Objective: To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. Methods: We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). Results: Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calciumbinding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. Interpretation: Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury.

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PURPOSE.Children with cerebral visual impairment (CVI) often have abnormal visual orienting behaviors due to impaired or damaged visual cortex. Alternatively, visualcortical function is intact but visual information is not transformed downstream into an appropriate oculomotor output (visuomotor dysfunction). We examined visual, anatomic, and oculomotor assessments to distinguish visuomotor dysfunction from CVI associated with severely reduced visual-cortical response. METHODS.We reviewed the medical records from children with CVI having abnormal visual orienting behaviors, normal ocular examinations, and born near term. Relevant data were visual evoked potentials (VEPs), Teller card acuity, eye movements recorded by video-oculography (VOG), and neuroimaging (magnetic resonance imaging [MRI]) including diffusion tensor imaging (DTI) tractography. RESULTS.Thirty subjects had visuomotor dysfunction based on a normal VEP; of these 33% had a normal MRI and 67% had white matter abnormalities associated with metabolic disease and/or decreased volume of brain parenchyma. VOG recordings showed smooth pursuit gains were uniformly reduced and saccades were dysmetric but followed the main sequence. Ten subjects had severe CVI based on VEPs at noise levels; visual acuities and MRI findings overlapped those of the visuomotor dysfunction group. Developmental delay, seizures, microcephaly, and hypotonia were common across all groups. All subjects with an abnormal conventional MRI had abnormal metrics on DTI tractography from the occipital lobe. CONCLUSIONS.A subset of patients with CVI have abnormal visual orienting behaviors despite a normal VEP (visuomotor dysfunction). A majority have abnormal white matter metrics on tractography suggesting a downstream defect in sensorimotor transformation. Clinically, visuomotor dysfunction is indistinguishable from severe CVI.

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he management of Graves disease (GD) requires integrated participation from multiple disciplines to provide optimal care for patients. Being familiar with the treatment options and their indications will help clinicians ensure optimal care for their patients, which may have positive consequences for quality of life.The incidence of pediatric GD is thought to be rising and varies widely. Prevalence rates have geographic variance worldwide, ranging from 1 case per 10 000 in the US to 1 case per 100 000 in the UK and Ireland and as many as 14 cases per 100 000 in Hong Kong. [1][2][3] Graves disease accounts for 10% to 15% of thyroid disorders during childhood and is much more frequent in female than in male patients. 1,4 This review focuses on the diagnosis and management of GD specifically in children. The evaluation of these patients includes biochemical tests and, possibly, imaging; it is important to know how to interpret these test results and how confident one can be in a diagnosis. The management options-specifically medical therapy, nuclear medicine therapy with radioactive iodine (RAI), or surgical therapy-will be discussed in detail, with a special focus on indications, contraindications, and adverse effects or complications of each modality. MethodsThe purpose of this review is to present a broad perspective on pediatric GD. The authors span a variety of disciplines relevant to the subject of pediatric GD, including otolaryngology-head and neck surgery, pediatric endocrinology, radiology with a focus on nuclear medicine, and ophthalmology. We conducted an extensive literature review and obtained expert opinion where appropriate. We also performed a PubMed literature search to identify the most up-todate and relevant information on the subject using the search terms Graves disease, hyperthyroidism, pediatric, Graves orbitopathy, methimazole, antithyroid drugs, radioactive iodine, and thyroidectomy, individually or in combination. Results DefinitionsThyrotoxicosis is defined by the 2016 American Thyroid Association's (ATA) guidelines as "a clinical state that results from inappro-IMPORTANCE The incidence of Graves disease (GD) is rising in children, and adequate care of these patients requires a multidisciplinary approach. Whether patients are seen in the context of endocrinology, nuclear medicine, or surgery, it is important to know the nuances of the therapeutic options in children.OBSERVATIONS Given the rarity of GD in children, it is important to recognize its various clinical presenting signs and symptoms, as well as the tests that may be important for diagnosis. The diagnosis is typically suspected clinically and then confirmed biochemically. Imaging tests, including thyroid ultrasonography and/or nuclear scintigraphy, may also be used as indicated during care. It is important to understand the indications for and interpretation of laboratory and imaging tools so that a diagnosis is made efficiently and unnecessary tests are not ordered. Clinicians should be well-versed in treatment options to appro...

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