Hemiplegic migraine is a common cause of acute brain attack in pediatrics. MR imaging sequences useful in differentiating hemiplegic migraine from other entities include arterial spin-labeling, SWI, MRA, and DWI. There has been limited exploration on the simultaneous use of these sequences in pediatrics. We present 12 pediatric patients with acute hemiplegic migraine or migraine with aura who underwent MR imaging within 12 hours of symptom onset. Quantitative and qualitative analyses were performed on arterial spin-labeling; and qualitative analysis, on SWI and MRA sequences. All 12 patients had normal DWI and abnormal arterial spin-labeling findings. Furthermore, we observed a more rapid transition from hypoperfusion to rebound hyperperfusion in 3 patients compared with prior reports. These findings support the use of multimodal MR imaging to distinguish migraine with aura from stroke and the simultaneous use of these MR imaging sequences to improve understanding of perfusion changes during migraine with aura.

Recurrence is an important consideration when treating intractable migraines. Age, gender, diagnosis, and location of treatment correlate with migraine recurrence, but the inclusion of steroids does not. Considering these factors in the management of migraines may improve the outcome of these patients and reduce the risk of recurrence.

Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mechanistic target of rapamycin (mTOR) pathway, are associated with epilepsy and malformations of cortical development. Little is known about the effects of NPRL3 loss on neuronal mTOR signaling and morphology, or cerebral cortical development and seizure susceptibility. We report the clinical phenotypic spectrum of a founder NPRL3 pedigree (c.349delG, p.Glu117LysFS; n = 133) among Old Order Mennonites dating to 1727. Next, as a strategy to define the role of NPRL3 in cortical development, CRISPR/Cas9 Nprl3 knockout in Neuro2a cells in vitro and in fetal mouse brain in vivo was used to assess effects of Nprl3 knockout on mTOR activation, subcellular mTOR localization, nutrient signaling, cell morphology and aggregation, cerebral cortical cytoarchitecture, and network integrity. The NPRL3 pedigree exhibited an epilepsy penetrance of 28% and heterogeneous clinical phenotypes with a range of epilepsy semiologies i.e., focal or generalized onset, brain imaging abnormalities i.e., polymicrogyria, focal cortical dysplasia, or normal imaging, and EEG findings, e.g., focal, multi-focal, or generalized spikes, focal or generalized slowing. Whole exome analysis comparing a seizure-free group (n = 37) to those with epilepsy (n = 24) to search for gene modifiers for epilepsy did not identify a unique genetic modifier that explained the variability in seizure penetrance in this cohort. Nprl3 knockout in vitro caused mTOR pathway hyperactivation, cell soma enlargement, and the formation of cellular aggregates seen in time-lapse videos that were prevented with the mTOR inhibitors rapamycin or torin1. In Nprl3 KO cells, mTOR remained localized on the lysosome in a constitutively active conformation, as evidenced by phosphorylation of S6 and 4E-BP1 proteins, even under nutrient starvation (amino acid free) conditions, demonstrating that Nprl3 loss decouples mTOR activation from neuronal metabolic state. To model human malformations of cortical development associated with NPRL3 variants, we created a focal Nprl3 KO in fetal mouse cortex by in utero electroporation and found altered cortical lamination and white matter heterotopic neurons, effects which were prevented with rapamycin treatment. EEG recordings showed network hyperexcitability and reduced seizure threshold to pentylenetetrazol treatment. NPRL3 variants are linked to a highly variable clinical phenotype which we propose result from mTOR-dependent effects on cell structure, cortical development, and network organization.

A 5-year-old developmentally normal male presented with acute left-sided weakness, right-eye deviation, and agitation after right-sided head trauma. Exam was notable for agitation, inability to speak, right gaze preference, and left hemiparesis. Magnetic resonance imaging (MRI) head five hours after symptom onset demonstrated right hemispheric decreased perfusion, decreased caliber of the middle cerebral artery (MCA), posterior cerebral artery (PCA), and anterior cerebral artery (ACA), and hypooxygenated cortical veins (Figure 1A-D). MRI on day 2 demonstrated persistent decreased perfusion and improved but decreased caliber of the right distal MCA/ACA/PCA, and hypertonic saline infusion was begun. MRI on day 4 demonstrated hyperperfusion with increased caliber of the ACA and PCA. MRI on day 8 demonstrated continued right cerebral hyperperfusion and edema. MRI on day 13 demonstrated hyperperfusion and cortical edema with increased caliber of the right distal MCA/ACA/PCA arteries (Figure 1E-F). Mental status and motor symptoms started improving on day 5. Neurologic exam at discharge (day 14) demonstrated persistent left-arm weakness and cognitive slowing. Genetic testing revealed a heterozygous variant (A297T: 889 G>A) in ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2). In silico analyses predicting deleterious effects for this non-conservative amino acid substitution supported the conclusion that this was a novel pathologic gene variant.