Objective: To report the clinical features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients Յ 18 years old. Methods: Information was obtained by the authors or referring physicians. Antibodies were determined by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA) using HEK293 cells ectopically expressing NR1. Results: Over an 8-month period, 81 patients (12 male) with anti-NMDAR encephalitis were identified. Thirty-two (40%) were Յ18 years old (youngest 23 months, median 14 years); 6 were male. The frequency of ovarian teratomas was 56% in women Ͼ18 years old, 31% in girls Յ18 years old ( p ϭ 0.05), and 9% in girls Յ14 years old ( p ϭ 0.008). None of the male patients had tumors. Of 32 patients Յ18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow-up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p ϭ 0.03). Interpretation: Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children.Ann Neurol 2009;66:11-18 Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently described disorder with a well defined set of clinical features.1 The associated syndrome has been characterized in adults, frequently young women with teratomas of the ovary who develop changes of mood, behavior, and personality, resembling acute psychosis. The clinical picture usually progresses to include seizures, decreased level of consciousness, dyskinesias, autonomic instability, and hypoventilation.2-5 Despite the severity of the disorder, patients often improve with immunotherapy and removal of the teratoma. 1,3,6 These findings and the discovery that all patients have serum and cerebrospinal fluid (CSF) antibodies that react with the cell surface of neurons suggested an immune-mediated pathogenesis. 1,7,8 Further studies demonstrated that the target antigen of patients' antibodies was the NR1 subunit of the NMDAR. Additionally, application of antibodies into cultures of hippocampal neurons resulted in a significant decrease of postsynaptic NMDAR clusters that was reversed after antibody removal. 9 A recent series of 100 patients showed that the disorder also occurs in patients without teratoma, and that men and children c...

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Background and Purpose To determine the incidence of neurovascular events as late complications in pediatric brain tumor patients and to evaluate radiation as a risk factor. Methods Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment 1/1/93-12/31/02, and at least two visits with Neuro-Oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack (TIA). Results Of 431 subjects, 14 had 19 events of stroke or TIA over a median follow-up of 6.3 years. The incidence rate was 548/100,000 person-years. Overall, 61.5% of subjects received radiation, including 13/14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/TIA hazard ratio for any brain irradiation was 8.0 (95% CI:1.05-62, p=0.045); for Circle of Willis (COW) radiation was 9.0 (95% CI:1.2-70, p=0.035); and for focal non-COW radiation was 3.4 (95% CI:0.21-55, p=0.38). Conclusions The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.

Neurofibromatosis type 1 (NF1) is one of the most common brain tumor predisposition syndromes, in which affected children are prone to the development of low-grade gliomas. While NF1-associated gliomas can be found in several brain regions, the majority arise in the optic nerves, chiasm, tracts, and radiations (optic pathway gliomas; OPGs). Owing to their location, 35-50% of affected children present with reduced visual acuity. Unfortunately, despite tumor stabilization following chemotherapy, vision does not improve in most children. For this reasons, more effective therapies are being sought that reflect a deeper understanding of the NF1 gene and the use of authenticated Nf1 genetically-engineered mouse strains. The implementation of these models for drug discovery and validation has galvanized molecularly-targeted clinical trials in children with NF1-OPG. Future research focused on defining the cellular and molecular factors that underlie optic glioma development and progression also has the potential to provide personalized risk assessment strategies for this pediatric population.