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BACKGROUND AND PURPOSE: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. METHODS: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. RESULTS: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. CONCLUSION: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Niño , Humanos , Rituximab/efectos adversos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Factores Inmunológicos/efectos adversos , Estudios Retrospectivos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , RecurrenciaRESUMEN
In the last decade, health-related quality of life (HrQoL) has become an increasingly important outcome parameter in children and adolescents with chronic health conditions; among them are pediatric patients with inborn metabolic diseases (IMDs). Hence, knowledge on this topic is increasing, but findings on non-medical influences on the HrQoL of IMD patients are still scarce. In the present study, we retrospectively evaluated the self-reported generic HrQoL of a cohort of pediatric patients (ages 7 to 17 years) with diverse IMDs (n = 204) and explored associations between HrQoL and psychosocial and medical characteristics of the patients. We aimed to identify risk factors for impaired HrQoL to improve and tailor support for the patients and economize resources. Generic HrQoL was assessed with the KINDL-R questionnaire. We compared the HrQoL scores to published German normative data and analyzed the impact of demographic variables and intellectual and psychosocial functioning on the HrQoL. Moreover, we examined the influence of the diagnostic category and the health impairment (as judged by the physicians) on our patients' HrQoL. Overall, the HrQoL of the adolescent patients was comparable to the HrQoL of the norm group. Disorders of intellectual development, impaired psychosocial functioning, and a severe health impairment were associated with lower HrQoL scores.Conclusion: We recommend evaluating these factors in children and adolescents with IMDs to identify patients at risk for impaired HrQoL. What is Known: ⢠Studies on HrQoL in pediatric patients with IMDs mainly focused on subgroups with specific diagnoses and found normal HrQoL in some of those subgroups. ⢠In healthy children and adolescents as well as in pediatric patients with various chronic diseases, associations between psychosocial factors and HrQoL are well known. What is New: ⢠Impaired psychosocial functioning, disorders of intellectual development, and a significant disease and/or treatment burden are risk factors for impaired HrQoL in pediatric patients with IMDs. ⢠Evaluating these factors in children and adolescents with IMDs can help identify patients and families in need of enhanced psychological support.
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Errores Innatos del Metabolismo , Calidad de Vida , Adolescente , Niño , Humanos , Errores Innatos del Metabolismo/complicaciones , Calidad de Vida/psicología , Estudios Retrospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
BACKGROUND: Recent research suggested an hippocalcin (HPCA)-related form of DYT2-like autosomal recessive dystonia. Two reports highlight a broad spectrum of the clinical phenotype. Here, we describe a novel HPCA gene variant in a pediatric patient and two affected relatives. METHODS: Whole exome sequencing was applied after a thorough clinical and neurological examination of the index patient and her family members. Results of neuropsychological testing were analyzed. RESULTS: Whole exome sequencing revealed a novel homozygous missense variant in the HPCA gene [c.182C>T p.(Ala61Val)] in our pediatric patient and the two affected family members. Clinically, the cases presented with dystonia, dysarthria, and jerky movements. We observed a particular cognitive profile with executive dysfunctions in our patient, which corresponds to the cognitive deficits that have been observed in the patients previously described. CONCLUSION: We present a novel genetic variant of the HPCA gene associated with autosomal recessive dystonia in a child with childhood-onset dystonia supporting its clinical features. Furthermore, we propose specific HPCA-related cognitive changes in homozygous carriers, underlining the importance of undertaking a systematic assessment of cognition in HPCA-related dystonia.
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Distonía , Trastornos Distónicos , Niño , Cognición , Distonía/genética , Trastornos Distónicos/genética , Femenino , Hipocalcina/genética , Hipocalcina/metabolismo , Humanos , MutaciónRESUMEN
AIM: This exploratory study evaluates rating scale usage by experts from the European Reference Network for Rare Neurological Diseases (ERN-RND) for paediatric MD, considering factors like diagnosis, intellectual disability, age, and transition to adult care. The aim is to propose a preliminary framework for consistent application. METHODS: A multicentre survey among 25 ERN-RND experts from 10 European countries examined rating scale usage in paediatric MD, categorizing MD into acute, non-progressive, and neurodegenerative types. Factors influencing scale choice and the transition to adult care practices were analysed. A comprehensive literature search was conducted to identify the earliest age of application of these scales in paediatric patients. RESULTS: The study identifies various rating scales and establishes their usage frequencies for different MDs. Experts highlighted the need for standardized scales and proposed preliminary evaluation strategies based on clinical contexts. Challenges in applying scales to young, non-cooperative patients were acknowledged. INTERPRETATION: The study recommends developing standardized rating scales for paediatric MDs to improve evaluations and data collection. It suggests potential scales for specific clinical scenarios to better evaluate disease progression. Comprehensive, patient-centred care remains crucial during the transition to adult care, despite the identified challenges. This exploratory approach aims to enhance patient outcomes and care.
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OBJECTIVE: Currently, there are no data available on SARS-CoV-2 vaccine responses in pediatric-onset multiple sclerosis (POMS), and little is known about the course of SARS-CoV-2 infection in this age group. We therefore investigated humoral immune responses after COVID-19 vaccination and/or infection in POMS. METHODS: We retrospectively analyzed seroconversion rates and SARS-CoV-2-specific antibody levels in 30 POMS and one pediatric CIS patient treated with no disease-modifying therapy (no DMT), immunomodulatory DMT (IM-DMT), or immunosuppressive DMT (IS-DMT) from two Austrian MS centers. RESULTS: The median age at MS onset was 15.39 years (interquartile range [IQR]: 1.97). The median age at the first COVID-19 vaccination was 17.43 years (IQR: 2.76). After two vaccine doses, seroconversion (≥0.8 BAU/ml) was reached in 25 of 28 patients (89.3%). All patients with no DMT or IM-DMT generated robust immune responses to vaccination (seroconversion: no DMT: 6/6, IM-DMT: 7/7 [100%]; median titers: no DMT: 2075 BAU [IQR: 1268.50], IM-DMT: 2500 BAU [IQR: 0]). In the IS-DMT group, seroconversion was achieved in 12 of 14 patients (80%), and median titers were 50.8 BAU (IQR 254.63). Titers were significantly higher in no DMT versus IS-DMT (P = 0.012) and in IM-DMT versus IS-DMT (P = 0.001). Infection with SARS-CoV-2 occurred in 11 of 31 patients, and symptoms were mild in all cases. One relapse occurred after infection, but no relapses were documented after vaccination. CONCLUSIONS: Generally, mRNA vaccinations were well tolerated in POMS patients with and without DMT. Immune response was significantly reduced in patients treated with IS-DMT. No unexpected adverse events or relapses related to vaccinations were observed.
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COVID-19 , Esclerosis Múltiple , Humanos , Niño , Adolescente , Preescolar , Inmunidad Humoral , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Estudios Retrospectivos , SARS-CoV-2 , Vacunación/efectos adversos , Anticuerpos Antivirales , N,N-Dimetiltriptamina , ARN MensajeroRESUMEN
DNA methylation classifiers ("episignatures") help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. We improved episignatures with respect to three categories. Applying (i) minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated re-training of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature-classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series, including KMT2B-variants with moderate effects and comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D-associated Kabuki syndrome. Conversely, episignature-classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico-mosaics that represented all the possible variation in degree of mosaicism, variant read sampling and methylation analysis.
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Anomalías Múltiples , Metilación de ADN , Humanos , Fenotipo , Anomalías Múltiples/genética , Alelos , MosaicismoRESUMEN
BACKGROUND: Deep brain stimulation of the subthalamic nucleus is an effective treatment for patients with advanced Parkinson's disease. However, affective side effects following subthalamic deep brain stimulation have been reported. Here, we aim to elucidate the influence of affective state on emotional processing as indexed by local field potential activity and to identify neurophysiological markers in patients at risk of developing depressive symptoms during subthalamic deep brain stimulation. METHODS: Subthalamic local field potentials were directly recorded via electrodes implanted for deep brain stimulation in 12 Parkinson's disease patients while viewing emotionally salient and neutral pictures. Parkinson's disease patients were assessed for depressive symptoms using the Beck depression inventory at the time of operation and 3 months after continuous subthalamic nucleus deep brain stimulation. RESULTS: We found a significant event-related desynchronization in the local alpha frequency band (8-12 Hz) for emotionally arousing but not neutral pictures. The the event-related desynchronization (ERD) in the alpha frequency band was reduced for pleasant stimuli in patients with mild to moderate depressive symptoms compared with patients without depression. The alpha-ERD to unpleasant stimuli showed the opposite pattern. Consistently, the index of event-related alpha desynchronization (alpha ERD for pleasant stimuli minus alpha ERD for unpleasant stimuli) correlated with the Beck depression inventory at the time of the recordings and at 3 months after continuous deep brain stimulation. The alpha ERD to unpleasant pictures correlated significantly with the Beck depression inventory score at 3 months after chronic deep brain stimulation. DISCUSSION: In conclusion, we found mood-congruent stimulus processing in the subthalamic nucleus of Parkinson's disease patients. Electrophysiological markers such as event-related desynchronization of subthalamic alpha activity reflect state-dependent emotional processing and may potentially be used to predict depressive mood disturbances in Parkinson's disease patients with chronic subthalamic deep brain stimulation at an early stage.
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Ritmo alfa/fisiología , Estimulación Encefálica Profunda/métodos , Depresión/terapia , Emociones/fisiología , Potenciales Evocados Visuales/fisiología , Núcleo Subtalámico/fisiología , Anciano , Depresión/etiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/terapia , Estimulación Luminosa/métodosRESUMEN
Biallelic truncating FAM149B1 variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known FAM149B1 c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in FAM149B1-ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the FAM149B1-related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of FAM149B1-related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.
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Anomalías Múltiples/genética , Cerebelo/anomalías , Ciliopatías/genética , Proteínas del Citoesqueleto/genética , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Malformaciones del Sistema Nervioso/genética , Retina/anomalías , Anomalías Múltiples/diagnóstico , Adolescente , Adulto , Ciliopatías/diagnóstico , Consanguinidad , Síndrome de Retracción de Duane/complicaciones , Síndrome de Retracción de Duane/diagnóstico , Síndrome de Retracción de Duane/genética , Anomalías del Ojo/complicaciones , Femenino , Humanos , Enfermedades Renales Quísticas/complicaciones , Masculino , Malformaciones del Sistema Nervioso/complicaciones , Malformaciones del Sistema Nervioso/diagnóstico , Fenotipo , Arabia Saudita , Hermanos , Adulto JovenRESUMEN
OBJECTIVES: Neurodegeneration with Brain Iron Accumulation type I (NBIA-I) is a rare hereditary neurodegenerative disorder with pallidal degeneration leading to disabling generalized dystonia and parkinsonism. Pallidal or subthalamic deep brain stimulation can partially alleviate motor symptoms. Disease-specific patterns of abnormally enhanced oscillatory neuronal activity recorded from the basal ganglia have been described in patients with movement disorders undergoing deep brain stimulation (DBS). Here we studied oscillatory activity recorded from the internal globus pallidus (GPi) and the subthalamic nucleus (STN) to characterize neuronal activity patterns in NBIA-I. METHODS: We recorded local field potentials (LFP) from DBS electrodes in 6 juvenile patients with NBIA-I who underwent functional neurosurgery. Four patients were implanted in the STN and two patients in the GPi. Recordings were performed during wakeful rest. An FFT-based approach was used to analyze the power spectrum in the target area. RESULTS: In all patients we found distinct peaks in the low frequency (7-12â¯Hz) and in 5 out 6 also in the beta frequency range (15-30â¯Hz) with the largest beta peak in the patient that presented with the most prominent bradykinesia. No distinct peaks occurred in the gamma frequency range (35-100â¯Hz). The oscillatory pattern did not differ between STN and GPi. CONCLUSIONS: Here we show for the first time the oscillatory activity pattern in the STN and the GPi in juvenile patients with dystonia plus syndrome due to NBIA-I. The low frequency peak we found is in line with previous studies in patients with isolated idiopathic dystonia. In our cohort, the pallidal beta band activity may be related to more severe motor slowing in dystonia plus syndrome such as NBIA-I. SIGNIFICANCE: Our results further support the link between hyperkinetic motor symptoms such as dystonia and enhanced basal ganglia low frequency activity irrespective of the underlying etiology of dystonia.
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Ritmo beta , Globo Pálido/fisiopatología , Neurodegeneración Asociada a Pantotenato Quinasa/fisiopatología , Núcleo Subtalámico/fisiopatología , Adolescente , Niño , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Gamma synchronization increases during movement and scales with kinematic parameters. Here, disease-specific characteristics of this synchronization and the dopamine-dependence of its scaling in Parkinson's disease are investigated. In 16 patients undergoing deep brain stimulation surgery, movements of different velocities revealed that subthalamic gamma power peaked in the sensorimotor part of the subthalamic nucleus, correlated positively with maximal velocity and negatively with symptom severity. These effects relied on movement-related bursts of transient synchrony in the gamma band. The gamma burst rate highly correlated with averaged power, increased gradually with larger movements and correlated with symptom severity. In the dopamine-depleted state, gamma power and burst rate significantly decreased, particularly when peak velocity was slower than ON medication. Burst amplitude and duration were unaffected by the medication state. We propose that insufficient recruitment of fast gamma bursts during movement may underlie bradykinesia as one of the cardinal symptoms in Parkinson's disease.
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Sincronización Cortical , Dopamina/metabolismo , Ritmo Gamma , Movimiento , Enfermedad de Parkinson/fisiopatología , Núcleo Subtalámico/fisiopatología , Potenciales de Acción , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Núcleo Subtalámico/patologíaAsunto(s)
Violencia Doméstica , Enfermedad de Parkinson/terapia , Pérdida de Peso , Antiparkinsonianos/uso terapéutico , Carbidopa/uso terapéutico , Cuidadores , Progresión de la Enfermedad , Combinación de Medicamentos , Ingestión de Alimentos , Femenino , Humanos , Hipertricosis/etiología , Levodopa/uso terapéutico , Persona de Mediana Edad , Estado Nutricional , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Error monitoring is essential for optimizing motor behavior. It has been linked to the medial frontal cortex, in particular to the anterior midcingulate cortex (aMCC). The aMCC subserves its performance-monitoring function in interaction with the basal ganglia (BG) circuits, as has been demonstrated in patients suffering from BG lesions or from Parkinson's disease (PD). The subthalamic nucleus (STN) has been assumed an integrative structure for emotional, cognitive and motor processing. Error-related behavioral adaptation such as post-error slowing has been linked to motor inhibition involving activation of an inhibitory network including the STN. However, direct involvement of the STN in error monitoring and post-error behavioral adjustment has not yet been demonstrated. Here, we used simultaneous scalp electroencephalogram (EEG) and local field potential (LFP) recordings from the BG in 17 patients undergoing deep brain stimulation (DBS) for PD to investigate error-related evoked activity in the human STN, its relation to post-error behavioral adjustment and the influence of dopamine during the performance of a speeded flanker task. We found an error-related positive deflection (STN-Pe) in the STN-LFP 260-450 msec after error commission. Importantly, the STN-Pe amplitude was larger in trials with post-error slowing compared to trials with post-error speeding. There was no overall effect of dopamine on error processing. Subgroup analysis revealed a higher error rate (ER) in younger patients with earlier disease onset ON medication compared to OFF medication (and vice versa in the older patient group), which was associated with modulatory effects of the early cortical error-related negativity (ERN) and late STN-Pe. The late error-related STN-Pe that is associated with post-error reaction time (RT) adjustments supports the notion that post-error slowing is implemented by motor inhibition involving the STN. Further, the modulation of behavioral performance by dopaminergic therapy depending on patients' age may suggest a dopamine overdose effect in patients with earlier onset of PD.