The densest transmural inflammatory infiltrate is typically found between the outer and middle membranes, consisting primarily of CD4 + T cells, macrophages, a small number of B cells, and eosinophils. In a normal artery, three distinct layers are separated by dense elastic fibers from the lumen outward: the inner, middle, and outer membranes. The inner membrane consists mainly of endothelial cells, while the middle membrane primarily consists of vascular smooth muscle cells. The outer membrane contains dense elastin, collagenous connective tissues, and fibroblast-produced vascular dendritic cells. The endothelium is characterized by vascular remodeling, fibrosis, thrombosis, and recanalization [2]. Venous sinus thrombosis usually occurs in the presence of intimal damage.
GCA is a T-cell-mediated disease, with its pathogenesis primarily involving immune cells. There are fewer CD8 + T cells in the outer and middle membranes than CD4 + T cells. Increased CD8 + T cell infiltration is associated with a more severe disease progression and a higher incidence of visual disturbances [3]. CD8 + T cells have been observed in vasculitis lesions in GCA [4]. Upon activation, dendritic cells at the mid-epithelial boundary release cytokines and chemokines, attracting more dendritic cells and activating CD4 + T cells. This activation stimulates the secretion of interferon-γ (IFN-γ) and interleukin-17 by helper cells (Th)-1 and Th-17 cells, respectively; they enable IFN-γ induce chemokine production by vascular smooth muscle cells, facilitate the migration of monocytes and macrophages to the vessel wall, and therefore contribute to sustained inflammatory responses in GCA. In addition, IFN-γ activates macrophages, which can fuse to form multinucleated giant cells, a pathological hallmark of GCA [5]. Vascular infiltrating macrophages continue to produce chemokines, reactive oxygen species, and matrix metalloproteinases between the inner and middle membranes, destroying the vessel wall's elastic membrane. Polymorphonuclear giant cells and macrophages produce platelet-derived growth factor and vascular endothelial growth factor, which activate vascular smooth muscle cells and promote angiogenesis during the progression of GCA [6].
Arteritis has been considered a risk factor for the prognosis of venous sinus thrombosis. Intracranial arteritis increases platelet adhesion and whole blood viscosity, thus enhancing the activation of platelet aggregation and ultimately leading to thrombosis. The meninges contain a significant population of immune cells that form the meningeal immunity responsible for the immune surveillance of the central nervous system (CNS) [7]. Although the dural sinus has long been considered primarily as a conduit for venous blood drainage without involvement in immune regulation, a study using whole tissue sections of adult and aged mice has revealed that PDGFRβ + fibroblasts regulate immune cells in the vicinity of the great vessels, particularly the superior sagittal and transverse sinuses. A recent study by Rustenhoven et al. [8] has demonstrated, for the first time, that CNS-derived antigens accumulate around the dural sinuses and can be captured by antigen-presenting cells (APCs) originating from venous sinus/meningeal lymphatic vessels, which are subsequently presented to T cells, enabling immune surveillance of the CNS. This study also showed that CD3 + T cells and MHCII + APCs were not evenly distributed within the dura mater. Instead, they were highly enriched around the dural sinus. These findings were consistently observed in human dura mater. Therefore, it could be concluded that the dural sinus serves as an immune hub within the CNS [9].
Furthermore, mesenchymal cells, such as mural and endothelial cells, play a synergistic role in regulating the immune surveillance function of the dural sinus. Dural endothelial cells, a subgroup of VWF + cells, lack tight junctions. The dura mater mainly comprises a non-cellular structure characterized by a dense collagen network. The endothelial cells in the dural sinus also lack tight junctions. However, high expression of adhesion molecules, such as Vcam1, Icam1, and Selp, were found in the VWF + venous sinus endothelial cells. These molecules play an important role in immune surveillance by capturing T cells in the venous sinus and facilitating their “extravasation” into the dural sinus [10]. In vivo imaging studies have revealed that T cells exhibit preferential transport through the dural sinus, leading to a high concentration of T cells around the dural sinus. Various chemokines are involved in recruiting T cells and other leukocytes (e.g., B cells and plasma cells) around the dural sinus. These cells are either presented by dural APCs or drained through the adjacent dural lymphatic vessels. These findings further support the idea that the dural sinus is a crucial site for immune-blood-brain interactions where CNS antigens are exposed. APCs capture and present these antigens to circulating T cells, which subsequently become activated for immune surveillance of the CNS [11, 12].
Cerebral venous thrombosis is associated with the development of systemic lupus erythematosus [13], LgA-associated vasculitis [14], and Behcet’s disease [15], but rarely GCA-related [16]. The occurrence of CVST is even more infrequent, accounting for less than 1% of all cases, with an estimated one-year incidence rate of 3–4 cases per one million people. The early identification of CVST is of great importance due to the atypical nature of symptoms [17]. In humans, the primary locations of CVST are the cortical veins and the dural venous sinuses, particularly the superior sagittal sinus [18]. In this patient, both GCA and CVST occurred in this location. Factors that affect the pathogenesis of GCA, such as leukocyte and platelet activation, may contribute to vascular inflammation and increase the risk of thromboembolic events in patients with GCA [19]. Iron deficiency anemia is known to cause hematological disorders [20], and it is more likely to cause cerebral venous thrombosis in men than in women [21]. Low serum ferritin levels may result in elevated plasma concentrations of coagulation factor VIII, thus increasing the risk of thrombosis [22]. In addition, endothelial damage caused by hypertension has been identified as an independent risk factor for thromboembolism [23]. Certain medications, such as diuretics, may exert a thrombogenic effect by increasing blood viscosity through their impact on fibrinogen concentration and clotting time, although the correlation is generally weak [23]. Ventricular tachycardia is another risk factor for venous thrombosis [24]. Vaccination and SARS-CoV-2 infection have also been reported to enhance immunity, mainly through polyclonal or transcriptional activation, antigen amplification, or molecular camouflage [25]. Other common causes of venous thrombosis include pregnancy and puerperium, head and neck infections (mainly in children), severe dehydration, hypercoagulable states (e.g., use of oral contraceptives or exogenous hormones), antiphospholipid antibody syndrome, thrombosis, malignancy, myeloproliferative disorders, and inflammatory bowel disease [26]. The patient presented here had several risk factors, including concomitant thrombocytosis, low ferritin levels, reduced Antithrombin III, lower limb intermuscular vein thrombosis, and infection, all of which significantly increased the risk of CVST.
The symptoms of GCA combined with venous sinus thrombosis include fever, malaise, weight loss, mild normocytic anemia with normal pigmentation, and leukocytosis [19]. CVST patients may also experience headaches, visual abnormalities, seizures, confusion, drowsiness, and ischemic stroke [26]. Some non-specific symptoms overlap between GCA and CVST. The timing of symptom onset is also critical, as GCA typically has a subacute onset, while CVST has a more defined point of onset. Due to the discontinuous distribution of GCA lesions and the delayed effects of glucocorticoid therapy, the rate of positive biopsy results is only 30–44%, suggesting that a negative biopsy cannot exclude GCA. Therefore, Doppler ultrasound of the head, neck, and upper limbs, rather than a temporal artery biopsy, is often used as the initial diagnostic method for GCA. In active arteritis, the presence of a hypoechoic area around the lumen of the affected vessel, known as the halo sign, supports the development of GCA. In GCA patients with impaired consciousness and elevated D-dimer levels, monitoring the development of venous sinus thrombosis is important. Magnetic resonance venography is necessary to identify thrombosis-associated intracranial hypertension and cerebral edema. Active GCA is associated with a more notable decrease in antithrombin compared to inactive GCA, which contributes to the development of coagulation. C-reactive protein levels are elevated in the active phase, and the sedimentation rate is often above 50 mm/hr or even above 100 mm/hr. Moreover, the sedimentation rate is positively correlated with D-dimer levels and inversely correlated with antithrombin levels in the active phase [27]. Laboratory features may also include leukopenia, anemia, polyclonal hyperglobulinemia, increased alpha-2 globulin levels, and mild elevation of alkaline phosphatase.
Treating patients with both GCA and venous sinus thrombosis is a complex task. Even if biopsy and diagnostic tests are negative, patients with a typical clinical presentation of GCA should be treated accordingly to prevent the risk of vision loss. Glucocorticoid therapy should be administered in appropriate doses for 4 to 6 weeks until the symptoms are effectively controlled, and the blood sedimentation rate reaches normal levels. Most patients discontinue glucocorticoid use within 1 to 2 years, but some require long-term low-dose maintenance therapy. Although glucocorticoids have potential side effects of increasing blood viscosity and promoting thrombosis, a recent meta-analysis of observational studies has suggested that combining glucocorticoids with antiplatelet/anticoagulation therapy may protect against severe ischemic complications after a GCA diagnosis without significantly increasing the risk of bleeding [28]. In a population-based cohort study of 364 patients with rheumatic polymyalgia, which was always accompanied by GCA [29], there was no significant increase in the risk of vascular disease in patients treated with glucocorticoids compared to those who received no glucocorticoid treatment. Instead, the data suggested a protective effect of glucocorticoid use in this population. Therefore, our patient was treated with glucocorticoids upon diagnosis of GCA combined with CVST. Following treatment, he had no fever, clear consciousness, significantly improved coagulation, and notably reduced levels of D-Dimer and fibrinogen degradation products. The efficacy of combined glucocorticoid treatment was superior to anticoagulation and antiplatelet therapy alone.
Granulocyte-macrophage colony-stimulating factor, produced by various types of cells in GCA-affected arteries, such as macrophages, T cells, myofibroblasts, and endothelial cells, has recently emerged as a promising therapeutic target for GCA. Ex vivo treatment of GCA arteries cultured with the anti-GM-CSF receptor antagonist mavrilimumab has alleviated vascular inflammation by reducing T cell and macrophage infiltration and neoangiogenesis [30]. Anticoagulation has long been the mainstay treatment for CVST as it prevents thrombotic spread and venous infarction. However, venous infarctions are susceptible to hemorrhagic transformation. In a randomized controlled trial conducted in patients with CVST [31], those who received intravenous heparin treatment showed a significant improvement in recovery rates (80% vs. 10%, P < 0.01) and a reduction in residual defects (20% vs. 60%, P < 0.01) in comparison to the placebo group.
Furthermore, a retrospective analysis [32] demonstrated that heparin treatment decreased the mortality rate of CVST patients with hemorrhagic venous infarction (15% vs. 69% in the placebo group). International guidelines recommend heparin as first-line treatment for CVST in the presence and absence of hemorrhagic venous infarctions. In addition, acute anticoagulation should be administered to most patients with CVST, even those with a hemorrhagic infarction [32]. Mechanical and/or pharmacological thrombolysis can be considered in patients with thrombotic spread or deteriorating clinical status [26]. In our case, the patient was admitted in a conscious state. Although no active thrombosis was detected, elevated levels of D-dimer and fibrinogen degradation products indicated the presence of hyperfibrinolysis and thrombosis. Therefore, early prophylactic anticoagulant therapy was administered.
In conclusion, the coexistence of GCA and CVST is not solely attributed to increased blood viscosity, vascular wall inflammation, and abnormal coagulation; a complex immunological network is involved. Early identification and personalized intervention for GCA patients combined with CVST are crucial.