The White Matter Rounds experience: The importance of a multidisciplinary network to accelerate the diagnostic process for adult patients with rare white matter disorders

Abstract

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.

Keywords: leukodystrophies; multidisciplinary (care or team); multiple sclerosis; online meeting; rare diseases; white matter diseases.

Figure 1

Map of the centers participating to the White Matter Rounds.

Figure 2

Patients discussed at the WM Rounds (total 74) according to the subspecialty of the referral physician. MS, multiple sclerosis; Dis, disorders.

Figure 3

Representative Brain MRI of patients referred to the WM Rounds according to their pattern of involvement. Representative axial FLAIR T2-weighted brain MR images of patients referred to the WMR according to their pattern of involvement. (A) 44-year-old man finally diagnosed with Peroxisomal Biogenesis Disorder showing confluent symmetric white matter abnormalities predominant in the posterior regions and affecting the splenium of the corpus callosum and the posterior limb of the internal capsules; (B) 29-year-old man diagnosed with X-linked Charcot-Marie-Tooth Disease and MS showing multifocal white matter lesions compatible with MS plaques; (C) 43-year-old man with suspected genetic MS mimicker showing bilateral periventricular white matter changes with involvement of the splenium of the corpus callosum and focal T2 hypointense lesions adjacent to the periventricular white matter; (D) 44-year-old man (no final diagnosis) with confluent symmetric white matter involvement in which focal T2-hypointense lesions suggestive of MS plaques were identified; (E) 38-year-old man with CADASIL (patient vignette no. 1) showing multifocal white matter abnormalities and anterior symmetric periventricular involvement; (F) 58-year-old woman (patient vignette no. 2) showing multifocal lobar white matter abnormalities.

Figure 4

Definite diagnoses in the cohort of 74 subjects presented at the WM Rounds. The data of patients with definite genetic diagnoses are presented according to the subspecialty of their referral physician (right).

Figure 5

Diagnostic algorithm for patients with atypical undiagnosed white matter abnormalities. Legend: HT, hypertension; NGS, next generation sequencing; OCB, oligoclonal bands; WM, white matter; pos, indicates the identification of verified disease-causing mutations; neg, indicates when the data analysis is negative or inconclusive.

Figure 6

Rate of diagnosis according to the year of presentation at the WM Rounds.