Management of Pediatric Graves Disease: A Review.

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 appropriately counsel families. There are specific scenarios in which medical therapy, radioactive iodine therapy, or surgery should be offered. Conclusions and Relevance: The diagnosis and treatment of pediatric patients with GD requires a multidisciplinary approach, involving pediatric specialists in the fields of endocrinology, ophthalmology, radiology, nuclear medicine, and surgery/otolaryngology. Antithyroid drugs are typically the first-line treatment, but sustained remission rates with medical management are low in the pediatric population. Consequently, definitive treatment is often necessary, either with radioactive iodine or with surgery, ideally performed by experienced, high-volume pediatric experts. Specific clinical characteristics, such as patients younger than 5 years or the presence of a thyroid nodule, may make surgery the optimal treatment for certain patients.

Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy.

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 calcium-binding 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. ANN NEUROL 2019.