We have described two patients from different families with an inflammatory-like presentation of CADASIL. In patient 1, a cysteine had replaced arginine at codon 90 and in patient 2 arginine was substituted by cysteine at codon 558. These two mutations in Notch3 gene, based on cysteine changes, correspond to the stereotyped mutations found in other reported patients with this diagnosis and are very likely pathogenic and a cause of CADASIL. The hallmark of these reports was the atypical clinical and MRI features in those patients that could rule out a diagnosis of CADASIL. The main unusual clinical findings were myelitis in patient 1 and optic neuritis in patient 2. Additional atypical findings were the lack of any history of migraine, corticosensitivity, and the absence of major disability over a long follow-up. Furthermore, unusual MRI findings for CADASIL were observed in patient 1: spinal cord lesion and gadolinium enhancement in the internal capsule. In patient 2, brain MRI did not show a typical CADASIL presentation, such as temporal involvement, lacunar infarct or microbleeds.
At first, whereas the diagnosis of CADASIL was genetically proven, in those patients, the occurrence of atypical presentation including myelitis and optic neuritis raised the question of an inflammatory process. Despite the lack of argument for an additional systemic autoimmune disorder, some findings such as a progressive spinal cord syndrome or relapsing optic neuritis, a possible therapeutic response to immunomodulators/corticosteroids, and MRI data, seemed to be in favor of MS. However, in those patients, the absence of oligoclonal bands and the aspect of extensive leukoencephalopathy on brain MRI with a microangiopathy aspect argued against that hypothesis. Furthermore, one should bear in mind that the improvement after anti-inflammatory treatment may have been overestimated because some degree of recovery from small ischemic lesions cannot be excluded and because the course of other inflammatory diseases of the CNS are often unpredictable.
An association of two diseases is also possible including CADASIL and MS: possibly a progressive form in patient 1 and a relapsing form in patient 2, fulfilling the MS diagnostic criteria with the limit that another diagnosis can be discussed (the no better explanation criteria). It is to note that, in the literature, no co-occurrence of CADASIL and MS has been found in any of 93 MS patients with a family history of MS [2
]. Despite those results, we had learned that, from a physiopathogenic point of view, genetic or epigenetic events could play a role to modify the course of diseases, including notch protein and signalling pathway in CADASIL and MS [3
], or mitochondrial cytopathies such as Leber’s disease or POLG
mutations which have been suggested to promote MS [4
Another hypothesis is that our patients had atypical CADASIL in which an inflammatory process occurred mimicking MS. In the literature, some of the above four findings evoking MS have, rarely, been associated with CADASIL, including a steroid-responsive spinal cord syndrome in one patient [6
] and progressive disability in another patient [7
]. The physiopathological mechanism invoked to explain those particularities in CADASIL remains unclear and involved chronic hypoperfusion for progressive disability [8
] or T-cell modulation, as observed in animal models [9
]. Increased vascular permeability of the blood–brain barrier could also be hypothesized because the accumulation of Notch-3 receptor ectodomain in the vascular wall is known to impair its structural and functional stability [10
]. At last, some metabolism disorders may produce new epitopes like myelin or neuronal debris leading to non specific inflammatory reactions as observed in our patients.
The aim of this study was to sensitize clinicians to such atypical presentations of CADASIL and not to establish epidemiological data. Selection biases were inherent in the constitution of the CADASIL cohort, because some patients may not have been declared, while others may have been classified as MS-patients because mutations in the Notch3
gene have not been researched. Whatsoever, the reported prevalence of CADASIL lies between 4 to 15 cases per 100000 [1
], which therefore makes the co-existence of another rare event improbable.
In conclusion, inflammatory-like presentation can occur in CADASIL. This condition should be known to clinicians because it could represent a challenge to make the right diagnosis. In these patients, immunomodulatory treatments, including corticosteroids, could be effective and should be proposed in the absence of validated therapeutic for CADASIL.