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.)

A common pattern of hypoxic-ischemic cerebral injury in the term newborn involves predominantly cerebral cortex and subcortical white matter. We describe 20 term newborns with moderate or severe acute hypoxic-ischemic encephalopathy who exhibit a different pattern of abnormalities on computed tomography, with evidence of decreased tissue attenuation predominantly in thalami and basal ganglia and relative preservation of cerebral cortex and white matter. Profound, acute hypoxic-ischemic insult (eg, umbilical cord prolapse, uterine rupture, or massive placental abruption) was documented in 16 of 20 infants (80%). Characteristic clinical features during the newborn period included irritability, tonic posturing of limbs, and persistent lower cranial nerve dysfunction, often with prominent tongue fasciculations. This pattern of central injury appears to be highly predictive of poor outcome; 7 newborns (35%) died, and all survivors who had follow-up to 18 months of age (11) had major neurological sequelae (eg, spastic quadriplegia, choreoathetosis, and persistent feeding problems). This pattern of hypoxic-ischemic cerebral injury corresponds closely to experimental animal models of "acute total" perinatal asphyxia.

White matter injury (WMI) is the characteristic pattern of brain injury detected on magnetic resonance imaging in the premature newborn. Focal noncystic WMI is increasingly recognized in populations of term newborns. The aim of this study was to describe the occurrence of focal noncystic WMI in a cohort of 48 term newborns with encephalopathy studied with magnetic resonance imaging at 72 Ϯ 12 h of life, and to identify clinical risk factors for this pattern of injury. Eleven newborns (23%; 95% CI 11-35) were found to have WMI (four minimal, three moderate, and four severe). In 10 of the 11 newborns, the WMI was associated with restricted diffusion on apparent diffusion coefficient maps. An increasing severity of WMI was associated with lower gestational age at birth (p ϭ 0.05), but not lower birth weight. Newborns with WMI had milder encephalopathy and fewer clinical seizures relative to other newborns in the cohort. Other brain injuries were seen in three of the 11 newborns: basal nuclei predominant pattern of injury in one and cortical strokes in two. These findings suggest that WMI in the term newborn is acquired near birth and that the state of brain maturation is an important determinant of this pattern of brain injury. injury (WMI) with characteristic topography that is well-recognized by cranial ultrasound in premature newborns (1,2). The increasing use of early-life magnetic resonance imaging (MRI) has revealed a spectrum of WMI that includes focal noncystic WMI (1,3,4). WMI is increasingly recognized as the most prevalent pattern of brain injury in the premature newborn (3,5,6). The severity of WMI in premature newborns is a predictor of adverse neurodevelopmental outcome (3,7). Recent studies suggest that the vulnerability of the premature newborn to WMI relates to the vulnerability of specific developmentally regulated cell populations prevalent in the white matter in the early-mid third trimester of gestation: e.g. late oligodendrocyte progenitor cells and subplate neurons (8 -11).However, WMI does not occur exclusively in premature newborns, and is increasingly recognized in some populations of term newborns. Term newborns with congenital heart disease (CHD) seem to be at particularly high risk of WMI, perhaps due to impairments in in utero brain development (12-15). Recent in vivo data suggest that newborns with CHD have delayed brain development before cardiac surgery, possibly as a result of impaired cerebral oxygen delivery in utero (15). WMI is also recognized in the setting of term neonatal encephalopathy (NE). In a series of postmortem examinations of term newborns with NE, three of 21 newborns (14%) had small foci of established gliosis in the periventricular white matter, in addition to evidence of acute hypoxic-ischemic lesions (16). In newborns with basal ganglia injury in the context of NE, white matter damage is seen on MRI in nearly one half of the cases (17,18). However, the timing of injury and risk factors for WMI in term newborns with NE remain largely unknown.The aim of ...

BACKGROUND AND PURPOSE:Low glucose values are often seen in term infants with NE, including HIE, yet the contribution of hypoglycemia to the pattern of neurologic injury remains unclear. We hypothesized that MR features of neonatal hypoglycemia could be detected, superimposed on the predominant HIE injury pattern.