Impact of nusinersen on the health-related quality of life and caregiver burden of patients with spinal muscular atrophy with symptom onset after age 6 months.

INTRODUCTION/AIMS: Novel disease-modifying approaches for spinal muscular atrophy (SMA) have highlighted the patient's perspective on functional changes over time. In this study, we evaluated the impact of nusinersen on the health-related quality of life (HRQoL) of patients with later-onset SMA and the caregiver burden. METHODS: We assessed the changes in HRQoL using the Pediatric Quality of Life Inventory 4.0 Generic Core Scale (PedsQL GCS) and the Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM) during 26 months of treatment. Caregiver burden was assessed using the Assessment of Caregiver Experience with Neuromuscular Disease. We also assessed motor function using the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Module score. RESULTS: Twenty-four patients and their caregivers were included. The median age of patients at treatment onset was 148.8 (6.8 to 269.4) months. A significant improvement was observed in psychosocial health in proxy-reported PedsQL (P = .023). However, the physical health scores of the PedsQL GCS and About my neuromuscular disorder subscores of the PedsQL NMM did not change, although there was a significant increase in HFMSE scores. Regarding the caregiver burden, the financial burden was reduced, whereas time burden increased. A higher HFMSE score was associated with better self-reported PedsQL GCS total scores (P < .001). DISCUSSION: Our results provide insights into the multifaceted implications of disease-modifying therapies for SMA through patient-reported outcome measures (PROMs). PROMs should be taken into consideration to assess the clinical significance of the functional changes identified by clinician-reported scales.

Short-term clinical outcomes of onasemnogene abeparvovec treatment for spinal muscular atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder long recognized as the most common genetic cause of infantile mortality described so far. However, the emergence of some innovative therapies, such as nusinersen and onasemnogene abeparvovec (AVXS-101), have made it possible to change the disease course of SMA. METHODS: In this study, five SMA type 1 and one SMA type 2 patients who received AVXS-101 were enrolled (7-24 months of age when administered). They were all previously treated with nusinersen, 4-5 times including loading doses, but stopped nusinersen maintenance after injection of AVXS-101. Patients were regularly followed up with laboratory tests and functional assessments after administration. RESULTS: Liver enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) and monocyte count tended to be elevated but normalized after several weeks. Platelets and white blood cells were transiently decreased for a few weeks after injection. Prolonged elevation of liver enzymes was associated with steroid tapering earlier than 1 month post treatment. During the follow-up period (ranging from 5 to 17 months after injection), all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. For one patient, use of bilevel positive airway pressure could be reduced from 16 h to 8 h a day during sleep at 6 months post treatment. CONCLUSION: Our experience of AVXS-101 treatment has shown that a single intravenous dose could be safe and effective for SMA patients without the need for any maintenance treatment.

Early-onset autosomal dominant GTP-cyclohydrolase I deficiency: Diagnostic delay and residual motor signs.

OBJECTIVE: Autosomal dominant (AD) guanosine triphosphate cyclohydrolase 1 (GCH1) deficiency is the most common cause of dopa-responsive dystonia (DRD). Patients with GCH1 deficiency are likely to experience diagnostic delay, but its consequences have not been described thoroughly in patients with early-onset disease. We describe the diagnostic delay and residual motor signs (RMS) observed in patients with early-onset (before 15 years of age) disease. METHODS: Twelve patients with early-onset AD GCH1 deficiency from a single center were included in the case series analysis. For the meta-analysis, the PubMed database was searched for articles on early-onset AD GCH1 deficiency published from 1995 to 2019. RESULTS: In the case series, the mean duration of diagnostic delay was 5.6 years. Two patients exhibited RMS, and four patients underwent orthopedic surgery. The literature search yielded 137 AD GCH1 deficiency cases for review; gait disturbance was reported in 92.7% of patients, diurnal fluctuation of symptoms in 91.9%, and RMS in 39%. The mean duration of diagnostic delay was 14.6 years overall: 12.0 years in RMS-negative patients and 21.2 years in RMS-positive patients. CONCLUSIONS: Diagnostic delay in early-onset AD GCH1 deficiency is more closely associated with later RMS. Early clinical suspicion, timely diagnosis, and levodopa treatment may reduce the occurrence of RMS in patients with early-onset AD GCH1 deficiency.

Clinical and Genetic Spectrum of ATP1A3-Related Disorders in a Korean Pediatric Population.

BACKGROUND AND PURPOSE: The aim of this study was to expand the understanding of the genotype-phenotype spectrum of ATP1A3-related disorders and to evaluate the therapeutic effect of a ketogenic diet in patients with alternating hemiplegia of childhood (AHC). METHODS: The clinical information of 13 patients with ATP1A3 mutations was analyzed by performing retrospective chart reviews. Patients with the AHC phenotype who consented to ketogenic diet were included in the trial. RESULTS: Ten patients presented with the clinical phenotype of AHC, two patients presented with rapid-onset dystonia parkinsonism, and one patient presented with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Two novel mutations of the AHC phenotype were identified: p.Ile363Thr and p.Asn743Ser. The clinical phenotypes of three mutations differed from those in previous reports: p.Arg597Pro, p.Thr769Pro, and p.Arg756Cys. One of the two patients who started a ketogenic diet experienced seizure provocation and so immediate stopped consuming the diet, while the other patient continued the ketogenic diet for 1 year, but this produced no clear benefit such as reduction of paroxysmal symptoms. CONCLUSIONS: Our study is the first case series of ATP1A3-related disorders to be described in Korea and which further expands the understanding of its genotype-phenotype spectrum. A ketogenic diet showed no clear benefit for the patients with AHC.

Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS).

OBJECTIVE: To reveal the changes of centrotemporal spikes that occur during the disease course of self-limited epilepsy with centrotemporal spikes (SLECTS). METHOD: We retrospectively reviewed the serial EEGs of 63 patients with SLECTS from initial diagnosis to remission. There were 32 patients who did not undergo treatment and 31 patients who underwent treatment with oxcarbazepine (OXC). The change of occurrence or abundance, voltage, and location of centrotemporal spikes of serial EEGs were analyzed and compared between the two groups. Clinical seizure evidenced and reported was counted. The time gap between seizure remission and EEG remission was measured in the two groups. RESULT: Changes of occurrence or abundance of the centrotemporal spikes were either abrupt (sudden disappearance of the frequent spikes on following EEG) or gradual (decline in number over 2 or more serial EEGs). Pattern of spike disappearance was not significantly different between the medication naïve group and OXC treated group. The spike voltage or the location of centrotemporal spikes did not change during the disease course in most cases. Delay between seizure remission and EEG normalization was 3.34 ± 1.75 (mean ± standard deviation, range: 0.77-7.97) years in untreated patients and 3.03 ± 1.41 (0.95-6.61) years in OXC-treated group. CONCLUSION: Pattern of spike disappearance in SLECTS was either abrupt or gradual. Treatment with OXC had no effect in the disappearance pattern. Precise data regarding the pattern of disappearance and delay between seizure remission and EEG normalization can help to understand the evolution of spike in SLECTS and to predict the timing of normalization of EEG after seizure remission.

Importance of early diagnosis in LMNA-related muscular dystrophy for cardiac surveillance.

INTRODUCTION: The identification of LMNA-related muscular dystrophy is important because it poses life-threatening cardiac complications. However, diagnosis of LMNA-related muscular dystrophy based on clinical features is challenging. METHODS: We reviewed the clinical phenotypes of 14 children with LMNA variants, focusing on the cardiac function and genotypes. RESULTS: Most patients presented with motor developmental delay or gait abnormalities. Eight (57%) patients had prominent neck extensor weakness or contractures. All patients showed ankle contractures at an early stage. Regular cardiac surveillance allowed for the detection of dysrhythmias in 57% of patients at a mean age of 14 years (range, 5-26). All patients had missense variants; however, there were no clear phenotype-genotype correlations. DISCUSSION: Early diagnosis of LMNA-related muscular dystrophy provides an opportunity for cardiac surveillance, potentially leading to the prevention of cardiac mortality in children.

Chronic inflammatory demyelinating polyneuropathy: Plasmapheresis or cyclosporine can be good treatment options in refractory cases.

Childhood chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare condition, and the optimal treatment strategy is not well established, especially in refractory cases. We analyzed the clinical features and treatment outcomes of 14 cases of childhood CIDP with more than 12 months of follow-up. Of the 14 cases, 10 cases were considered refractory to the conventional first-line treatment. In the monophasic group (n = 6), plasmapheresis resulted in a better treatment response than did IVIG. Monophasic refractory cases (n = 4) were especially responsive to plasmapheresis. In the polyphasic group (n = 8), IVIG and plasmapheresis had comparable effects. Among them six polyphasic patients were refractory to the first-line treatment options and received additional immunosuppressants. Four treatment-refractory polyphasic patients received cyclosporine and achieved successful disease control. With regard to the long-term outcomes, six patients showed minimal symptoms and no relapse within 6 months. Our results suggest that early administration of plasmapheresis in a monophasic course and cyclosporine in a polyphasic course may be effective treatment options for refractory childhood CIDP.

Antiepileptic Drug Withdrawal after Surgery in Children with Focal Cortical Dysplasia: Seizure Recurrence and Its Predictors.

BACKGROUND AND PURPOSE: This study investigated the seizure recurrence rate and potential predictors of seizure recurrence following antiepileptic drug (AED) withdrawal after resective epilepsy surgery in children with focal cortical dysplasia (FCD). METHODS: We retrospectively analyzed the records of 70 children and adolescents with FCD types I, II, and IIIa who underwent resective epilepsy surgery between 2004 and 2015 and were followed for at least 2 years after surgery. RESULTS: We attempted AED withdrawal in 40 patients. The median time of starting the AED reduction was 10.8 months after surgery. Of these 40 patients, 14 patients (35%) experienced seizure recurrence during AED reduction or after AED withdrawal. Half of the 14 patients who experienced recurrence regained seizure freedom after AED reintroduction and optimization. Compared with their preoperative status, the AED dose or number was decreased in 57.1% of patients, and remained unchanged in 14.3% after surgery. A multivariate analysis found that incomplete resection (p=0.004) and epileptic discharges on the postoperative EEG (p=0.025) were important predictors of seizure recurrence after AED withdrawal. Over the mean follow-up duration of 4.5 years after surgery, 34 patients (48.6% of the entire cohort) were seizure-free with and without AEDs. CONCLUSIONS: Children with incomplete resection and epileptic discharges on postoperative EEG are at a high risk of seizure recurrence after drug withdrawal. Complete resection of FCD may lead to a favorable surgical outcome and successful AED withdrawal after surgery.