Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy vs. multiple sclerosis. Either one or sometimes both?

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), is the most common cause of inherited cerebral small vessel disease, inherited stroke and inherited vascular dementia. It is not infrequent for CADASIL to be mistaken and mistreated for multiple sclerosis (MS). A much less frequent but existing scenario is the co-occurrence of CADASIL and MS (or MS-like inflammatory condition). Such patients may present with spinal cord lesions, brain or spinal cord enhancing lesions, positive oligoclonal bands and high IgG index in the cerebrospinal fluid and good response to corticosteroids or immunomodulating treatments. CADASIL through various mechanisms may trigger or modulate autoimmune reactions, and either be complicated by an inflammatory component or cause an MS-like disorder.

CADASIL vs. Multiple Sclerosis: Is It Misdiagnosis or Concomitant? A Case Series

“…Although we cannot confirm the same causal mechanism leads to the coexistence of two conditions, CADASIL and MS, the involvement of (systematic) autoimmune mechanisms in some patients with CADASIL is explained (7,8). A few studies have previously reported a rare occurrence of autoimmune disorders and inflammatory disease process among patients with CADASIL including coexistence of MS confirmed by subsequent response to steroid treatment (18)(19)(20). Tanuja et al reported an interesting case with clinical presentation and confirmed diagnosis of Balo concentric sclerosis (a rare form of MS), who later tested positive for NOTCH3 mutation (21).…”

Cysteine-Altering NOTCH3 Variants Are Associated with an Increased Risk of Autoimmune Diseases

“…Although this is the first study evaluating the potential connection between NOTCH3 cys mutations and the immune system in a population-based study, several previous studies have hypothesized about this connection. In recent years, the idea of "inflammatory CADASIL" has emerged after observing several cases of CADASIL presenting alongside autoimmune diseases, including multiple sclerosis [3][4][5]8,14]. Although the association can be partially related to misdiagnosis due to some similarities in imaging phenotype, one hypothesis of why MS and CADASIL may co-occur is due to the breakdown of the blood-brain barrier from either direct cerebral micro vessel damage or local breakdown of the endovascular wall due to acute ischemia, allowing exposure of CNS antigens previously unknown by the immune system, initiating a subsequent immune attack [14,15].…”

“…Panarteritis nodosa-like changes were found in the arteries of patients with a known NOTCH3 pathogenic variant and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) [1,2]. Additionally, markers of inflammation, including positive antinuclear antibodies (ANA), antiphospholipid antibodies, or oligoclonal bands, have been found in the serum of patients with a NOTCH3 pathogenic variant [3][4][5][6].…”

“…It has been hypothesized that interactions between the immune system and the NOTCH3 signaling pathway could be altered by NOTCH3 pathogenic variants [4]. The NOTCH3 pathogenic variant seen in CADASIL results in the gain of a novel/toxic function of the mutant NOTCH3 protein [5].…”

“…Although several case studies [1,3,4,8] presented CADASIL associations with autoimmune conditions, a population-wide study has not yet examined this association. This study aimed to investigate the co-occurrence of autoimmune illnesses and markers of inflammation in a population of participants with a NOTCH3 cysteine-altering variant from the Geisinger MyCode ® Community Health Initiative (MyCode ® ).…”