2021 Volume 7 Pages 25-29
Takayasu arteritis is primarily a granulomatous large vessel vasculitis mainly involving the aorta and its main branches. Here we report a 45-year-old woman developing gait disturbance and visual loss with abnormal lesions in bilateral pons, left cerebellum and bilateral occipital to parietal areas on brain magnetic resonance imaging (MRI). Her symptoms and brain MRI findings were refractory to initial steroid therapy, but muscle weakness in left upper limb later occurred with new abnormal lesion in right frontal area with Gadolinium-enhancement. The brain biopsy finally demonstrated a marked gliosis and demyelination with cytotoxic helper T cell and microglia accumulation predominantly around the small vessel, and the new brain lesion plus new neurological symptoms improved after the second steroid therapy except for visual loss. The present case reported a unique intracranial small vessel involvement in the course of Takayasu arteritis.
CD, cluster of differentiation; CSF, cerebrospinal fluid; CT, computed tomography; ESR, erythrocyte sedimentation rate; 18F-FDG PET, Fluorine-18 fluorodeoxyglucose positron emission tomography; FLAIR, fluid attenuated inversion recovery; Gd, Gadolinium; IgG, immunoglobulin G; IL-6, interleukin-6; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging.
Takayasu arteritis known as “pulseless disease” is primarily a granulomatous large vessel vasculitis mainly involving the aorta and its main branches, as well as coronary and pulmonary arteries1). Cerebral lesions associated with Takayasu arteritis are supposed to be mainly caused by ischemia due to large vessel stenosis. However, small vessel ischemic lesions are also reported on brain magnetic resonance imaging (MRI) with hyperintense white matter lesions on T2-weighted image2). Here we report a first case of cerebral lesions with Takayasu arteritis, who demonstrated a marked gliosis and demyelination with cytotoxic T cell and microglia accumulation around the small vessel confirmed by brain biopsy.
A 45-year-old woman developed a progressive gait disturbance (left >> right) in two months. She had an immediate history of Takayasu arteritis treated with aspirin for previous 6 months. Although she admitted to a nearby hospital found hyperintensities in bilateral occipital to parietal areas on T2-weighted image of brain MRI on day -46, she was not treated there because autoantibodies and cerebrospinal fluid (CSF) analysis were normal. However, the symptoms were getting worse, and thus she admitted to our hospital for further examination.
On admission (day 1), bilateral bruits were audible at supraclavicular fossa, and neurological examinations showed diminished visual acuity and truncal ataxia. Neither papilledema nor inflammatory change in fundi was found. There were no other abnormal neurological findings in motor, sensory or autonomic systems. Serum analyses showed normal white blood cells count (6,740/μL, normal 3,300–8,600/μL) with increased erythrocyte sedimentation rate (ESR, 64 mm/h, 103 mm/2h), and mild elevation of C-reactive protein (0.4 mg/dL, normal 0.00–0.14 mg/dL), immunoglobulin G (IgG, 1,917 mg/dL, normal 861–1,747 mg/dL), and elevation of immunoglobulin A (721.8 mg/dL, normal 93–393 mg/dL) and immunoglobulin E (1,494 IU/mL, normal <170 IU/mL). Serum autoantibody test showed elevation of anti-thyroglobulin antibody (11.1 IU/mL, normal <5.0 IU/mL) and anti-cardiolipin IgG antibody (34 U/mL, normal <9 U/mL), and serum interleukin-6 (IL-6) was greatly elevated (2,680 pg/mL, normal <4.0 pg/mL).
A CSF study showed normal pressure (initial 130 and terminal 50 mmH2O), mildly elevated cell counts (11/μL, monocyte 100%) and protein (100 mg/dL, normal 10–40 mg/dL) with normal glucose level (47 mg/dL) and IL-6 (3.5 pg/mL, normal <4.3 pg/mL). CSF oligoclonal bands were detected.
Whole body computed tomography (CT) revealed aortic stenosis with calcification in descending aorta (Fig. 1A, arrowhead) and CT angiography revealed right subclavian artery stenosis (Fig. 1B, arrowhead). Brain magnetic resonance angiography (MRA) revealed no obvious stenosis (Fig. 1C). Brain MRI showed high intensity lesions in bilateral tegmentum of pons, left cerebellar hemisphere and bilateral occipital to right dominant bilateral parietal areas on fluid-attenuated in version recovery (FLAIR) images (Fig. 1D) without enhancement on Gadolinium (Gd)-enhanced T1-weighted images (Fig. 1E). Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed decreased uptake of the tracer in the above lesions (Fig. 1F, arrowheads) on day 8. Because an autoimmune encephalopathy was suspected at this moment, three cycles of intravenous high-dose methylprednisolone (1000 mg per day, 3days) were started on day11. Although visual loss was sustained, truncal ataxia was gradually improved. She discharged from our hospital on day 46 and transferred to a different hospital for rehabilitation.
However, she later noticed muscle weakness in left upper limb around day 60 and gradually worsen. Thus, she came to our hospital on day 99 again. Serum analyses showed a normal ESR (8 mm/h, 21 mm/2h) and C-reactive protein (0.09 mg/dL), and a mild elevation of IL-6 (4.3 pg/mL). A CSF study showed normal cell counts (1/μL, monocyte 100%), mildly elevated protein (100 mg/dL, normal 10–40 mg/dL) and IL-6 (4.5 pg/mL). Brain MRI showed a new high intensity lesion on FLAIR image (Fig. 1G, arrowhead) with Gd-enhancement appeared in right frontal area (Fig. 1H, arrowhead). 18F-FDG PET revealed a further decreased uptake in the right frontal to parietal lesions (Fig. 1I, arrowheads) on day 105. In order to confirm the diagnosis, brain biopsy was performed from white matter lesions of right frontal and parietal lobe by stereotaxic technique on day 115. Pathological study found a marked gliosis with demyelination and a diffuse accumulation of lymphocytes predominantly around small vessel (Fig. 2). Elastica van Gieson (EVG) stain revealed that there was perivascular space without internal elastic lamina or smooth muscle in the small vessel. Immunohistological examination showed that monocytes were mainly positive for cluster of differentiation 3 (CD3), CD8 and CD68, weakly positive for CD4, and negative for CD20 (Fig. 2), suggesting that cytotoxic T cell and microglia accumulation in the lesions. After the brain biopsy, three cycles of intravenous high-dose methylprednisolone (1000 mg per day, 3days) were started again on day 117, and administration of oral prednisolone (20 mg/day) was started in day 134. With those therapies, weakness in the left limb was gradually improved. On day 127, brain MRI showed high intensity lesions were slightly expanded on FLAIR image (Fig. 1J), whereas frontal enhanced lesion disappeared on Gd-enhanced T1-weighted image (Fig. 1K). Finally, she discharged on day 144.
We described a patient who suffered from Takayasu arteritis, eventually developing gait disturbance and visual loss with high intensity lesions in bilateral pons, left cerebellum and bilateral occipital to parietal areas on FLAIR images (Fig. 1D) and a hypometabolism on 18F-FDG PET (Fig. 1F). Clinically, her visual acuity gradually worsened as the high intensity lesions in bilateral occipital lobe extended to parietal lobe. Neither papilledema nor inflammatory change in fundi was found. Therefore, the indicated visual loss was might be due to inflammation-related damage in the tract to the visual cortex. Her symptoms and brain MRI findings were refractory to initial steroid therapy, but muscle weakness in left upper limb later occurred with new high intensity lesion in right frontal area with Gd-enhancement. The brain biopsy finally demonstrated a marked gliosis and demyelination with cytotoxic helper T cell and microglia accumulation (Fig. 2), and the new brain lesion plus new neurological symptoms improved after the second steroid therapy except for visual loss (Fig. 3).
Takayasu arteritis is primarily a granulomatous large vessel vasculitis, which is characterized by stenosis, occlusion and sometimes aneurysm of the aorta and its main branches1,2). The pathogenesis of Takayasu arteritis is cellular infiltration of CD3 positive, CD8 positive, but not CD4 positive cytotoxic T cell3), macrophages, CD4 positive T cell, CD8 positive T cell, natural killer T cell and γδ T cell4) in aortic tissue. In the present case, the brain biopsy showed the accumulation of mainly CD68 positive microglia, and CD3 and CD8 positive cytotoxic T cell, weakly CD3 and CD4 positive helper T cell (Fig. 2), which happened predominantly around the small vessel. On the other hand, there was no eosinophilic red neurons which indicated acute ischemia in the lesion5). These findings suggested that inflammation of small vessels might reflect T2 high intensity of brain MRI. EVG stain revealed that there was perivascular space without internal elastic lamina or smooth muscle in the small vessel, and the diameter of this artery was about 30 to 100μm, therefore, this small vessel with inflammation was supposed to be a post-capillary venule6), but is pathologically similar to the previous pathological findings in the aortic tissue of the Takayasu arteritis.
IL-6 is a pro-inflammatory cytokine which is mainly synthesized by activated T cells and macrophages, and serum concentration of IL-6 is increased with Takayasu arteritis patients7). In the present case, serum concentration of IL-6 on first admission (day 1) was greatly elevated, however it turned better to almost normal range after three cycles of intravenous high-dose methylprednisolone therapy. Whereas CSF IL-6 level was slightly worsened after initial therapy (Fig. 3), suggesting a sustained intrathecal inflammation. Thus the second intravenous high-dose methylprednisolone therapy and oral prednisolone were effective.
Here we reported the first case of the leukoencephalopathy accompanied by Takayasu arteritis with the pathological characteristic of marked gliosis and demyelination with microglia and cytotoxic T cell accumulation predominantly around the small vessel. Our case suggested an interesting relation of leukoencephalopathy and Takayasu arteritis with microglia and cytotoxic T cell accumulation.
The authors declared no potential conflicts of interest.
We appreciate the patient’s cooperation. This work was partly supported by a Grant-in-Aid for Scientific Research (B) 17H0419611, (C) 15K0931607, 17H0975609, and 17K1082709, and by Grants-in-Aid from the Research Committees (Kaji R, Toba K, and Tsuji S) from the Japan Agency for Medical Research and Development 7211800049, 7211800130, and 7211700121.
