Assessment and Diagnosis of Down Syndrome Regression Disorder: International Expert Consensus.

Objective: To develop standardization for nomenclature, diagnostic work up and diagnostic criteria for cases of neurocognitive regression in Down syndrome. Background: There 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. Methods: The 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. Results: During 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). Conclusions: The 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.

Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder.

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.

Inadequate Vaccine Responses in Children With Multiple Sclerosis.

Objective: Immunizations against Hepatitis B virus (HBV) and Varicella Zoster virus (VZV), are recommended for patients with pediatric onset multiple sclerosis (POMS) and may be required prior to initiation of some disease modifying therapies. However, the efficacy of routine vaccine administration in POMS has never been studied. We sought to assess the humoral mediated vaccine response to HBV and VZV in children with POMS. Methods: A multi-center retrospective chart-based review of 62 patients with POMS was performed. Clinical data and antibody titers against HBV and VZV were collected prior to initiation of disease modifying therapy or steroids and compared to institutional control data, using t-test and chi squared analysis. Results: There were low rates of immunity against both HBV and VZV (33 and 25% respectively) among individuals with POMS. Fifteen individuals (24%) were non-immune to both. Compared to institutional control data, individuals with POMS were significantly less likely to be immune to and HBV (p = 0.003, 95% CI: 0.22-0.75) and VZV (p < 0.001, 95% CI: 0.09-0.39). Interpretation: Individuals with POMS have low rates of antibody-mediated immunity against HBV and VZV, despite receiving the appropriate vaccinations. This suggests an association between POMS and systemic immune dysregulation although further study is needed.

Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease.

Objective: To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population. Methods: A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression. Results: The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively (p < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times (p < 0.001, 95% CI: 1.82-5.58) higher than the idiopathic moyamoya group and 1.5 times (p = 0.002, 95% CI: 1.17-1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder (p = 0.05, 95%CI: 1.08-6.08). Interpretation: This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.

Gray Matter Atrophy: The Impacts of Resective Surgery and Vagus Nerve Stimulation in Drug-Resistant Epilepsy.

BACKGROUND: There is great concern for cognitive function after resective temporal lobe surgery for drug-resistant epilepsy. However, few studies have investigated postoperative anatomical changes, and the downstream effects of surgery are poorly understood. This study investigated volumetric changes after resective surgery and vagus nerve stimulation (VNS) for epilepsy. METHODS: Preoperative and latest postoperative (mean, 28 months) structural T1 magnetic resonance imaging scans were retrospectively obtained for 43 patients: 27 temporal lobe resections (TLRs), 6 extratemporal lobe resections, and 10 VNS, undergoing surgery for drug-resistant epilepsy between 2012 and 2017. Automated volumetric analyses of predefined cortical gray matter and subcortical structures were performed. Preoperative and postoperative volumes were compared, and the effects of age, gender, operation type, resection laterality, selectivity, time since surgery, and seizure outcome on volumetric changes were analyzed. RESULTS: After TLRs, there were reductions in contralateral hemispheric gray matter, temporal lobe, entorhinal cortex, parahippocampal, superior temporal, middle temporal, inferior temporal (P = 0.02), lingual, fusiform, precentral, paracentral, postcentral, pericalcarine gyri, and ipsilateral superior parietal gyrus. After VNS, there was bilateral atrophy in the thalamus, putamen, cerebellum, rostral anterior cingulate, posterior cingulate, medial orbitofrontal, paracentral, fusiform, and transverse temporal gyri. There was a significant effect of surgery type but no effect of age, gender, operation type, resection laterality, selectivity, time since surgery, and seizure outcome on contralateral hippocampal gray matter change. CONCLUSION: This is the first study to demonstrate volumetric decreases in temporal and connected regions after TLRs and VNS. These results provide interesting insight into functional network changes.