abilities. We describe whether relatives perceived caregiving to be a positive experience and test whether relatives' perceptions vary in relation to their view of the patient as a valued person, the degree of involvement in care, and the level of support provided by social network and professionals. The study sample included 502 key relatives of patients aged 4-25 years, suffering from Duchenne, Becker, or limb-girdle MD, in treatment for at least 6 months to one of the eight participating centers, living with at least one relative aged 18-80 years. Of key relatives, 88 % stated that they had gotten something positive out of the situation, 96 % considered their patients to be sensitive, and 94 % viewed their patients as talented. Positive aspects of caregiving were more recognized by key relatives who were more convinced that the patient was sensitive and who perceived that they received higher level of professional help and psychological social support. These results suggest that most key relatives consider that their caregiving experience has had a positive impact on their lives, despite the practical difficulties of caring for patients with MD. Professionals should help relatives to identify the benefits of caregiving without denying its difficulties. Clinicians themselves should develop positive attitudes towards family involvement in the care of patients with long-term diseases.