BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.

To study presentations and outcome of posterior reversible encephalopathy syndrome in children, we retrospectively analyzed 14 patients admitted to our pediatric intensive care unit. We further assessed 94 additional pediatric cases from a systematic review. Our patients had a mean age of 11.6 years. Their precipitating factors were hypertension (100%), immunosuppressants (71%), antineoplastic agents (21%), and hemodialysis (14%). Initial neurologic manifestations included seizures (100%), mental change (100%), headache (79%), and visual disturbance (57%). After prompt diagnosis by magnetic resonance imaging (MRI) with intensive management, all patients had complete clinical recovery with subsequent radiologic resolution. Systemic literature review indicated that seizures (90%), hypertension (85%), and atypical neuroimaging findings (80%) are common presentations in childhood posterior reversible encephalopathy syndrome. We conclude that in children presenting with seizures and hypertension, a pediatric neurologist should consider posterior reversible encephalopathy syndrome within a comprehensive differential diagnosis of acute encephalopathy. Early recognition and intensive care are essential to ensure complete neurologic recovery in children with posterior reversible encephalopathy syndrome.

We read with great interest the recently published articles regarding neurological involvement associated with COVID-19 infection by Asadi-Pooya et al. and Roman et al. [1,2]. Compared with adult patients, children account for only 1-5% of COVID-19 (SARS-CoV-2) cases, of which more than 80% are asymptomatic or mild cases [3]. SARS-CoV-2 may have neuroinvasive potential because 36% of adult patients are reported to have a variety of neurological manifestations, including headache, dizziness, acute cerebrovascular events, and changes in mental status. [4]. However, another study of 171 Chinese children with COVID-19 infection did not report neurological involvement [5]. According to the latest data from Western countries, non-specific headaches were the only reported neurological symptoms, accounting for 4-28% of COVID-19 infected children [3]. Of note, recent reports described emerging cases diagnosed with multisystem inflammation syndrome in children (MIS-C) related to COVID-19 infection, which share common characteristics with toxic shock syndrome and incomplete Kawasaki disease. [6]. When reviewing 187 children from the six latest reports of MIS-C cases, we found that these children had an unexpectedly high incidence (34%) of neurological involvement [6-11]. Compared with Kawasaki disease shock syndrome (KDSS), which shares several clinical features and severity with MIS-C, the neurological manifestations of KDSS have been found in as high as 54% of the affected children [12]. The high incidence of neurological complications in children with MIS-C Kawasakilike disease remains unclear; nevertheless, the mechanism might be different from the thromboembolic mechanism of the cerebrovascular system observed frequently in adult COVID-19 patients. In these MIS-C cases, 46% and 92% of children were reported positive COVID-19 reverse transcription polymerase chain reaction (RT-PCR) and serum antibody (IgG and/or IgM), respectively. This evidence suggests that while MIS-C occurred, most children might not have an active COVID-19 infection (Table 1). Of the 187 children, 64 had varying degrees of neurological symptoms, most of which were headaches, positive meningeal signs (meningism), and altered mental status. However, although their symptoms strongly implied the need to rule out the

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Posterior reversible encephalopathy syndrome (PRES) is a novel clinicoradiological syndrome characterized by convulsions, headache, altered mentality, and impaired vision, which are usually accompanied by hypertension. As its nomination, PRES is usually diagnosed according to the presence of typical neuroimage showing vasogenic edema predominately involving the posterior brain area. With the widespread utilization of magnetic resonance imaging (MRI), PRES is becoming more perceptible in different medical fields. Compared to adult cases, childhood PRES seems to have a broader clinical and neuroradiological spectrum. PRES can be associated with various underlying comorbidities, medication use, and therapeutic modalities in children with diverse neurological manifestations. Moreover, pediatric patients with PRES have a more significant propensity for atypical MRI findings beyond the typically posterior cerebral areas. The knowledge of typical and atypical presentations in children is essential to avoid misdiagnosing or missing PRES, which is a potentially treatable entity. Early supportive care is the mainstay of treatment, with particular attention to the treatment of hypertension with rigorous attention to all body systems. Prompt identification and symptom-directed management are imperative to achieve a reversible prognosis in childhood PRES. Future studies specially designed for the child population are required to determine potential outcome predictors, and further, to develop novel strategies of neuroprotection in childhood PRES.

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Combined NIV/MIE is a safe and effective approach to rapidly improve physiologic indices and decrease the need for intubation in NMD children with ARF. NIV/MIE provides a good alternative for those refusing intubation.