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Isolated Cerebral Vasculitis in the Unilateral Middle Cerebral Artery in a Case with SLE

A 47-year-old woman, who was diagnosed to have systemic lupus erythematosus (SLE), was admitted because she suffered a severe ischemic stroke three weeks after experiencing a transient attack of aphasia. Diffusion-weighted MRI revealed high intensity at the borderzone of the middle cerebral artery (MCA), while the proximal portion of the left MCA was occluded with its vascular wall enhanced by gadolinium. Intravenous methylprednisolone and heparin were administrated without any symptomatic benefit. She developed severe right hemiparesis with aphasia. Isolated cerebral vasculitis in the large vessel has been rarely reported in SLE patients. The presence of an enhanced vascular wall in the MRI with gadolinium could support the diagnosis.


Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs, including the central nervous system (CNS). Neurological complications in patients with SLE are known as neuropsychiatric SLE (NPSLE). Brain ischemia due to CNS vasculitis has also occurred in such patients (1). Although vasculitis of the cerebral small-vessels is well known, such an occurrence in large-vessels has rarely been reported in SLE patients (2)(3)(4)(5). We herein report a patient with SLE presenting with a progressive ischemic stroke due to vasculitis isolated in the unilateral middle cerebral artery (MCA).

Case Report
A 47-year-old woman was admitted to our emergency room because of sudden development of aphasia. She presented with photosensitivity, arthritis, anemia and proteinuria at 27 years of age and was diagnosed to have lupus nephritis [World Health Organization (WHO) type III] based on a renal biopsy, leading to the administration of intravenous methylprednisolone and subsequent oral glucocorticoid and cyclosporine. Recently, she was administered 5 mg per day of oral prednisolone and here symptoms were well controlled. She had no family history of neurological disorders and no history of smoking nor any medical history of hypertension, diabetes mellitus, or dyslipidemia. A neurological examination on admission revealed non-fluent aphasia and mild weakness in the right arm, which was estimated as a score of 2 on the National Institute of Health Stroke Scale (NIHSS). MRI with diffusion-weighted imaging (DWI) identified high signal intensity at the border around the left MCA ( Fig. 1). Magnetic resonance angiography (MRA) revealed stenosis in her left MCA (Fig. 1). A brain infarction was confirmed and oral cilostazol was initiated. The vascular wall of the left MCA was clearly enhanced on gadoliniumenhanced MRI, thus suggesting vascular wall inflammation, which thus led to a high suspicion of vasculitis. SLE-related inflammatory reactions such as fever, discoid rash, or cheek and lymph-node swelling were absent. Laboratory studies showed elevated white blood cell of 14.2×10 3 /μL, C-reactive protein level of 4.09 mg/dL and erythrocyte sedimentation rate of 58 mm/hour with decrease level of hemoglobin of 9.6 g/dL. Platelet count of 316×10 3 /μL were within the normal limits. An immunological test showed a positive finding for antinuclear antibodies of 26.6 by ELISA and double-Intern Med 59: 3225-3227, 2020 DOI: 10.2169/internalmedicine.4958-20   (Fig. 1). MRA indicated that the left MCA was nearly completely occluded and gadolinium-enhanced MRI revealed thickening of the vascular wall from the cervical portion of the internal carotid artery (ICA) to the horizontal portion of the MCA (Fig. 2), indicating a progression of vasculitis leading to the left MCA occlusion. An examination revealed normal cerebrospinal fluid (CSF) without any oligoclonal bands, however, the interleukin-6 (IL-6) level of the cerebrospinal fluid was elevated (24.9 pg/mL; normal 0-4 pg/mL). The intravenous administration of methylprednisolone (1,000 mg/day, 3 days) with heparinization was initiated. However, her nonfluent aphasia and right hemiparesis worsened after two days, and her NIHSS score rose to 10. A re-examination via DWI revealed significant enlargement of the ischemic lesion in her left corona radiate. Therefore, treatment with a high dose of oral steroids and cyclophosphamide was initiated, and a follow-up study of CSF indicated the IL-6 level to have decreased to 2.9 pg/mL. However, her neurological deficits did not improve. She had severe motor aphasia and right hemiparesis and an NIHSS score of 15 on day 41. The imaging findings were unchanged, and she was transferred to another hospital for rehabilitation on day 62.

Discussion
According to the American College of Rheumatology classification criteria, our case is classified as having cerebrovascular disease. It is reported that, among NPSLE patients, 30-40% are complicated with ischemic stroke. In addition, the three subtypes of vasculopathy are classified by neuroimaging analyses, including inflammatory-like lesions, small-vessel disease (SVD), and large-vessel disease (LVD). Among these, the most common type is SVD, which accounts for 60% of cases with NPSLE (2). SVD is an intrinsic disorder of the brain-perforating arteries, characterized by white matter and subcortical legions of the brain. In contrast, LVD in cases with NPSLE is relatively rare. According to a previous article, 13% of cases with NPSLE have been classified to the LVD type (2). The cause of LVD in SLE cases may vary, including circulating lupus-anticoagulant, Libman-Sacks endocarditis, sepsis, atherosclerotic disease or vasculitis. Previously, MRA or cerebral angiography was performed for the evaluation of LVD vasculitis (3)(4)(5). On the other hand, contrast-enhanced MRI with the T1-CUBE sequence, which we used in this case, can clearly exhibit the thickening of the vessel wall with enhancement. These findings may provide evidence of inflammation in the vessel wall, thus indicating a diagnosis of cerebral vasculitis (6). In such cases of cerebral vasculitis, we believe the possible etiologies to include infection, giant-cell arteritis, granulomatosis with polyangiitis, Behçet disease, Sjögren syndrome and drug-induced arteritis. However, all of these etiologies were ruled out based on her clinical features and laboratory findings. Therefore, we concluded that the patient suffered from large vessel vasculitis in the central nervous system related to SLE when making the diagnosis (7).
Patients with LVD vasculitis related to SLE should undergo strong immunotherapy as early as possible, however, no useful biomarkers have been established for the early diagnosis or treatment efficacy. Although the effectiveness of rituximab therapy has been reported for the refractory neuropsychiatric lupus (8), there is little evidence that it would have any beneficial effect on the LVD vasculitis caused by SLE. An increased level of IL-6 in cerebrospinal fluid could be a biomarker for the activity of NPSLE. It has been recognized that the IL-6 level has a strong association with a diagnosis of NPSLE, the activity of SLE vasculitis, clinical deterioration, and treatment response (9). In our case, an increased IL-6 level was obvious at the second hospitalization, thus indicating the activity of SLE vasculitis. Stroke could also have caused an elevation of IL-6 in our case (10). However, because there is no evidence of a disruption of the blood-brain barrier, such as increase of protein or albumin in the CSF, the elevation of IL-6 in our case most likely reflects the activity of SLE vasculitis. Our case suggests that increased CSF IL6 levels associated with vascular wall thickening and enhancement on contrast-enhanced MRI may suggest a possible diagnosis of SLE-associated LVD.

Conclusion
We experienced a case of ischemic stroke with an occluded MCA due to SLE vasculitis. This case was an atypical NPSLE in that the patient demonstrated vasculitis of a large cerebral artery. The IL-6 levels in the CSF and gadolinium-enhanced MRI might play an important role in predicting the clinical course and treatment response.