European Journal of Cardiovascular Medicine

Cerebral venous sinus thrombosis (CVST) is a rare neurovascular disorder characterized by thrombosis in cerebral veins or dural sinuses, primarily affecting young individuals and accounting for 0.5% to 1% of all strokes^1,2. First described by Ribes in 1825, CVST results from impaired venous drainage, leading to increased intracranial pressure and variable clinical presentations including headaches, seizures, and focal neurological deficits.³ Multiple risk factors contribute to CVST, including genetic and acquired prothrombotic states, infections, cancer, pregnancy, and oral contraceptive use. Notably, geographical variations influence its clinical manifestations, with differences observed between Western and Asian populations⁴. Early diagnosis using neuroimaging is crucial, as timely treatment significantly reduces morbidity and mortality. Hyperhomocysteinemia (HHcy), defined as elevated plasma homocysteine levels above 15 µmol/L, is an important independent risk factor for CVST, reported in 27–43% of patients. Homocysteine metabolism depends on vitamins B6, B12, and folate, and deficiencies in these cofactors can lead to HHcy. Elevated homocysteine promotes thrombosis via endothelial injury, platelet activation, and impaired anticoagulant pathways. In India, widespread vegetarianism contributes to a high prevalence of vitamin B12 deficiency, potentially leading to HHcy and increased thrombotic risk⁵. Studies show inconsistent associations between homocysteine, vitamin B12, and folate levels in CVST, highlighting the need for further research, especially in northern India. Dyslipidemia may also influence thrombotic risk in CVST. Elevated triglycerides and LDL cholesterol, along with low HDL cholesterol, can promote a prothrombotic state by affecting hemostasis, platelet function, and fibrinolysis. Some studies link abnormal lipid profiles with increased homocysteine, while others find no clear association⁶. Supplementation with vitamins B6, B12, and folate has shown protective effects by lowering homocysteine levels and reducing stroke risk. Despite epidemiological evidence supporting the role of HHcy and vitamin deficiencies in CVST, mechanisms remain poorly understood, particularly in Indian populations. This study aims to investigate the relationship between homocysteine, lipid profile, vitamin B12, and folic acid in CVST patients at a tertiary care center to better understand modifiable risk factors and development of preventive strategies.

AIM

A study of the ―Biomarkers and their correlation with Cerebral venous sinus thrombosis at Tertiary care center.

This prospective, observational hospital-based study was conducted at the Department of General Medicine, Mahatma Gandhi Medical College and Hospital (MGMC\&H), Jaipur. The study spanned 18 months, commencing from the date of approval by the Institutional Ethical Committee (IEC) of MGMC\&H. It included patients under the age of 40 years who presented with clinical or radiological evidence of cerebral venous sinus thrombosis (CVST) and who provided written informed consent to participate. Patients with infections or sepsis, as well as those with postpartum vasculitis, were excluded from the study to eliminate confounding factors that could affect the clinical assessment and outcomes.

Table 1: Age and gender-wise distribution of CVST patients

The study cohort of 50 individuals showed equal gender representation, with the 26–30 age group being most affected (females 13, males 10), and variations across age strata suggesting that while CVST typically shows female preponderance, gender ratios can differ by age group.

Table 2:Association Between Gender and Presence of Headache, Seizure and Visual Impairment in CVST Patients

In this CVST cohort, headache was more common in males (64%) than females (48%), seizures were more frequent in females (44% vs. 28%), and visual impairment occurred slightly more in males (32% vs. 20%), indicating potential gender-based differences in symptom presentation that merit further investigation.

Table 3: Mean serum homocysteine and vitamin B12 levels in CVST patients

In this CVST cohort, mildly elevated mean homocysteine levels (16.84 µmol/L) and low-normal vitamin B12 levels (243.90 pg/mL) suggest a possible link between subclinical B12 deficiency and hyperhomocysteinemia, supporting their role in CVST pathogenesis, especially in predominantly vegetarian populations.

Table 4: Association between folic acid status and serum homocysteine levels in CVST patients

A significant inverse association between folic acid and homocysteine levels (χ² = 0.019) highlights folate deficiency as a modifiable risk factor for hyperhomocysteinemia and potentially CVST, underscoring the importance of nutritional screening and supplementation in at-risk groups.

Table 5: Association Between Vitamin B12 Status and Serum Homocysteine Levels and Lipid Profile Status and Serum Homocysteine Levels

Statistically significant associations of elevated homocysteine with both vitamin B12 deficiency (χ² = 0.023) and deranged lipid profiles (χ² = 0.047) in CVST patients highlight the role of impaired B12-dependent metabolism and dyslipidemia in thrombotic risk, emphasizing the need for targeted nutritional and lipid screening.

Table 6:Association Between Vitamin B12 Status and Homocysteine Levels

Patients with vitamin B12 deficiency had significantly higher mean homocysteine levels (p = 0.012), reinforcing the inverse relationship between B12 status and homocysteine and highlighting the importance of B12 evaluation in suspected CVST cases.

Table 7:Mean Lipid Profile Parameters in CVST Patients

 Despite normal total cholesterol, CVST patients exhibited a prothrombotic lipid pattern with elevated triglycerides and VLDL, borderline-high LDL, and low HDL, underscoring the role of specific lipid fractions in contributing to thrombotic risk.

Table 8: Pearson correlation between serum folic acid and lipid parameters

Pearson correlation analysis showed a significant positive correlation between folic acid and HDL, a strong inverse relationship between LDL and VLDL, and perfect collinearity between triglycerides and VLDL, highlighting complex interplays among lipid fractions and nutrient levels in CVST patients.

Table 9:Correlation of Serum Homocysteine with Vitamin B12, Folic Acid, and Lipid Profile

Pearson correlation analysis revealed a significant inverse relationship between vitamin B12 and homocysteine, protective association with HDL, and positive correlations with total cholesterol, LDL, and triglycerides, suggesting that dyslipidemia and low B12 may contribute to elevated homocysteine levels in CVST patients.

Table 10: Correlation of serum homocysteine with lipid profile and folic acid levels

Spearman correlation analysis showed significant positive correlations of homocysteine with LDL and total cholesterol, a weak inverse correlation with triglycerides, and no significant link with VLDL or folic acid, suggesting a complex interplay between lipid metabolism and homocysteine levels in CVST.

Table 11: Impact of Lifestyle and Nutritional Factors on Serum Homocysteine Levels

Mann–Whitney U test revealed that alcohol use and nutritional deficiencies were significantly associated with higher homocysteine levels, while smoking showed no significant effect, highlighting the impact of modifiable lifestyle and nutritional factors on thrombotic risk in CVST

In the present study, hyperhomocysteinemia was observed in 52% of patients diagnosed with cerebral venous sinus thrombosis (CVST), with a mean serum homocysteine level of 16.84 ± 8.31 µmol/L. These findings align closely with previous literature demonstrating a strong association between elevated plasma homocysteine levels and increased risk of CVST. For instance, Kalita et al. [17] reported that 52.1% of CVST patients had hyperhomocysteinemia, with additional associations to MTHFR mutation and low vitamin B12. This result mirrors our findings, where elevated homocysteine was statistically linked with lower B12 and folic acid levels.

The present study demonstrates a statistically significant inverse relationship between serum homocysteine and vitamin B12 levels in patients with cerebral venous sinus thrombosis (CVST). Among those with B12 deficiency (<200 pg/mL), 81% exhibited elevated homocysteine levels, compared to just 31% of those with normal B12 levels. Additionally, patients with folic acid deficiency (<4 ng/mL) universally demonstrated elevated homocysteine, underscoring the essential role these vitamins play in homocysteine metabolism. Our findings are consistent with those of Kalita et al. ⁷ who reported that CVST patients with hyperhomocysteinemia were significantly more likely to have low serum vitamin B12 and folic acid levels, as well as MTHFR C677T polymorphism.

Our findings also show a significant difference in mean homocysteine levels between B12-deficient and sufficient groups (18.1 ± 4.5 vs. 14.6 ± 3.9 µmol/L, p = 0.012), reinforcing the biochemical connection. Although B12 deficiency did not show statistically significant correlation with clinical outcomes like seizure or altered sensorium in this cohort, trends suggest it may contribute to more severe neurological presentations, consistent with the observations by Baby et al. ⁸ .

Our study revealed significant alterations in the lipid profile of patients diagnosed with cerebral venous sinus thrombosis (CVST). While the mean total cholesterol (174.86 ± 34.18 mg/dL), the triglyceride (157.25 ± 34.10 mg/dL) and VLDL (31.45 ± 6.82 mg/dL) levels were elevated. Furthermore, HDL levels averaged 45.14 ± 10.64 mg/dL—just at the lower protective threshold—suggesting a lipid pattern potentially conducive to a prothrombotic state.

More importantly, our results demonstrated a statistically significant association between deranged lipid profiles and elevated serum homocysteine levels (χ² = 0.047). Among patients with lipid abnormalities, 85% exhibited hyperhomocysteinemia compared to only 20% in those with normal lipid values. This strong association implies that lipid dysregulation may amplify the thrombotic risk posed by hyperhomocysteinemia.

These findings correspond with the study by Doggen et al. ⁹, who analyzed serum lipid levels in postmenopausal women with venous thrombosis. They found no association with total cholesterol but reported a significant inverse relationship between HDL levels and thrombosis risk. In addition, triglyceride levels >1.05 mmol/L were associated with a doubling of venous thrombosis risk. The present study similarly identified low HDL and elevated triglycerides as more prominent abnormalities than changes in total cholesterol, reinforcing the concept that specific lipid fractions, rather than overall cholesterol, are more predictive of thrombotic events.

The positive correlation observed in our cohort between homocysteine and both LDL (r = 0.334, p = 0.018) and triglycerides (r = 0.347, p = 0.015), alongside a negative correlation with HDL (r = –0.294, p = 0.035), supports a mechanistic interplay. Elevated LDL and triglycerides may promote oxidative stress and endothelial dysfunction, which in concert with hyperhomocysteinemia, facilitate thrombogenesis. This view is further supported by Meshram et al. ¹¹ who emphasized that elevated homocysteine and vitamin B12 deficiency, along with metabolic factors, were primary modifiable risks in their cohort of CVST patients.

In our study of 50 cerebral venous sinus thrombosis (CVST) patients, the most commonly reported clinical symptoms included headache (56%), seizures (36%) and visual impairment (26%). These findings are in line with established literature emphasizing the variable and often non-specific clinical presentation of CVST, necessitating a high index of suspicion for timely diagnosis.

Interestingly, our data also revealed gender-based variations in symptom presentation. Headache was more commonly reported in males (64%) compared to females (48%). Conversely, seizures were more prevalent in females (44%) than males (28%). Altered sensorium also had a slightly higher occurrence in females (44%) compared to males (36%). While these differences did not reach statistical significance, they reflect important clinical patterns that may aid in early recognition of CVST. The prominence of headache as a presenting symptom is well-documented, and our finding that it occurred in over half of the patients is consistent with studies such as Kalita et al. ⁷ who identified headache as the most common initial complaint in CVST. Similar trends were seen with altered sensorium (40% vs. 12%), reinforcing findings from Patil and Faruqi [30], who described a case of CVST with B12 and folate deficiency resulting in significant neurocognitive impairment. Kapur et al. ¹⁰ both presented cases of CVST in young patients who initially manifested with generalized seizures and altered consciousness, underlining the importance of considering CVST in differential diagnosis of new-onset seizures, especially in young adults without other risk factors. The common denominator in many of these cases was underlying hyperhomocysteinemia due to nutritional deficiency—an issue relevant to our Indian patient population where vegetarian diets can predispose to subclinical B12 deficiency.

Among our patients, those with documented nutritional deficiencies exhibited significantly higher mean homocysteine levels (19.0 ± 5.3 µmol/L) compared to those without such deficiencies (16.0 ± 4.5 µmol/L; p = 0.027). Alcohol consumption was also significantly associated with higher homocysteine levels (18.2 ± 4.9 µmol/L vs. 16.4 ± 4.8 µmol/L; p = 0.041). These findings emphasize that beyond genetic predispositions, environmental and behavioral factors play a critical role in the development of CVST through modulation of homocysteine metabolism. Our results closely parallel those of Meshram et al.¹¹, who found that 67% of CVST patients either had elevated homocysteine levels or vitamin B12 deficiency—two interrelated conditions often linked to dietary insufficiency.  Vitamin B12 is primarily obtained from animal sources; thus, individuals adhering to vegetarian diets are at increased risk for B12 deficiency, which in turn impairs the remethylation of homocysteine to methionine, leading to accumulation of plasma homocysteine.

Although smoking was not significantly associated with homocysteine levels in our study (p = 0.452), prior reports suggest that chronic smoking may impact vascular integrity and homocysteine metabolism. However, the low prevalence of smokers in our cohort may have limited the power to detect a statistically meaningful difference.

In conclusion, this study reinforces the multifactorial etiology of CVST, emphasizing the critical interplay between homocysteine metabolism, nutritional deficiencies, lipid abnormalities, and lifestyle factors. The path forward lies in bridging clinical vigilance with biochemical assessment, ensuring that each patient receives timely, targeted, and preventive care. Continued research and longitudinal studies with larger sample sizes are essential to validate these associations and translate them into standardized therapeutic protocols.

1. Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. The Lancet Neurology. 2007 Feb 1;6(2):162-70.
2. Liang ZW, Gao WL, Feng LM. Clinical characteristics and prognosis of cerebral venous thrombosis in Chinese women during pregnancy and puerperium. Scientific reports. 2017 Mar 6;7(1):43866.
3. Silvis SM, De Sousa DA, Ferro JM, Coutinho JM. Cerebral venous thrombosis. Nature Reviews Neurology. 2017 Sep;13(9):555-65.
4. Bano S, Farooq MU, Nazir S, Aslam A, Tariq A, Javed MA, Rehman H, Numan A. Structural imaging characteristic, clinical features and risk factors of cerebral venous sinus thrombosis: A prospective cross-sectional analysis from a tertiary care hospital in Pakistan. Diagnostics. 2021 May 26;11(6):958.
5. Appenzeller S, Zeller CB, Annichino-Bizzachi JM, Costallat LT, Deus-Silva L, Voetsch B, Faria AV, Zanardi VA, Damasceno BP, Cendes F. Cerebral venous thrombosis: influence of risk factors and imaging findings on prognosis. Clinical neurology and neurosurgery. 2005 Aug 1;107(5):371-8.
6. Yang Y, Cheng J, Peng Y, Luo Y, Zou D, Yang Y, Ma Y. Clinical features of patients with cerebral venous sinus thrombosis at plateau areas. Brain and Behavior. 2023 Jun;13(6):e2998.
7. Kalita J, Singh VK, Misra UK. A study of hyperhomocysteinemia in cerebral venous sinus thrombosis. Indian Journal of Medical Research. 2020 Dec 1;152(6):584-94.
8. Baby N, George M, Rajasekharan A, Ajith S, Zabeer M, Radhakrishnan S. Cerebral venous sinus thrombosis secondary to Vitamin B12 deficiency–A case series with emphasis on food fortification. Annals of African Medicine. 2024 Jul 1;23(3):496-500.
9. Doggen CJ, Smith NL, Lemaitre RN, Heckbert SR, Rosendaal FR, Psaty BM. Serum lipid levels and the risk of venous thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 2004 Oct 1;24(10):1970-5.
10. Kapur V, D’Cruz S, Kaur R. An uncommon presentation of hyperhomocysteinemia and vitamin B 12 deficiency: A case report. Journal of medical case reports. 2019 Dec;13:1-5.
11. Meshram A, Meshram C, Mundle R, Sangole M, Manohar T. Vitamin B12 deficiency and hyperhomocysteinemia as risk factors for cerebral venous sinus thrombosis. Journal of the Neurological Sciences. 2023 Dec 1;455.