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.)

Super-refractory status epilepticus (SRSE) is an important neurological emergency associated with high mortality and morbidity and poses a heavy economic burden on patients. Ketogenic diet parenteral nutrition (KD-PN) is ketogenic diet therapy provided through parenteral administration and may be an adjuvant treatment for these who cannot accept enteral diet. However, the calculation and management of KD-PN presents a challenge for clinicians. This review focuses on the practical aspects of KD-PN therapy for treatment of SRSE, including the dietary composition, potential drug-diet interactions, and monitoring during KD-PN treatment. As with all SRSE treatments, KD-PN has many adverse effects, like hyperlipemia, hepatotoxicity, metabolic acidosis, insufficient ketosis or hyper-ketosis, and propofol infusion syndrome. We summarize monitoring and treatment methods in our review. This review provides some practical aspects for treatment of SRSE.

Objective The last decade has seen an increase in the use of anti‐seizure medications (ASMs); however, the burden of treating drug‐resistant epilepsy has not fallen. We performed this meta‐analysis to evaluate the optimal dose of Perampanel (PER) as a new adjunctive treatment for drug‐resistant seizures. Methods We searched for studies published from inception to February 1, 2021 from PubMed, Central Register of Controlled Trials (CENTRAL), and ScienceDirect. Research characteristics, patients' characteristics, and treatment regimen, concomitant ASMs, clinical outcomes were extracted. The practical outcome included a reduction in seizures frequency ≥50%, ≥75%, and ≥100% from baseline convulsive seizure frequency, and the safety outcome included the proportion of drug withdrawal and adverse reactions. Odds ratios (OR) for 95% confidence intervals (95% CI) were estimated by the inverse variance method. Results Four trials which enrolled 2187 participants (1569 in the PER group and 618 in the placebo group) were included. Results showed that 8 or 12 mg per day had the best effect on all three outcomes, with no significant difference between 8 and 12 mg per day (≥50% reduction, 35.5% vs 36.1%, P = .84; ≥75% reduction, 17.8% vs 19.1%, P = .64; seizure‐free, 3.5% vs 3.7%, P = .85). In addition, 12‐mg PER compared to 8 mg had a higher proportion of trial withdrawal (8.7% vs 17.0%; P < .00001) and treatment‐emergent adverse event (TEAE) resulting in dose reduction/discontinuation (18.5% vs 32.0%; P < .00001). The adverse events (AEs) significantly associated with adjunctive PER were dizziness, somnolence, fatigue, and irritability. Significance Adjunctive treatment of PER was associated with a more significant reduction in the frequency of seizures in patients with refractory epilepsy than placebo, but with a higher frequency of AEs. PER at a daily dose of 8 mg appears to have the best ratio between efficacy and tolerance in most study participants.

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