Multiple Sclerosis in Patients with Intracranial Aneurysms: Coincidence or Correlation?

1. Introduction

Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the central nervous system (CNS). A scientific basis for the association between MS and intracranial aneurysms (IA) has not been established, although overlapping neuroinflammatory pathways have also been implicated in both conditions. MS has been linked to cardiovascular pathologies, but it remains unclear if these relate to genetic predisposition, are unrelated, or even secondary to treatment. We present 2 cases of MS with unruptured bilateral IA and discuss possible mechanistic links between the two conditions.

2. Case Report

Case 1.

A 32-year-old man with relapsing-remitting MS, previously managed on interferon beta-1a and reporting excessive fatigue, presented for evaluation for participation in a clinical trial involving ocrelizumab. Physical examination revealed limited to sensory changes of the upper extremities. There was no family history of vascular disease and no tobacco use. Screening magnetic resonance angiography (MRA) revealed multiple bilateral internal carotid artery aneurysms. Diagnostic cerebral angiography demonstrated a 3.5 mm right superior hypophyseal artery aneurysm with an irregular daughter sac at the apex, indicating a higher risk for rupture. A small aneurysmal dilatation was also found on the lateral aspect of the right supraclinoid internal carotid artery [Fig.1a]. A laterally projecting aneurysmal dilatation of the paraclinoid carotid was seen on the left [Fig.1b]. Given the segmental disease and high-risk features of the aneurysm on the right, the patient underwent successful treatment with Pipeline^™ Flex Embolization Device (PED, Medtronic). The low risk left-sided lesion was followed with serial MRAs.

Fig. 1.

Case 1: 3-dimensional rotational angiography demonstrates (A) 4 × 3 mm broad-based, shallow, medially projecting right superior hypophyseal artery aneurysm with irregular daughter sac at the apex (arrow). The left internal carotid artery (B), demonstrates a 2 × 2 mm broad-based, laterally-projecting dilatation (arrow).

Case 2.

A 63-year-old woman with relapsing-remitting MS and no smoking history presented to the emergency department with severe headache. CT angiogram revealed bilateral unruptured IA. Family history was remarkable for 2 first degree relatives with IA. Her MS was managed with interferon beta-1a. Relapsing episodes resulted in extremity weakness, paresthesia and vision every 5 years, with recently increased relapse frequency of every other year. Angiography demonstrated a 4 mm irregularly shaped right superior hypophyseal artery [Fig.2a] and a 5 mm irregularly-shaped left internal carotid artery aneurysm with a 1 mm proximal aneurysmal dilatation [Fig.2b]. Given the segmental disease and high-risk features of both aneurysms, the patient underwent sequential endovascular treatment with bilateral PED 6 weeks apart.

Fig. 2.

Case 2: 3-dimensional rotational angiography demonstrates (A) irregularly shaped 4 × 3 mm right internal carotid artery aneurysm (arrow) and (B) a smooth, medially-projecting left internal carotid artery aneurysm, 5 × 4 mm (double arrows), with a 1 × 1 mm dilatation slightly proximal to this (arrowhead).

3. Discussion

IA occur in approximately 1–3% of the population with an average rupture risk of 1%, highly dependent on size, location and aneurysm morphology. Aneurysm pathogenesis remains unclear; extracellular matrix (ECM) and endothelial cell dysfunction together with hemodynamic stressors and neuroinflammation have been implicated. Inflammatory processes in IA vessel walls have been demonstrated, including lymphocyte and macrophage infiltration and up-regulation of cytokines.¹

The association between autoimmune disease and extracranial and intracranial vascular pathology is established, especially for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). An association between autoimmune disease and inflammatory aortic aneurysm has been demonstrated, due to a genetic predisposition mapped to the HLA-DR molecule. SLE affects the CNS in 25 – 50% of cases, with a higher incidence of subarachnoid hemorrhage compared to the general population (49.4% versus 10.2% per 100,000 person-years).² It is hypothesized that CNS vasculitis is the predisposing factor.² RA results in high concentrations of TNF-α, which is highly expressed in the wall of ruptured and unruptured IA.¹ Still unknown is whether these associations represent overlap in the underlying pathogenesis of MS and IA, or a final common pathway of tissue pathology.

Genetic associations between MS and IA have been described. In 2 patients with MS, the ADAM17 gene involved in ECM remodeling was overexpressed, whereas their IA showed overexpression of ECM integrity genes with upregulation of Cathepsin B.³ In this same report, the TNFRSF1A pro-inflammatory gene was shown to be upregulated with expression of mitogen-activated protein kinases.³ Furthermore, multiple proteolytic enzymes were found to be elevated in patients with IA, particularly the matrix metalloproteinases.

Patients with autoimmune diseases have a predisposition for elevated concentrations of circulating pro-inflammatory cytokines. This cytokine increase is associated with extracranial vascular pathologies such as abdominal aortic aneurysm. C-C motif chemokine ligand 20 (CCL20) is produced by cells related to inflammatory and autoimmune conditions in response to TNF-α, IFN-γ and other interleukins, resulting in inflammatory cell recruitment, particularly the Th17 lymphocytes.⁴ Serum CCL20 is elevated in patients with MS and atherosclerosis compared with healthy controls.^4,5 CCL20 has been proposed as a biomarker of abdominal aortic aneurysms and is localized to endothelial cells and tunica media of the aneurysm wall.⁵

Routine cerebrovascular imaging is not currently indicated for MS, but we recommend a dedicated vascular sequence during initial workup or with significant clinical changes requiring MRI. The incidence of IA in MS patients is unknown, suggesting an important direction for future research. For example, Finland has amongst the highest population incidence of both MS and IA.

4. Conclusion

This report describes two patients with bilateral aneurysms arising from segmental disease of the internal carotid artery. We highlight the neuroinflammatory pathways implicated in both MS and IA and discuss possible genetic associations. Occurrences of IA may be underestimated in MS patients given that dedicated vascular imaging is infrequently acquired during evaluation. Further investigation into genetic neuroinflammatory biomarkers is warranted to elucidate the nature of this association as more aggressive management of IA in this setting may be required.