Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

OBJECTIVE: Facioscapulohumeral dystrophy (FSHD) is one of the most frequent heritable muscular dystrophies, with a large variety in age at onset and disease severity. The natural history and molecular characteristics of FSHD in childhood are incompletely understood. Our objective is to clinically and genetically characterize FSHD in childhood. METHODS: We performed a nationwide, single-investigator, natural history study on FSHD in childhood. RESULTS: Multiple-source recruitment resulted in 32 patients with FSHD (0-17 years), leading to an estimated prevalence of 1 in 100,000 children in The Netherlands. This series of 32 children with FSHD revealed a heterogeneous phenotype and genotype in childhood. The phenotypic hallmarks of FSHD in childhood are: facial weakness with normal or only mildly affected motor performance, decreased functional exercise capacity (6-minute walk test), lumbar hyperlordosis, and increased echo intensity on muscle ultrasonography. In addition, pain and fatigue were frequent and patients experienced a lower quality of life compared to healthy peers. In contrast to the literature on early-onset FSHD, systemic features such as hearing loss and retinal and cardiac abnormalities were infrequent and subclinical, and epilepsy and intellectual disability were absent. Genotypically, patients had a mean D4Z4 repeat array of 5 units (range, 2-9), and 14% of the mutations were de novo. INTERPRETATION: FSHD in childhood is more prevalent than previously known and the genotype resembles classic FSHD. Importantly, FSHD mainly affects functional exercise capacity and quality of life in children. As such, these results are paramount for counseling, clinical management, and stratification in clinical research. Ann Neurol 2018;84:635-645.

The difficulty of diagnosing NCSE in clinical practice; external validation of the Salzburg criteria.

To improve the diagnostic accuracy of electroencephalography (EEG) criteria for nonconvulsive status epilepticus (NCSE), external validation of the recently proposed Salzburg criteria is paramount. We performed an external, retrospective, diagnostic accuracy study of the Salzburg criteria, using EEG recordings from patients with and without a clinical suspicion of having NCSE. Of the 191 EEG recordings, 12 (12%) was classified as an NCSE according to the reference standard. In the validation cohort, sensitivity was 67% and specificity was 89%. The positive predictive value was 47% and the negative predictive value was 95%. Ten patients in the control group (n = 93) were false positive, resulting in a specificity of 89.2%. The interrater agreement between the reference standards and between the scorers of the Salzburg criteria was moderate; disagreement occurred mainly in patients with an epileptic encephalopathy. The Salzburg criteria showed a lower diagnostic accuracy in our external validation study than in the original design, suggesting that they cannot replace the current practice of careful weighing of both clinical and EEG information on an individual basis.

Facioscapulohumeral dystrophy in children: design of a prospective, observational study on natural history, predictors and clinical impact (iFocus FSHD).

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901) is a progressive skeletal muscle dystrophy, characterized by an autosomal dominant inheritance pattern. One of the major unsolved questions in FSHD is the marked clinical heterogeneity, ranging from asymptomatic individuals to severely affected patients with an early onset. An estimated 10% of FSHD patients have an early onset (onset before 10 years of age) and are traditionally classified as infantile FSHD. This subgroup is regarded as severely affected and extra-muscular symptoms, such as hearing loss and retinopathy, are frequently described. However, information on the prevalence, natural history and clinical management of early onset FSHD is currently lacking, thereby hampering adequate patient counselling and management. Therefore, a population-based prospective cohort study on FSHD in children is highly needed. METHODS/DESIGN: This explorative study aims to recruit all children (aged 0-17 years) with a genetically confirmed diagnosis of FSHD in The Netherlands. The children will be assessed at baseline and at 2-year follow-up. The general aim of the study is the description of the clinical features and genetic characteristics of this paediatric cohort. The primary outcome is the motor function as measured by the Motor Function Measure. Secondary outcomes include quantitative and qualitative description of the clinical phenotype, muscle imaging, genotyping and prevalence estimations. The ultimate objective will be a thorough description of the natural history, predictors of disease severity and quality of life in children with FSHD. DISCUSSION: The results of this population-based study are vital for adequate patient management and clinical trial-readiness. Furthermore, this study is expected to provide additional insight in the epigenetic and environmental disease modifying factors. In addition to improve counselling, this could contribute to unravelling the aetiology of FSHD. TRIAL REGISTRATION: clinicaltrials.gov NCT02625662.

Transition to adult care in epilepsy: A systematic review.

The transfer from paediatric to adult care can be a complex process in children with epilepsy. Inadequate care during this phase can affect long-term medical and psychosocial outcomes. The aim of this study was to review studies on transitional care from paediatric to adult healthcare for young persons with epilepsy in order to synthesize evidence for best practice. We undertook a systematic review following PRISMA guidelines and employed narrative synthesis. A total of 36 articles were included, of which 11 were interventional studies and 25 observational studies. Study quality was rated as 'good' for only four studies. Interventions included joint or multidisciplinary clinics, education (patient and health professional education) and extended service provision (Saturday clinics, peer-groups). All studies observed a positive effect experienced by the participants, regardless of intervention type. Observational studies showed that transition plans/programmes are asked for but frequently not existing or not adapted to subgroups with intellectual disability or other neurodevelopmental conditions. The results of this systematic review on transitional care in epilepsy suggest that a planned transition process likely enhances medical and psychosocial outcomes for young people with epilepsy, but the body of evidence is limited and there are significant gaps in knowledge of what efficacious transition constitutes. More studies are needed employing qualitative and quantitative methods to further explore the needs of young people with epilepsy and their families but also robust study designs to investigate the impact of interventions on medical and psychosocial outcomes.

Natural History of Facioscapulohumeral Dystrophy in Children: A 2-Year Follow-up.

BACKGROUND AND OBJECTIVES: Data on the natural history of facioscapulohumeral dystrophy (FSHD) in childhood are limited and critical for improved patient care and clinical trial readiness. Our objective was to describe the disease course of FSHD in children. METHODS: We performed a nationwide, single-center, prospective cohort study of FSHD in childhood assessing muscle functioning, imaging, and quality of life over 2 years of follow-up. RESULTS: We included 20 children with genetically confirmed FSHD who were 2 to 17 years of age. Overall, symptoms were slowly progressive, and the mean FSHD clinical score increased from 2.1 to 2.8 (p = 0.003). The rate of progression was highly variable. At baseline, 16 of 20 symptomatic children had facial weakness; after 2 years, facial weakness was observed in 19 of 20 children. Muscle strength did not change between baseline and follow-up. The most frequently and most severely affected muscles were the trapezius and deltoid. The functional exercise capacity, measured with the 6-minute walk test, improved. Systemic features were infrequent and nonprogressive. Weakness-associated complications such as lumbar hyperlordosis and dysarthria were common, and their prevalence increased during follow-up. Pain and fatigue were frequent complaints in children, and their prevalence also increased during follow-up. Muscle ultrasonography revealed a progressive increase in echogenicity. DISCUSSION: FSHD in childhood has a slowly progressive but variable course over 2 years of follow-up. The most promising outcome measures to detect progression were the FSHD clinical score and muscle ultrasonography. Despite this disease progression, an improvement on functional capacity may still occur as the child grows up. Pain, fatigue, and a decreased quality of life were common symptoms and need to be addressed in the management of childhood FSHD. Our data can be used to counsel patients and as baseline measures for treatment trials in childhood FSHD.

Muscle ultrasound is a responsive biomarker in facioscapulohumeral dystrophy.

OBJECTIVE: With drug trials starting soon, responsive, relevant, and patient-friendly biomarkers are highly needed in facioscapulohumeral dystrophy (FSHD). Our objective was to assess muscle ultrasound (MUS) as an imaging biomarker in patients with FSHD. METHODS: One-year observational, longitudinal study of both quantitative and qualitative MUS changes in FSHD. RESULTS: Twenty-two patients with symptomatic FSHD1 underwent a clinical examination and MUS at baseline and after 1-year follow-up. The qualitative MUS sum score increased from 18.59 to 20.32 (p = 0.005) and the quantitative MUS sum z scores increased from 19.96 to 24.72 (p = 0.003). The clinical scores did not change over 1 year. Muscle echogenicity correlated with the FSHD clinical score at baseline (r = 0.61, p = 0.002). CONCLUSIONS: MUS shows a significant increase in echogenicity in FSHD over 1 year. Both quantitative and qualitative MUS correlate cross-sectionally with clinical severity in FSHD and identify structural muscle changes in a clinically stable group of patients. MUS thus seems a potentially responsive biomarker that could be standardized between centers. We recommend its use in therapeutic trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patents with FSHD1, MUS findings correlate with baseline FSHD clinical scores.

Ophthalmological findings in facioscapulohumeral dystrophy.

Ophthalmological abnormalities in facioscapulohumeral dystrophy may lead to treatable vision loss, facilitate diagnostics, could help unravelling the pathophysiology and serve as biomarkers. In this study, we provide a detailed description of the ophthalmological findings in a well-defined cohort of patients with facioscapulohumeral dystrophy using state of the art retina imaging techniques. Thirty-three genetically confirmed patients (aged 7-80 years) and 24 unrelated healthy controls (aged 6-68 years) underwent clinical ophthalmological examination, fundus photography, optical coherence tomography/angiography, genotyping and neurological examination. All patients had normal corrected visual acuity and normal intraocular pressure. In 27 of the 33 patients, weakness of the orbicularis oculi was observed. Central retinal pathology, only seen in patients and not in healthy controls, included twisting (tortuosity) of the retinal arteries in 25 of the 33 patients and retinal pigment epithelium defects in 4 of the 33 patients. Asymmetrical foveal hypoplasia was present in three patients, and exudative abnormalities were observed in one patient. There was a correlation between the severity of retinal tortuosity and the D4Z4 repeat array size (R 2 = 0.44, P < 0.005). Follow-up examination in a subgroup of six patients did not show any changes after 2 years. To conclude, retinal abnormalities were frequent but almost always subclinical in patients with facioscapulohumeral dystrophy and consisted primarily of arterial tortuosity and foveal abnormalities. Retinal tortuosity was seen in the retinal arterioles and correlated with the D4Z4 repeat array size, thereby providing clinical evidence for an underlying genetic linkage between the retina and facioscapulohumeral dystrophy.

Early onset as a marker for disease severity in facioscapulohumeral muscular dystrophy.

OBJECTIVE: To assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD). METHODS: In this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups. RESULTS: Twenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2-3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8-9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%). CONCLUSIONS: Patients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

Neurological disorders of gait, balance and posture: a sign-based approach.

Neurological disorders of gait, balance and posture are both debilitating and common. Adequate recognition of these so-called disorders of axial mobility is important as they can offer useful clues to the underlying pathology in patients with an uncertain clinical diagnosis, such as those early in the course of neurological disorders. Medical teaching programmes typically take classic clinical presentations as the starting point and present students with a representative constellation of features that jointly characterize a particular axial motor syndrome. However, patients rarely present in this way to a physician in clinical practice. Particularly in the early stages of a disease, patients might display just one (or at best only a few) abnormal signs of gait, balance or posture. Importantly, these individual signs are never pathognomonic for any specific disorder but rather come with an associated differential diagnosis. In this Perspective, we offer a new diagnostic approach in which the presenting signs are taken as the starting point for a focused differential diagnosis and a tailored search into the underlying neurological syndrome.

A 22-year follow-up reveals a variable disease severity in early-onset facioscapulohumeral dystrophy.

AIM: To assess the long-term natural course of early-onset facioscapulohumeral dystrophy (FSHD), which is important for patient management and trial-readiness, and is currently lacking. METHODS: We had the unique opportunity to evaluate 10 patients with early-onset FSHD after 22 years follow-up. Patients underwent a semi-structured interview, physical examination and additional genotyping. RESULTS: Nine initial study participants (median age 37 years) were included, one patient died shortly after first publication. At first examination, one patient was wheelchair dependent, one patient walked aided, and eight patients walked unaided. After 22 years, four patients were wheelchair dependent, three walked aided, and two walked unaided. Systemic features, including hearing loss (56%), intellectual disability (44%), and a decreased respiratory function (56%), were frequent. Patients participated socially and economically with most patients living in a regular house (n = 6) and/or having a paid job (n = 4). DISCUSSION: Patients with early-onset FSHD generally had a severe phenotype compared to classical onset FSHD. However, after 22 years of follow up they showed a wide variation in severity and, despite these physical limitations, participated socially and economically. These observations are important for patient management and should be taken into account in clinical trials.

Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data.

Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness.

[Beriberi after bariatric surgery]. / Beriberi na bariatrische chirurgie.

UNLABELLED: Bariatric surgery is in general the only effective treatment for morbid obesity. Bariatric surgery is frequently associated with vitamin and mineral deficiencies which may lead to neurological and other symptoms. We describe a case of severe vitamin B1 (thiamine) deficiency. CASE DESCRIPTION: A 49-year-old man visited the emergency department with acute confusion, muscle weakness in arms and legs and visual impairment after a period of dysphagia and recurrent vomiting. Four months earlier, he had had bariatric gastric sleeve surgery for morbid obesity. Laboratory tests demonstrated that he had vitamin B1 deficiency, in view of which the diagnosis of beriberi and Wernicke encephalopathy was made. Despite normalisation of the vitamin B1 concentration following intravenous supplementation, the muscle strength hardly recovered and the patient developed Korsakov syndrome. CONCLUSION: For this deficiency there is no other treatment than vitamin B1 supplementation. Timely recognition of vitamin deficiencies and pro-active supplementation are essential in order to prevent serious complications following bariatric surgery.