Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.

Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a+/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a+/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.

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31 Background: Diagnostic resources are often limited in low- and middle-income countries (LMICs). Transportability of diagnostic specimens facilitates outreach services, potentially giving LMICs access to state-of-the-art services, which results in more precise therapies. The aim of this work was to evaluate the clinical impact of our ongoing international outreach consult service and to identify specific challenges that LMICs face, with the ultimate goal of guiding focused interventions to address needs in LMICs. Methods: Cases received were catalogued, noting demographics, anatomic site, and initial and final diagnoses. Differences between initial and final diagnoses were categorized as minor or major discrepancies with or without clinical impact affecting management and prognosis. A fifth reclassification category was created for cases in which only a broad diagnosis was initially achieved, and for which more definitive classification was subsequently provided. Results: Five hundred forty-five cases were identified. Initial histopathologic diagnoses were available for 318. Of these, 196 (62%) had discrepant definitive diagnoses, including 165 (52%) with clinical impact. Of those with clinical impact, 95 (58%) were reclassifications, 55 (33%) were major discrepancies, and 15 (9%) were minor differences. Of discrepancies with clinical impact, hematopathology cases were most frequent (40; 24%), then neuropathology (28; 17%), soft tissue (27; 16%), bone (18; 11%), and developmental tumors (18; 11%). Conclusion: Global outreach pathology consult services to LMICs have significant clinical and social impact, which is reflected by one half of the cases reviewed resulting in major change or reclassification in diagnoses that significantly impacted clinical management. Although distribution of discrepant diagnoses in this series may reflect a pediatric referral bias, they also provide insight into particular challenges that are faced by pathologists and clinicians from LMICs as a result of limited access to ancillary techniques, such as immunohistochemistry or molecular diagnostics. In addition, many cases were un- or misdiagnosed because of lack of expertise in certain areas. These trends suggest that, other than direct consultative diagnostic support, concerted efforts to improve laboratory infrastructure, resources, and training in LMICs would be efficacious in the long run. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST No COIs from the authors.