Tắc động mạch cảnh nội tiến triển trong bệnh liên quan IgG4: Báo cáo ca bệnh và tổng quan tài liệu

Abstract

Immunoglobulin G4–related disease (IgG4-RD) is a systemic fibroinflammatory disorder capable of multiorgan involvement, though its association with cerebral vasculitis and large-vessel occlusion remains rare and poorly characterized. We report a novel case of cryptogenic ischemic stroke secondary to progressive internal carotid artery (ICA) stenosis and occlusion, ultimately attributed to IgG4-RD. The patient exhibited multifocal hypermetabolic lesions on positron emission tomography–computed tomography, correlating with arterial wall thickening and subsequent pathologic confirmation of IgG4-positive plasma cell infiltration. This case highlights IgG4-RD as an underrecognized cause of progressive ICA stenosis and occlusion, offering critical insights into the diagnostic work-up of cryptogenic stroke and expanding the spectrum of vascular manifestations in IgG4-RD.

Background

Immunoglobulin G4–related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by immune-mediated infiltration of IgG4-positive plasma cells, leading to tumefacien lesions and fibrosis across multiple organs. The clinical presentation of IgG4-RD is highly heterogeneous. Within the central nervous system, IgG4-RD involvement has been documented in cases of hypophysitis 1, pachymeningitis 2, and inflammatory pseudotumor of the trigeminal nerve 3. However, reports of IgG4-RD–associated cerebral vasculitis are scarce. Here, we describe a novel case of cryptogenic cerebral infarction secondary to progressive internal carotid artery (ICA) stenosis and occlusion, ultimately attributed to IgG4-RD. This presentation expands the recognized phenotypic spectrum of IgG4-RD, highlighting its potential role in unexplained large-vessel vasculopathy.

Case Report

A 56-year-old man presented to our department with a 3-month history of left upper limb numbness and weakness. Initial brain magnetic resonance imaging (MRI) revealed acute microinfarcts in the bilateral parietal and occipital lobes (Figure 1, A1–4), whereas MR angiography showed no significant abnormalities. Cervical ultrasound demonstrated plaque in the left carotid artery, with normal vertebral artery flow bilaterally. Based on an initial diagnosis of cerebral infarction, antithrombotic therapy was initiated. Neurologic examination identified left peripheral facial palsy, left upper limb weakness (House–Brackmann grade V) and superficial sensation, and bilateral positive pathologic signs. Subsequent brain and neck computed tomography angiography revealed a noncalcified atherosclerotic plaque at the origin of the right ICA, causing mild luminal stenosis (Figure 1, C). During the disease course, the patient developed cortical myoclonus. Levetiracetam provided limited benefit, but symptoms were controlled after adding perampanel, 4 mg nightly.

The patient had a 1-week history of newly diagnosed hypertension, now well controlled with medication. He did not report history of smoking, hyperlipidemia, or diabetes. Cardiac examination was unremarkable. He lacked traditional risk factors for severe ICA stenosis and presented with a minor arterial ischemic stroke. Cerebral spinal fluid analysis ruled out central nervous system infection and demyelination. To exclude intravascular lymphoma, he had whole-body ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT), which revealed enlargement and increased glucose uptake at the base of the tongue and bilateral tonsils; increased uptake along the bilateral nasopharyngeal walls; and multiple enlarged lymph nodes in both sides of the neck (Figure 1, E1-4). Following ear, nose and throat department consultation, flexible laryngoscopy revealed rhinitis, nasopharyngeal lymphoid hyperplasia, pharyngitis, and tonsillar hypertrophy. Concurrently, core needle biopsies were obtained from the bilateral tonsils and base of the tongue. Histologic sections revealed preservation of the tonsillar architecture, hyperplasia of lymphoid tissue within the mucosa, formation of lymphoid follicles with expanded reactive germinal centers, prominent lymphoplasmacytic infiltration in the interfollicular areas, and significant fibrous tissue hyperplasia. Plasma cells were mature without sign of atypia. Immunohistochemical analysis confirmed greater than 40% of IgG+ plasma cells being IgG4+ and greater than 10 cells/high-powered field of biopsy sample. The immunohistochemical results are as follows: Lymphoid follicles: CD20(+), CD19(+), CD79a(+), IgD (mantle zone +). Interfollicular area: CD3(+), CD5(+), Ki67 (5%). Germinal centers: CD10(+), BCL-2–, BCL-6(+), Ki67 (90%). Follicular dendritic cell network: CD21(+). Plasma cells: MUM-1(+), CD30 (scattered +), CD38(+), Kappa-Lambda (partially +, no light chain restriction indicated), IgG(+), IgG4(+). Others: S-100 (scattered, few +), MNDA (scattered +), AE1/AE3 (epithelial +), CD68 (histiocytes +), PD-1 (helper T cells +), CyclinD1–, EBER–. The immunophenotype described above can rule out diseases that are histologically similar to IgG4-related disease (Figure 2). Laboratory investigations were unremarkable apart from a markedly elevated serum IgG4 level (2050 mg/dL). These findings fulfilled the diagnostic criteria for IgG4-RD.

The patient’s neurologic status deteriorated, with left upper limb flaccid paralysis, delayed responsiveness, and dysarthria. Repeat brain MRI showed new scattered acute-subacute infarcts in bilateral cerebral lobes (Figure 1, B1–4), and CTA revealed severe right ICA stenosis at C1 (Figure 1, D). Treatment with intravenous immunoglobulin, methylprednisolone, and leflunomide improved symptoms and lowered serum IgG4 to 1890 mg/dL. Entecavir was given for hepatitis B virus. Following discharge, prednisone and rehabilitation continued; after influenza resolved, the patient received mycophenolate mofetil. At 2-month follow-up, partial functional recovery was noted and IgG4 declined to 620 mg/dL.

Discussion

A systematic review identified 10 reported cases of IgG4-RD involving intracranial arteries 1–9. Including the present case, a total of 11 cases have been documented (Table 1). The cohort demonstrated a marked male predominance (72%), with a mean age of 63 years. Acute cerebral ischemia was the most common clinical manifestation (55%), whereas intracranial hemorrhage was rare (9%). Presenting symptoms were primarily focal, with speech disturbance (45%) and limb numbness or weakness (36%) occurring most frequently. Other reported symptoms included impaired consciousness (27%), headache (18%), localized pain (18%), organ enlargement or edema (18%), diplopia (9%), and cognitive impairment (9%). Elevated serum IgG4 levels, a hallmark of the disease, were noted in 82% of patients, with a mean concentration of 1612 mg/dL.

According to the 2020 Revised Comprehensive Diagnostic (RCD) Criteria for IgG4-RD.

Histopathologic evaluation was available for 9 cases. All exhibited characteristic plasmacytic infiltration. However, only 1 case fulfilled all 3 major histologic criteria for IgG4-RD, whereas 7 (78%) met 2 criteria. Radiologically, arterial stenosis was the predominant finding (55%), followed by vessel wall thickening or dilation (36%) and aneurysm formation (27%). The ICA was the most frequently involved vessel (∼45%), followed by the middle cerebral and vertebral arteries (27% each). Management strategies varied. Corticosteroid therapy, employed in 6 patients (55%), was uniformly associated with a favorable clinical response. One patient treated with a combination of glucocorticoids and intravenous immunoglobulin achieved both clinical remission and serologic normalization. Rituximab was used successfully in 1 case. Surgical interventions, performed in 4 patients, yielded mixed outcomes, ranging from mortality to marked improvement. Conservative management alone was ineffective in the 2 cases in which it was applied.

Immunoglobulin G4–related disease is a systemic fibroinflammatory condition (10). While neurologic involvement such as hypophysitis (11) or pachymeningitis (12) is recognized, isolated involvement of major intracranial arteries such as the ICA is exceptionally rare. Our patient’s presentation with progressive cerebral infarction, refractory to standard antiplatelet and statin therapy, prompted an investigation for an alternate cause. The absence of an embolic source led to a systemic work-up. Whole-body ¹⁸F-FDG PET/CT was pivotal, revealing multifocal hypermetabolism in the Waldeyer ring and cervical lymph nodes. Histopathologic analysis of biopsied tonsillar and tongue base tissue confirmed a dense lymphoplasmacytic infiltrate with a significant IgG4-positive plasma cell component. This tissue diagnosis, combined with markedly elevated serum IgG4 levels, satisfied the 2020 Revised Comprehensive Diagnostic Criteria for IgG4-RD (13). The subsequent clinical and serologic improvement following immunotherapy with intravenous immunoglobulin and glucocorticoids provides compelling evidence that the ICA pathology was a direct manifestation of systemic IgG4-RD.

This case highlights several critical clinical implications. First, it underscores that IgG4-RD should be included in the differential diagnosis of cryptogenic stroke, particularly when associated with unusual or progressive intracranial vasculopathy. Second, advanced vascular imaging, specifically MR vessel wall imaging, can be a valuable noninvasive tool to help differentiate the concentric 9, enhancing wall thickening typical of inflammatory vasculitis from atherosclerotic plaque. Finally, the management course illustrates the complexity of treating IgG4-RD in patients with comorbid conditions. Although early immunosuppression is crucial for improving prognosis, our patient’s concurrent chronic hepatitis B virus infection and acute influenza A necessitated a deliberate, staged therapeutic approach. The initiation of more potent immunosuppressants such as rituximab was deferred, and maintenance therapy with mycophenolate mofetil was administered only after resolution of the acute infection and stabilization of hepatitis B with antiviral therapy. This emphasizes the imperative for highly individualized treatment strategies in the management of complex IgG4-RD.