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Page 4 of 6 Paraskevas et al. Neuroimmunol Neuroinflammation 2018;5:49 I http://dx.doi.org/10.20517/2347-8659.2018.50

Relapsing optic neuritis without CSF oligoclonal bands has been described in a CADASIL patient with sen-
[27]
sorimotor leg deficit, showing good response to corticosteroids and later to glatiramer acetate . According
to the authors, this patient would otherwise fulfill the diagnostic criteria of MS.

[29]
Balo concentric sclerosis has been reported in a patient carrying a NOTCH3 mutation . Oligoclonal bands
were absent and response to corticosteroids was minimal. However, significant improvement was noted after
5 sessions of plasmapheresis. He was then treated as a clinically isolated syndrome with β-interferon-1a and
no relapse was noted for at least 1 year.

The above reports of cases or families indicate that, rarely, MS or MS-like conditions may coexist with CA-
DASIL. The presence of CSF oligoclonal bands or high IgG index and/or the responsiveness to immunologi-
cal treatments points towards the autoimmune nature of these conditions. They may represent true MS or
some other related demyelinative disease or an inflammatory form/component of CADASIL [27-29] . The co-
occurrence of the two conditions could be coincidental. But, is there a possibility that NOTCH3 mutations
may somehow provoke (or at least alter) autoimmune phenomena?

THE INTERPLAY BETWEEN CADASIL AND AUTOIMMUNITY
It has been hypothesized that an interaction may be normally present between the immune and NOTCH3
signaling systems. This interaction may be altered by NOTCH3 mutations or Notch3 dysfunction [30,31] . In ad-
[1,4]
dition, the gain of a novel/toxic function of the mutant Notch3 protein, suggested to occur in CADASIL ,
may be associated, through altered protein-protein interactions, with immune dysregulation and/or presen-
[27]
tation of new epitopes leading to autoimmunity. This presentation of new epitopes may be facilitated by
abnormal aggregations of extracellular matrix proteins, forming complexes with the extracellular domain of
[32]
the Notch3 receptor . Dysregulation of T-cells by altered Notch3 function may offer an additional or alter-
[31]
native mechanism for inflammatory demyelination .

[4]
Alterations of the vascular wall occurring in CADASIL are thought to affect the blood brain barrier and,
[23]
indeed, many patients have CSF evidence of blood brain barrier dysfunction (increased protein) . Such a
dysfunction, possibly augmented by ischemia, may expose central nervous system antigens to the immune
[28]
system, initiating an autoimmune reaction . It seems possible however, that the NOTCH3 mutations alone
are not enough to trigger autoimmunity since, most patients do not have such coexisting disorders. Other
genetic or epigenetic factors may participate.

CADASIL is not the only genetic encephalopathy, which may (rarely) present with autoimmune comorbidity
or be confused with MS. Indeed, some genetic white matter diseases, including adrenoleucodystrophy, may
[5]
be complicated by an inflammatory component during disease progression . Interestingly enough, some
other genetic conditions may have both an ischemic and an inflammatory component, they may be accom-
panied by migraine with aura and ischemic events (including stroke or stroke-like episodes) and they may
result in cognitive impairment and psychiatric/behavioral symptoms. Retinal vasculopathy with cerebral
leucodystrophy (RVCL), due to mutations of TREX1 is one such disorder, presenting with many, sometimes
[33]
overlapping phenotypes . Renal and retinal involvement, together with contrast-enhancing mass lesions
[34]
in brain imaging, distinguish this disorder from CADASIL. Mitochondrial diseases including MELAS ,
[35]
[36]
POLG-related , and OPA1-related disorders may sometimes have an autoimmune component.
CONCLUSION
[37]
It is not infrequent for CADASIL to be mistaken for MS . Better understanding of the disease is required
for clinical neurologists and radiologists, in order to avoid diagnostic pitfalls and mistreatments. A much
less frequent, yet existing scenario, is the co-occurrence of CADASIL and MS (or MS-like inflammatory