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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1056-1061
 

Predictors of seizures and associated functional outcome in a cerebral venous thrombosis cohort: An ambispective cohort study


1 Department of Neurology, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi, India
2 Department of Neuroradiology, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi, India
3 Department of Biostatistics, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi, India

Date of Submission25-Mar-2022
Date of Decision29-Mar-2022
Date of Acceptance31-Mar-2022
Date of Web Publication08-Jun-2022

Correspondence Address:
Venugopalan Y Vishnu
Department of Neurology, All India Institute of Medical Sciences (AIIMS), New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_281_22

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   Abstract 


Background and Purpose: We aimed to explore the characteristics, clinical features, predictors of seizure, and associated clinical outcomes in patients with cerebral venous thrombosis (CVT). Methods: We enrolled patients with CVT from January 2014 to July 2020. Prospectively patients were recruited from December 2018. We analyzed predictors of seizures and associated good functional outcomes (modified Rankin Scale, mRS: 0–2) using multivariable logistic regression. Results: We enrolled 153 patients with CVT in which 77 (50%) had presented with a seizure. The median age was 31 years (IQR 16-46), and the majority were men (73.2%). Focal to bilateral tonic-clonic was the most common seizure type (27%), followed by generalized seizures (22%). None of the patients had status epilepticus. Antiseizure medications (ASM) were used in 71% of patients at diagnosis, 42% having received them prophylactically. Supratentorial parenchymal involvement was seen in 72% of seizure patients compared to 38% in those without, and superior sagittal sinus was most commonly involved. Percentage of patients who achieved good clinical outcome (mRS 0-2) at 3 months did not vary significantly between both groups. The only predictor for seizures with CVT was the presence of a parenchymal lesion (OR-3.75, 95% CI 1.79-7.85), whereas seizure occurrence (OR- 12.55, 95% CI- 1.53-102.59) was associated with statistically significant risk for recurrent seizures, by multiple logistic regression analysis. Seizure occurrence was not associated with adverse functional outcomes. Conclusion: Seizures at presentation occurred in 50% of patients with CVT which was associated with a parenchymal lesion in the brain. There was no association between seizure at presentation and clinical outcome.


Keywords: Cerebral venous thrombosis, functional outcome, parenchymal, seizure


How to cite this article:
Shakywar M, Agarwal A, Padma Srivastava M V, Bhatia R, Singh MB, Rajan R, Gupta A, Pandit AK, Garg A, Sharma J, Gupta A, Upadhyay A, Vishnu VY. Predictors of seizures and associated functional outcome in a cerebral venous thrombosis cohort: An ambispective cohort study. Ann Indian Acad Neurol 2022;25:1056-61

How to cite this URL:
Shakywar M, Agarwal A, Padma Srivastava M V, Bhatia R, Singh MB, Rajan R, Gupta A, Pandit AK, Garg A, Sharma J, Gupta A, Upadhyay A, Vishnu VY. Predictors of seizures and associated functional outcome in a cerebral venous thrombosis cohort: An ambispective cohort study. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1056-61. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1056/347021





   Introduction Top


Intracranial cerebral venous thrombosis (CVT) is a rare cerebrovascular disease which occurs due to the occlusion of dural sinus or cerebral veins. CVT has an incidence rate of 1-12 cases per million and constitutes 0.5-3% of all types of cerebrovascular diseases and is more prevalent in younger patients.[1]

Risk factor profile is highly variable in patients with CVT.[2] In the Indian scenario, pregnancy, puerperium, and oral contraceptive intake are the commonest causes among females, whereas alcohol intake, hyperhomocysteinemia, and genetic thrombophilia are common among males. Genetic thrombophilia is responsible in 20% of patients with CVT.[3],[4],[5],[6] The common presenting signs and symptoms of CVT are headache (60-94%), seizure (30-50%), papilledema (16–60%), focal motor deficits (20–50%), altered mental status (15–25%), and coma (5–15%).[4],[5],[6],[7]

The diagnosis of CVT has become easier with magnetic resonance imaging (MRI) and magnetic resonance (MR)/computerized tomography (CT) venography, which together can provide a diagnosis in almost all cases.[8] Patients with CVT are treated with intravenous (IV) heparin or subcutaneous low molecular weight heparin (LMWH) initially followed by anticoagulants for 3-12 months depending on the etiology.[9]

Seizure frequently occurs in patients with CVT with an incidence of 30-40% as compared to 2-9% of acute ischemic stroke and 8-14% of intracerebral hemorrhage (ICH). Nearly 80% of early-onset seizures develop before establishing a diagnosis of CVT.[10] Seizures influence the prognosis of patients with CVT by adversely affecting intracranial pressure (ICP) and mortality can be increased by three times compared to patients without a seizure.[10]

Hence, the present study was performed to determine the predictors of seizures in CVT patients, and their association with good functional outcome.


   Patients and Methods Top


The study was a single center, ambispective, observational cohort study conducted at a tertiary care institute in India. We enrolled adult patients (≥18 years) with CT/MRI brain and CT/MR venography proven CVT. The study was approved by the Institutional Ethics Committee. Refusal of consent was the only exclusion criteria.

Patients of CVT, who presented from January 2019 to July 2020, were recruited in the prospective arm, whereas patients with CVT who were following up since January 2014 were enrolled in the retrospective arm.

Clinical assessment

A detailed history and clinical examination were carried out for all patients as per the standardized proforma. Patients classified into three groups based on the time of presentation: Acute (<48 hours), subacute (48 hours to 30 days) and chronic (≥30 days). Neurological assessment and functional scores were recorded by a trained neurologist.

All patients were evaluated for the presence of early or late seizure, seizure semiology (focal/focal to bilateral tonic-clonic, or generalized tonic-clonic) and whether the patient received ASMs or not. Early seizure (ES) was defined as the seizure occurring within 14 days of symptom onset or 7 days of CVT diagnosis. Late seizure (LS) encompassed all other seizures. Other parameters evaluated were headache, vision loss, papilledema, nausea/vomiting, weakness of any limb, GCS, altered sensorium, and cranial nerve palsy. Risk factors for CVT assessed included dehydration, hyperhomocysteinemia, pregnancy, puerperium, OCP intake, infection, drugs, malignancy, and previous history of venous thromboembolism. Imaging characteristics evaluated included the location of the lesion, presence of parenchymal lesion, midline shift, sinuses involved, and the number of sinuses affected, as per CT/MRI brain and CTV/MRV findings.

The functional outcome was assessed by mRS score at 3 months. Evaluation was done in person by a trained neurologist, with telephonic assessment for those patients unable to come for follow up. mRS score of 0-2 was classified as a good outcome.

Outcome

The main outcomes were the predictors of seizures in patients with CVT and their functional clinical outcome.

Statistical analysis

Data were analyzed using STATA (version 14) software. Continuous variables were expressed as mean ± standard deviations (SD) or median with interquartile range (IQR), and categorical variables were presented as proportions or percentages. The student's t-test was used to compare the parametric values, whereas the Mann–Whitney U test was performed to compare non-parametric values. For comparison of categorical data, the Chi-square/Fisher exact test was used. A univariate followed by multivariable logistic regression analysis was performed to assess the outcome predictors. A P value of less than 0.05 was considered statistically significant.


   Results Top


We enrolled 153 patients during the study period: Prospective arm consisted of 52 patients while 101 patients were enrolled retrospectively. Clinical characteristics of the enrolled patients are mentioned in [Table 1]. Seventy seven patients had a seizure (50.3%).
Table 1: Clinical characteristics

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The median age of study participants was 31 (IQR 16-46) years, in which the majority were males (n = 112; 73.2%). At least one risk factor was observed in 91 (59.5%) patients. Majority of the patients (70.1%) presented in the sub-acute phase in the seizure group, with a median symptom duration being 9 days, compared to those without who routinely presented in the chronic phase. Patients with seizures were more likely to have altered sensorium, abnormal neurological examination while nausea/vomiting was commoner in those without. Seizure patients were more likely to have parenchymal involvement (72.7%), with frontal lobe (20.8%) being the most commonly involved [Table 2].
Table 2: Characteristics of patients with CVT with and without seizure

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Early seizures occurred more commonly with CVT (81.2%) with the most common seizure semiology being focal to bilateral tonic clonic (81.8%) [Table 3]. Recurrent seizures were seen in 12 (15.5%) patients. ASMs were prescribed to 109 patients with CVT (71.2%) during the study period, of which 32 patients had no history of seizures pre- or post-CVT occurrence. Some patients with parenchymal lesions without seizures (n = 11) were not prescribed prophylactic ASMs [Table 4].
Table 3: Characteristics of seizure in patients with CVT

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Table 4: Number of patients on antiseizure medications (ASM) and characteristics with seizure

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Univariate analysis for predictors of seizures with CVT included altered mental status (GCS ≤14), abnormal neurological examination, symptom duration, and parenchymal involvement [Table 5]. Recurrent seizures were associated with occurrence of both early and late seizures and focal to bilateral tonic clonic seizure semiology. Multivariate logistic regression analysis revealed parenchymal involvement (OR-3.75, 95% CI 1.79-7.85) as the only predictor for the occurrence of seizures with CVT while seizure occurrence (OR- 12.55, 95% CI- 1.53-102.59) was associated with risk for recurrent seizures [Table 6].
Table 5: Univariate analysis of seizure at presentation and recurrent seizure in patients with CVT

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Table 6: Predictor of seizure at presentation and recurrent seizure by logistic regression

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Seizure occurrence was not associated with functional outcome at 3 months after CVT as 86.9% patients with seizures and 90.4% without seizures had a good functional outcome (mRS 0-2) [Table 2].


   Discussion Top


CVT is more prevalent in the younger population. We recruited 153 patients of CVT with a median age of 31 years (IQR 16-36). This was comparable to another study from India by Narayan et al.[4] Our study predominantly consisted of male patients (73%), which was similar to other studies performed from the last decade,[4],[5] but different to older studies where females were predominantly affected.[11] This might be attributable to the advent of safer obstetrics practices and use of lower hormonal content oral contraceptive pills.

Most patients with CVT presented in the sub-acute stage (70.1%) with the median duration of symptoms before presentation being 9 days. This could be due to their presentation with early seizures leading to hospitalization and eventual CVT diagnosis. Patients with seizures also commonly presented in the subacute phase with a significant number presenting in the chronic phase (39.5%). Initial ignorance of symptoms like headache and nausea/vomiting and absence of a red flag symptoms like seizures might explain these findings.

Risk factors were present in 91 (59.5%) patients, in which hyperhomocysteinemia was the most common. Alcohol intake (15%), puerperium (8.5%), and previous venous thromboembolism (7.2%) also found to be other important risk factors. Narayan D, et al.[4] also suggest that alcoholism and hyperhomocysteinemia were common risk factors, especially in male patients. This finding was different from Duman et al.[1] and Ferro et al.[11] in which gynaecological factors (OCP and puerperium) and thrombophilia were the commonest risk factors.

Headache was the most common presenting symptom (87.6%) followed by seizures (50.3%). Ferro et al.[11] and Anadure et al.[5] had also observed headache as the most common symptom.

Most patients with CVT had an early seizure at presentation (41.2%) with focal to bilateral tonic-clonic as the most common seizure subtype. Twelve (7.8%) patients had a recurrent seizure. Seizure occurrence was associated with cerebral parenchymal involvement and therefore was more likely to have abnormal neurological examination or altered sensorium at presentation. Ferro et al.[11] obtained similar results and observed that 39.3% of patients with CVT presented with seizure and 6.9% developed a seizure within 14 days. Narayan et al.[4] showed that 45.2% of patients with CVT present with seizure, which is slightly higher than our study. Similarly, Kalita et al.[12] observed that presenting seizure was seen in 46.7% and focal with secondary generalized seizure was the most common seizure subtype, and five patients had a recurrent seizure, which is similar to our study.

In our study, 109 (71%) patients received antiseizure medications (ASM), of which 32 (42%) patients did not have seizures. This is concordant with our usual clinical practice of starting ASMs with CVT diagnosis. Studies showing characteristics of antiseizure drug prescription in patients with CVT among Indian populations are lacking. Ferro et al.[13] found that only 50.4% of patients with supratentorial parenchymal lesion received AED in their study.

Forty-four patients did not receive ASM, of which 11 patients had parenchymal involvement. Our analysis revealed parenchymal lesions to be the only independent predictor of seizure occurrence post-CVT. However, the fact that not all patients with parenchymal involvement developed seizures and some without do. This entails a more complex mechanism whereby other risk factors act as add-ons. This entails the need for a seizure risk prediction score with CVT like those available post-ischemic stroke (SeLECT score)[14] and hemorrhagic stroke (CAVE score)[15] to better stratify patients needing prophylactic ASM treatment.

Parenchymal lesions were seen in 85 (55.5%) patients, of which 56 developed seizures. The most common lesions were infarction (26.8%) and hemorrhagic infarction (24.2%). Most of the patients showed two or more lobe involvement, with frontal lobe (12.4%) being the most frequently involved. In the VENOSOT study, the parenchymal involvement was slightly lower (40.1%), infarction was the commonest lesion (19.1%), and intracerebral hemorrhage was seen in 3.8% patients.[1] Narayan et al.[4] show that the hemorrhagic infarct was commonest (45.6%) followed by infarction (15.8%), which is different from our findings.

Frontal lobe and superior sagittal sinus thrombosis (17%) were the most common isolated lobe and sinus involved. However, most patients had ≥2 lobar and sinus involvement (43.8%). Lobar (i.e., parenchymal involvement) was commoner in the seizure group but the sinus involved did not vary between the two groups. Duman et al.[1] and Narayan et al.[4] also observed that SSS is the most commonly involved sinus. Contrary to our observation, Anadure et al.[5] found that transverse sinus was the most commonly affected (74% of patients).

Seizures at presentation was found to be an independent predictor for seizure recurrence. However, patients with seizures did not have a statistically significant worse outcome when compared with those without. This might entail most seizures being acute symptomatic seizures, which help in bringing patients to medical attention earlier and resolve (clinically and radiologically) post-prompt treatment.

The strength of our study was an ambispective enrolment with a uniform evaluation of etiological, clinical features, radiological factors, and seizure predictors and seizure recurrence.

Our limitation was a relatively small sample size due to the COVID-19 pandemic. Prothrombotic profile was available for a limited number of patients.


   Conclusion Top


CVT is a rare disease in which early diagnosis and treatment greatly influence the outcome. Headache and seizures were the most common presenting symptoms, with hyperhomocysteinemia being the most prevalent risk factor. A parenchymal lesion on imaging is the only predictor for seizure occurrence. The prognosis of most patients is good and seizures do not alter this functional outcome at 3 months.

Financial support and sponsorship

Grant from Department of Science and Technology, Government of India.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Duman T, Uluduz D, Midi I, Bektas H, Kablan Y, Goksel BK, et al. A multicenter study of 1144 patients with cerebral venous thrombosis: The VENOST study. J Stroke Cerebrovasc Dis 2017;26:1848-57.  Back to cited text no. 1
    
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Ferro JM, Canhão P, Aguiar de Sousa D. Cerebral venous thrombosis. Presse Med 2016;45:e429-50.  Back to cited text no. 2
    
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Pai N, Ghosh K, Shetty S. Hereditary thrombophilia in cerebral venous thrombosis: A study from India. Blood Coagul Fibrinolysis 2013;24:540-3.  Back to cited text no. 3
    
4.
Narayan D, Kaul S, Ravishankar K, Suryaprabha T, Srinivasarao Bandaru VCS, Rukmini Mridula K, et al. Risk factors, clinical profile, and long-term outcome of 428 patients of cerebral sinus venous thrombosis: Insights from Nizam's Institute Venous Stroke Registry, Hyderabad (India). Neurol India 2012;60:154-9.  Back to cited text no. 4
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Anadure RK, Wilson V, Sahu S, Singhal A, Kota S. A study of clinical, radiological and etiological profile of cerebral venous sinus thrombosis at a tertiary care center. Med J Armed Forces India 2018;74:326-32.  Back to cited text no. 5
    
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Lafitte F, Boukobza M, Guichard JP, Hoeffel C, Reizine D, Ille O, et al. MRI and MRA for diagnosis and follow-up of Cerebral venous thrombosis (CVT). Clin Radiol 1997;52:672-9.  Back to cited text no. 8
    
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Ferro JM, Aguiar de Sousa D. Cerebral venous thrombosis: An update. Curr Neurol Neurosci Rep 2019;19:74.  Back to cited text no. 9
    
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Ferro JM, Correia M, Rosas MJ, Pinto AN, Neves G. Seizures in cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2003;15:78-83.  Back to cited text no. 10
    
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Ferro JM, Canhão P, Stam J, Bousser M-G, Barinagarrementeria F, ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: Results of the International study on cerebral vein and dural sinus thrombosis (ISCVT). Stroke 2004;35:664-70.  Back to cited text no. 11
    
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Kalita J, Chandra S, Misra UK. Significance of seizure in cerebral venous sinus thrombosis. Seizure 2012;21:639-42.  Back to cited text no. 12
    
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Ferro JM, Canhão P, Bousser M-G, Stam J, Barinagarrementeria F. Early seizures in cerebral vein and dural sinus thrombosis: Risk factors and role of antiepileptics. Stroke 2008;39:1152-8.  Back to cited text no. 13
    
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Galovic M, Döhler N, Erdélyi-Canavese B, Felbecker A, Siebel P, Conrad J, et al. Prediction of late seizures after ischaemic stroke with a novel prognostic model (the SeLECT score): A multivariable prediction model development and validation study. Lancet Neurol 2018;17:143-52.  Back to cited text no. 14
    
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Haapaniemi E, Strbian D, Rossi C, Putaala J, Sipi T, Mustanoja S, et al. The CAVE score for predicting late seizures after intracerebral hemorrhage. Stroke 2014;45:1971-6.  Back to cited text no. 15
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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