Cerebral Venous Sinus Thrombosis: Current Updates in the Asian Context

Cerebral venous sinus thrombosis (CVT), though rare, remains a significant cause of stroke in the young. As CVT has various clinical and radiological manifestations, clinicians may often miss the diagnosis. Population-based epidemiological studies on CVT from Asian countries are scarce, and most of our information is from hospital-based registries. This review paper is focused on the epidemiological risk factors, genetics, and the prevalent treatment strategies in comparison in Asia over the past 2 decades.

The epidemiology of CVT has evolved over the years. Although CVT contributes to less than 0.5–1% of all strokes [1], it has significant morbidity and mortality. With advances in neuroimaging and a higher index of clinical suspicion, CVT is commonly diagnosed and has become a treatable disease with improved outcomes. Among strokes in young, CVT contributes to 10–20% of cases [2]. Worldwide, the annual incidence of CVT varies across geographical regions. The incidence is 12.1 cases per million based on systematic reviews and metanalysis [3]. There are no reliable data on racial or geographical distribution, but evidence from South Asia reports a higher incidence of CVT than in the Western world. Most of the CVT studies and registries are from the USA and Europe.

South Asia is considered to have a high prevalence of CVT. Prior Asian cohorts have shown that CVT contributes up to 50% of all young strokes and 40% of young strokes in women [4]. In an extensive registry of CVT from South India, Vellore, the incidence was 96 per 100,000 cases [5]. There is female preponderance noted across all age groups in CVT, and the majority of cases are noted during the peripartum or postpartum period or among patients on oral contraceptive pills across global cohorts. In Asian countries, 36% of all CVTs are due to pregnancy and puerperium, and 5% are related to oral contraceptive use [6]. Young age group, high frequency of anemia, and higher frequency of hypercoagulable states are noted in Asian CVTs compared to Western [7].

CVT is an essential cause of stroke in the postpartum period in Asia. The first epidemiological study of hemiplegia due to stroke in South India by Abraham et al. [8] showed that the majority of strokes in young women occurred in the puerperal period. In a nationwide study on strokes associated with pregnancy and puerperium from Japan, CVT contributed to 24.3% [9]. A study from Taiwan on cerebrovascular disorders complicating pregnancy and puerperium has identified CVT contributing to 27% of the reported strokes [10]. Fluid restriction during the puerperal period is a typical traditional practice in South India. This was identified as an essential risk factor for CVT, specifically in the postpartum period [11, 12]. However, with improving awareness and maternal care, there seems to be a significant reduction in puerperal CVT in many Asian countries. In the Asian Study of Cerebral Venous Thrombosis, which included patients from 9 Asian countries, 18% were associated with pregnancy [7]. An analysis of 1701 CVT cases from the Vellore CVT registry showed a declining incidence of postpartum CVT after 2010 compared with the decade before 2010 (50% vs. 20%) [5]. Anemia has been identified as an essential risk factor for CVT in Asian countries compared to the Western CVT studies [7, 13]. Compared to the ISCVT study, Asian CVT patients were younger, anemia was more common, oral contraceptive pills (OCP) use as a predisposing factor for CVT was much less, and the overall outcome was better [7]. Certain inflammatory disorders are more prevalent in some Asian countries, which can be a risk factor for CVT. Behcet’s disease is more common in those countries along the historic Silk Road, which connects the countries around the Mediterranean Sea and Middle Eastern region to the Far East [14]. In a Saudi Arabian study, Behçet’s disease was the cause of CVT in up to 25% of patients [15]. Similarly, Behçet’s disease contributed up to 10% of the CVT cohort from Kuwait [16].

India and many countries in the Arabian Peninsula have a high prevalence of sickle cell disease. Sickle cell disease has a multitude of neurological manifestations, including thrombosis of the venous system [17]. CVT as a complication of sickle cell disease has been reported in many Asian countries [18, 19]. Infections are also a predisposing cause for CVT in Asia. In recent years, CVT has been reported as a complication of severe scrub typhus caused by Orientia tsutsugamushi in Southeast Asian countries [20‒22]. Tropical infections such as dengue are also a significant risk factor for the development of CVT. Cerebral malaria is a severe complication caused due to Plasmodium falciparum infection; however, Plasmodium vivax is also implicated in severe malaria. The pathogenesis of occurrence in CVT in cerebral malaria appears to be an alteration of phospholipids, resulting in a hypercoagulable state [23]. Melioidosis is an infection caused by the soil-dwelling Gram-negative organism Burkholderia pseudomallei, which is endemic in Southeast Asia. Bahuleyan et al. [24] reported a concomitant occurrence of CVT in cranial melioidosis. Despite Asia having a high burden of tuberculous meningitis, CVT as a complication is seldom reported [25]. Climate and environmental factors are risk factors in CVT. Published reports from India and Iran show an increase in the incidence of CVT cases during the hot summer months [26, 27]. A time-series analysis showed this trend was consistent across 18 years.

Evidence from the Middle Eastern countries like Iran and Saudi Arabia has indicated that observing fasting during Ramadan causes CVT secondary to dehydration [28, 29]. This is more common in women who are on OCPs during the Ramadan month, which are usually taken to postpone their periods to fulfill religious commitments. Vegetarian diet or diet with less meat intake might predispose to B12 deficiency and further cause acquired hyper-homocysteinemia and venous thrombosis [30]. The risk factors are summarized in Table 1.

Despite recognizing a wide variety of predisposing risk factors for CVT, up to 15% of cases have no identified risk factors, suggesting that undetermined genetic factors may be at least partly responsible. However, reasonable evidence supports genetic susceptibility, with genetic factors accounting for around 20–30% of CVT cases. While factor V Leiden and prothrombin mutations are the most reported genetic abnormalities among Caucasians, deficiencies of natural anticoagulants such as AT III and proteins C and S have higher implications in the Asian populations.

The Leiden mutation is a single-point mutation in exon 10 of the factor V gene, resulting in a molecular change, making it resistant to activated protein C [31]. It is reported to be present in around 5% of the white population; however, it is absent among the indigenous Asian, African, American, and Australian populations [32]. This mutation is known to confer an increased risk for CVT in the Western population, with a prevalence of around 10–25% [33]. Contrarily, this polymorphism was not detected in the Chinese Han population with thrombosis [34]. Similarly, despite a reported prevalence of 0–10% in India in the average population, a large study with 172 peripartum women [35] established no association between this polymorphism and increased risk of CVT. On the other hand, another study from North India with 69 CVT [36] patients reported a significant association with this mutation, possibly reflecting the genetic heterogeneity in the country.

Prothrombin G20210 mutation is the second most commonly reported genetic polymorphism, where the G to A transition occurs in the 3′ untranslated region at 20210 nucleotide position. In Europe, the prevalence in the general population is reported between 0.7% and 4% [37]. However, studies assessing CVT with the mutation have reported significant association and higher frequencies varying from 0 to 50%. On the other hand, this polymorphism is almost nonexistent in Africa and Asia. Similarly, South and North China studies have reported a very low prevalence [38] of factor V Leiden and prothrombin G20210A mutations in their population. Multiple studies from India also report a lack of detection of this genetic polymorphism in CVT patients and normal controls [35, 39, 40]. To date, the only reported case of prothrombin G20210A variant from India was identified in 1 person in an anthropological survey sample of 158 individuals [41]. However, contrary to previous studies, more recently, a study comparing different ethnic groups between North and South India was able to demonstrate the significantly higher prevalence of the heterozygous allele of G20210A in the North Indian cohort manifesting with increased risk for thrombosis [42]. The authors alluded to the heterogeneity in the country’s genetic makeup for this variation.

Homozygous MTFHR 677T, especially in folate deficiency, is associated with hyper-homocysteinemia. Around 12% of Caucasians [43] are known to carry the 677TT genotype with increased homocysteine levels compared to those with the 677CC genotype. Contrastingly, Indian Asians were noted to have a lower frequency of this polymorphism (3.1% vs. 9.7%) [44] compared to European whites, with no contribution toward hyper-homocysteinemia from the MTFHR 677T allele. Indian studies have reported a lower prevalence [35, 45]of the homozygous genotype than the heterozygous variant. This is similar to reports from southern China, which document a 3% prevalence [38] of homozygous MTFHR 677TT and a 7% prevalence of carrier 677T.

Deficiencies of naturally occurring anticoagulants, such as proteins C and S, as well as AT III, can contribute to thrombosis and are seen to be more common in the Thai and Asian populations. A study from Western India [39] noted the highest prevalence of deficiency of protein C (9.9%), followed by protein S (6.8%), and the lowest for AT III (2.6%) in their cohort. In contrast, a Thai study [46] reported a prevalence of 3.7% compared to 2% in Caucasians. Antithrombin is a serine protease inhibitor and functions as an anticoagulant by inhibiting thrombin. AT deficiency is an autosomal dominant disorder and is one of the rare conditions that cause CVT. Type I deficiency with low levels of AT activity and AT antigen has a higher predisposition for thrombotic episodes than type II, with low levels of AT activity but regular AT antigen. We found a report from a Taiwanese family with AT-I type [47] deficiency presenting with CVT in our review.

A relatively new gene variant is the C-T substitution in the 5′ untranslated region of the F12 gene, resulting in reduced FXII levels. In 2008, Reuner et al. [48] suggested an association of this polymorphism with venous thrombosis, which was later replicated in a small Spanish study [49]. Though only a few studies from Asia have studied this variant, a study from South India demonstrated a 2.9-fold increase in CVT risk among women with the F12 46TT genotype [50], with an 8-fold increase in risk when combined with the use of oral contraceptives.

Another less studied genetic risk is the PAI-1 4G/4G [51] genotype, which has been associated with an almost 7-fold risk of thrombosis in veins of internal organs. While no correlation has been established with the risk of CVT, evidence suggests that in the presence of other inherited thrombophilia, the 4G/4G genotype may confer additional risk for CVT [51].

Since identifying the V617F mutation in the JAK2 protein as a marker of Philadelphia adverse chronic myeloproliferative disorders, it has been extensively studied in relation to the risk of thrombosis; however, its association with CVT is unclear. A few studies that have assessed this association have reported a prevalence ranging from 0% to 6.3%. In Italy, a 6.3% prevalence of JAK2V617F mutation has been reported among CVT patients without MPD; in France, this was noted to be 1.1%. A study conducted among Asian Indians demonstrated a 5.9% prevalence of this mutation among CVT patients, with a 5.47-fold increase [52] in conferred risk, independent of other variables. The importance of the presence of this mutation in a healthy population still needs to be determined, thereby leaving the question of systematic screening for the same inconclusive.

Patients with CVT are treated in the initial phase with systemic anticoagulation and continued on maintenance therapy with oral anticoagulants. The usual practice is to give vitamin K antagonists for a period of 6 months to 1 year or longer if there is an underlying prothrombotic risk factor or recurrence of CVT. The RE-SPECT CVT trial (which included many centers from India) showed that dabigatran at a dose of 150 mg twice daily is as safe and efficacious as the traditional vitamin K antagonists [53]. However, due to the high cost of the NOACS, many clinicians in developing countries prefer the traditional vitamin K antagonist [54].

Supportive management includes adequate hydration; most patients recover rapidly after initiation of hydration in terms of reduction of headache and improvement in sensorium. There are no large studies or RCT supporting the use of prophylactic antiepileptic drugs [55]. Risk factors for early seizures include presence of hemorrhagic venous infarctions and cortical vein thrombosis [56]. There are no Asian studies that delineate the duration of antiepileptic drugs; however, most consensus guidelines indicate treatment up to 3–6 months and gradual withdrawal as tolerated [57]. The incidence of scar epilepsy in the context of CVT is unknown. Anti-edema measures are mandatory, with preferred choices being hypertonic saline and acetazolamide.

Endovascular treatment in the context of CVT includes mechanical thrombectomy or intrasinus thrombolysis (IST) [58]. Most centers use mechanical thrombectomy or IST as a last resort; however, the recommended practice would be to select candidates if they have rapid clinical deterioration despite anticoagulation, persistent coma, deep CVT, and posterior fossa involvement [59‒61]. Various devices are used for endovascular treatment, such as aspiration catheters, stent retrievers, or Fogarty catheters with balloon angioplasty. AngioJet^™ device is favored in the West as it macerates and aspirates the clot using its hydrodynamic thrombolytic properties. Among patients who deteriorate despite the best medical management, the Fogarty balloon angioplasty and thrombectomy using a Terumo catheter with IST have offered good outcomes [58, 62] (Fig. 1). The TO-ACT trial failed to demonstrate the superiority of endovascular therapy in addition to medical therapy compared to medical therapy alone [63]. Well-powered trials with good patient selection criteria are the need of the hour to demonstrate if there is benefit.

In patients with large hemispheric venous infarcts, surgical decompression may be needed as an effective life-saving treatment that is associated with favorable outcomes. Most evidence of the benefits of decompressive surgery in CVT has been from Asian countries [64‒66]. The DECOMPRESS 2 study is an international prospective cohort assessing the long-term outcomes of patients with CVT treated by decompressive neurosurgery. The majority of the recruited patients were from India [67]. This study showed that the outcome of decompression in CVT patients was better when compared with those patients who underwent surgery for malignant middle cerebral artery infarcts.

Improved clinical outcomes have been noted in the past decade. About 80–90% show favorable outcomes with treatment (mRS 1–3 at 6 months) [68, 69]. Asian cohorts have shown 87% good functional outcome (mRS <3 at 90 days follow-up) [7]. Untreated CVT reported mortality up to 13.8–48%. Seizures at onset and hemorrhagic transformation of infarcts are noted to have an increased risk of mortality. Poor prognosis is seen in CVT patients with active malignancy, coma at presentation, higher NIHSS score, substance abuse, and deep venous CVT. Motor weakness at presentation GCS of 9 or less and mental status disorder are predictors for long-term morbidity [7]. In-hospital mortality predictors in CVT patients are brain herniation, cerebral edema, sepsis, and cardiac issues. Long-term complications include seizures, recurrent CVT and benign intracranial hypertension, and dural A-V fistula in the setting of chronic CVT. CVT in the postpartum setting is not a contraindication for future pregnancies; however, they might require prophylaxis during subsequent pregnancies [70].

CVT is a significant cause of strokes in the young Asian population. The majority of the risk factors are modifiable. Early recognition of CVT has improved outcomes. Medical management is the cornerstone of the management, with endovascular therapy and decompressive hemicraniectomy having significant benefits in select candidates. More studies focusing on the Asian population regarding genetic factors, natural history, and management are warranted to improve diagnosis and management [71].

The authors have no conflicts of interest to declare.

There is no specific funding obtained.

A.M.T., D.B., I.S., and S.S.: conceptualization, data curation, methodology, resources, and writing – original draft. S.A. and J.D.P.: conceptualization, data curation, methodology, resources, supervision, and writing – review and editing.