L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Status epilepticus amauroticus and posterior reversible encephalopathy syndrome in children.

INTRODUCTION: Transient cortical visual impairment is a common aura of occipital lobe seizures. However, status amauroticus for hours has rarely been described as a manifestation of occipital lobe status epilepticus. PURPOSE: To describe status amauroticus caused by focal status epilepticus of occipital lobe origin in two children with MRI findings consistent with posterior reversible encephalopathy syndrome. METHODS: Retrospective review of clinical records of two children who developed status amauroticus in association with posterior reversible encephalopathy syndrome, identified through the EEG database at British Columbia Children's Hospital. RESULTS: Case 1: A 15-year-old boy with chronic renal failure on hemodialysis developed acute headache, hypertension, vomiting, and blurred vision followed by severe visual impairment and a secondarily generalized clonic seizure. EEG demonstrated independent right and left occipital seizures. After phenytoin therapy, visual acuity was 20/20 within 48 hours. Case 2: A 10-year-old girl with beta-thalassemia treated with allogenic bone marrow transplantation developed acute headache, hypertension, severe visual impairment (light perception), encephalopathy, and intermittent dysconjugate gaze. EEG showed status epilepticus of biposterior quadrant origin. After phenytoin treatment, vision normalized within 72 hours. CONCLUSIONS: Reversible status amauroticus because of occipital lobe status epilepticus may be the presenting symptom of posterior reversible encephalopathy syndrome and EEG recording should be performed.