Background Down syndrome regression disorder is a symptom cluster consisting of neuropsychiatric regression without cause. This study evaluated the incidence of neurodiagnostic abnormalities in individuals with Down syndrome regression disorder and determined if abnormalities are indicative of responses to therapeutic intervention. Methods A retrospective, multi-center, case-control study was performed. Patients were required to have subacute onset and the presence of four of five symptom groups present (cognitive decline, expressive language, sleep derangement, loss of ability to perform activities of daily living, and/or a new movement disorder) and no other explanation for symptoms. Results Individuals with Down syndrome regression disorder were comparable to a cohort of individuals with only Down syndrome although had higher rates of autoimmune disease (p = 0.02, 95%CI 1.04–1.75). Neurodiagnostic abnormalities were found on EEG (n = 19, 26%), neuroimaging (n = 16, 22%), and CSF (n = 9, 17%). Pleocytosis was appreciated in five cases, elevated total protein in nine, elevated IgG index in seven, and oligoclonal bands in two. Testing within 2 years of symptom onset was more likely to have neurodiagnostic abnormalities (p = 0.01, 95%CI 1.64–37.06). In individuals with neurodiagnostic abnormalities, immunotherapy was nearly four times more likely to have a therapeutic effect than in those without neurodiagnostic abnormalities (OR 4.11, 95%CI 1.88–9.02). In those with normal neurodiagnostic studies (n = 43), IVIg was effective in 14 of 17 (82%) patients as well although other immunotherapies were uniformly ineffective. Conclusions This study reports the novel presence of neurodiagnostic testing abnormalities in individuals with Down syndrome regression disorder, providing credence to this symptom cluster potentially being of neurologic and/or neuroimmunologic etiology.

Maddison LA, Joest KE, Kammeyer RM, Chen W. Skeletal muscle insulin resistance in zebrafish induces alterations in ␤-cell number and glucose tolerance in an age-and diet-dependent manner.

ObjectiveTo develop standardization for nomenclature, diagnostic work up and diagnostic criteria for cases of neurocognitive regression in Down syndrome.BackgroundThere are no consensus criteria for the evaluation or diagnosis of neurocognitive regression in persons with Down syndrome. As such, previously published data on this condition is relegated to smaller case series with heterogenous data sets. Lack of standardized assessment tools has slowed research in this clinical area.MethodsThe authors performed a two-round traditional Delphi method survey of an international group of clinicians with experience in treating Down syndrome to develop a standardized approach to clinical care and research in this area. Thirty-eight potential panelists who had either previously published on neurocognitive regression in Down syndrome or were involved in national or international working groups on this condition were invited to participate. In total, 27 panelists (71%) represented nine medical specialties and six different countries reached agreement on preliminary standards in this disease area. Moderators developed a proposed nomenclature, diagnostic work up and diagnostic criteria based on previously published reports of regression in persons with Down syndrome.ResultsDuring the first round of survey, agreement on nomenclature for the condition was reached with 78% of panelists agreeing to use the term Down Syndrome Regression Disorder (DSRD). Agreement on diagnostic work up and diagnostic criteria was not reach on the first round due to low agreement amongst panelists with regards to the need for neurodiagnostic testing. Following incorporation of panelist feedback, diagnostic criteria were agreed upon (96% agreement on neuroimaging, 100% agreement on bloodwork, 88% agreement on lumbar puncture, 100% agreement on urine studies, and 96% agreement on “other” studies) as were diagnostic criteria (96% agreement).ConclusionsThe authors present international consensus agreement on the nomenclature, diagnostic work up, and diagnostic criteria for DSRD, providing an initial practical framework that can advance both research and clinical practices for this condition.

ImportanceIt is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.ObjectiveTo evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.Design, Setting, and ParticipantsThis was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.ExposuresGenetic test results.Main Outcomes and MeasuresClinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.ResultsAmong 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).Conclusions and RelevanceResults of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

Multiple sclerosis is being increasingly recognized and diagnosed in children. In the past several years, advances have been made in diagnosing multiple sclerosis in children, identifying new genetic and environmental risk factors, delineating underlying immunobiology, characterizing imaging findings, and implementing new treatment strategies. In this review, we discuss these advances. Future research into the determinants of multiple sclerosis in children and into new treatment options will be aided by continued international collaboration.

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A 54-year-old man with hemoglobin SC disease and a history of substance abuse presented to the Emergency Department from a nursing home with 2 days of progressive weakness, shortness of breath, and lower back pain. He developed a fever, hypoxia, and tachycardia on the day of admission. He did not have any recent changes in medications, and his family as well as the nursing home staff denied any access to illicit drugs.The patient's clinical presentation raises concern for a vaso-occlusive crisis, specifically acute chest syndrome (ACS.) ACS should be suspected when a patient with a sickle cell disorder (SCD) experiences fever, chest pain, and dyspnea, with laboratory testing demonstrating the presence of a leukocytosis and an associated decrease in hemoglobin and platelets [1]. Supportive care with hydration, oxygen, pain control, and broad-spectrum antibiotics should be initiated while awaiting hematologic, metabolic, infectious, and radiographic workups.On arrival to the hospital, his vital signs demonstrated a temperature of 39.48C, a heart rate of 140 beats per minute, and a blood pressure of 159/120 mmHg. He was hypoxic and required supplemental oxygen. Physical exam was remarkable for altered mental status (AMS) and a rapidly decreasing level of consciousness, dry mucous membranes, dilated, slightly irregular, and nonreactive pupils, and a torsional nystagmus. A later review of records from his ophthalmologist documented the presence of iris atrophy as a complication of his sickle cell disease. Upon evaluation, the patient was intubated for airway protection.ACS and the systemic inflammatory response syndrome (SIRS) remain atop the differential diagnosis. Other important considerations include severe sepsis secondary to pneumonia or meningitis, illicit drug use, metabolic disturbances, heart failure, hypertensive emergency, and embolic diseases. In general, neurologic complications are seen in 11% of patients presenting with ACS, with 31% of those patients also developing a relative thrombocytopenia [2]. While there are many etiologies that might contribute to this clinical picture, one finding that stands out is his torsional nystagmus, indicating a dysfunction in his cerebellum or brainstem. With such a finding, a metabolic or ischemic cause for his acute encephalopathy becomes more likely.Initial complete blood count showed a decrease in hemoglobin from a baseline of 13-14 to 12.4 g/dl, a decrease in platelets from a baseline of 222 to 92 k/mm 3 , and serum WBCs of 11.8 k/ml. Peripheral blood smears showed moderate amount of target cells and sickle cells, a markedly elevated number of nucleated red blood cells (65 nucleated RBCs/100 WBCs), and a slight number of schistocytes.There also was evidence of neutrophil precursors with 3% neutrophil bands, 2% metamyelocytes, and 1% myelocytes. A comprehensive metabolic panel showed an elevation of serum creatinine from a baseline of 1.2 to 1.6 mg/dl and a total bilirubin of 3.4 mg/dl. His troponin I level was 0.96 ng/ml. Further hematological work-up demonstrat...

Myelopathy is an increasingly recognized presentation of many antibody-mediated neuroinflammatory disorders. While specific features of certain autoimmune myelopathies such as aquaporin-4 antibody associated neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein associated disorder (MOGAD) are well-characterized, other less commonly seen antibody-associated myelopathies are not as well-defined. These include but are not limited to, Hu/ANNA1, anti-glial fibrillary acidic protein (GFAP), anti-CV2/collapsin response mediator protein (CRMP5), and amphiphysin. Here, we review the mentioned more common antibody mediated myelopathies as well those that as less common, followed by a review of differentials that may mimic these disorders.