RESUMO
Introduction: Adult genetic leukoencephalopathies are rare neurological disorders that present unique diagnostic challenges due to their clinical and radiological overlap with more common white matter diseases, notably multiple sclerosis (MS). In this context, a strong collaborative multidisciplinary network is beneficial for shortening the diagnostic odyssey of these patients and preventing misdiagnosis. The White Matter Rounds (WM Rounds) are multidisciplinary international online meetings attended by more than 30 physicians and scientists from 15 participating sites that gather every month to discuss patients with atypical white matter disorders. We aim to present the experience of the WM Rounds Network and demonstrate the value of collaborative multidisciplinary international case discussion meetings in differentiating and preventing misdiagnoses between genetic white matter diseases and atypical MS. Methods: We retrospectively reviewed the demographic, clinical and radiological data of all the subjects presented at the WM Rounds since their creation in 2013. Results: Seventy-four patients (mean age 44.3) have been referred and discussed at the WM Rounds since 2013. Twenty-five (33.8%) of these patients were referred by an MS specialist for having an atypical presentation of MS, while in most of the remaining cases, the referring physician was a geneticist (23; 31.1%). Based on the WM Rounds recommendations, a definite diagnosis was made in 36/69 (52.2%) patients for which information was available for retrospective review. Of these diagnosed patients, 20 (55.6%) had a genetic disease, 8 (22.2%) had MS, 3 (8.3%) had both MS and a genetic disorder and 5 (13.9%) had other non-genetic conditions. Interestingly, among the patients initially referred by an MS specialist, 7/25 were definitively diagnosed with MS, 5/25 had a genetic condition (e.g., X-linked adrenoleukodystrophy and hereditary small vessel diseases like Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and COL4A1-related disorder), and one had both MS and a genetic demyelinating neuropathy. Thanks to the WM Rounds collaborative efforts, the subjects who currently remain without a definite diagnosis, despite extensive investigations performed in the clinical setting, have been recruited in research studies aimed at identifying novel forms of genetic MS mimickers. Conclusions: The experience of the WM Rounds Network demonstrates the benefit of collective discussions on complex cases to increase the diagnostic rate and decrease misdiagnosis in patients with rare or atypical white matter diseases. Networks of this nature allow physicians and scientists to compare and share information on challenging cases from across the world, provide a basis for future multicenter research studies, and serve as model for other rare diseases.
RESUMO
BACKGROUND: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. OBJECTIVES: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. METHODS: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. RESULTS: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. CONCLUSIONS: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.