Simultaneous occurrence of subarachnoid hemorrhage and cerebral venous sinus thrombosis: A systematic review of cases

Abstract Although the leading causes of subarachnoid hemorrhage (SAH) are aneurysm rupture and arteriovenous malformations, cerebral venous sinus thrombosis (CVST) can, in rare cases, be associated with SAH. This phenomenon is an uncommon presentation, with less than a hundred cases reported based on our review of the literature. The purpose of this review is to highlight what is known regarding these cases, how they are managed and to highlight the need for further studies that will serve as a basis for the development of a standard management guideline across board. The following databases were searched: PubMed and Ovid Embase. A complementary search of Google Scholar and AJOL was done. Gray literature search was also conducted on the Google search engine for any additional relevant papers. We were able to extract data regarding 33 cases from 29 identified studies. The mean age was 46.6 ± 14.08. 17 (51.5%) of the cases were female, and the female‐to‐male ratio is 1.1:1. Headache was by far the commonest symptom, occurring in 82% of cases followed by seizures in 42% of cases. Four patients (12%) had loss of consciousness while 5 patients (15%) had some form of focal neurologic deficit. Twenty patients had cerebral venous sinus thrombosis in at least two different sinuses. The superior sagittal sinus was the most common location for CVSTs (79%), followed by the transverse sinus (57.5%). Twenty‐nine cases (89%) were managed with anticoagulation alone and one case had a mechanical thrombectomy. We have performed a comprehensive review of cases that had the simultaneous occurrence of SAH and CVST and have identified their peculiarities and the challenges to management. Further research is needed in order to identify a causal relationship and to serve as a basis for the development of a standard management guideline across the board.

view of the literature. The purpose of this review is to highlight what is known regarding these cases, how they are managed and to highlight the need for further studies that will serve as a basis for the development of a standard management guideline across board. The following databases were searched: PubMed and Ovid Embase. A complementary search of Google Scholar and AJOL was done.
Gray literature search was also conducted on the Google search engine for any additional relevant papers. We were able to extract data regarding 33 cases from 29 identified studies. The mean age was 46.6 ± 14.08. 17 (51.5%) of the cases were female, and the female-to-male ratio is 1.1:1. Headache was by far the commonest symptom, occurring in 82% of cases followed by seizures in 42% of cases. Four patients (12%) had loss of consciousness while 5 patients (15%) had some form of focal neurologic deficit. Twenty patients had cerebral venous sinus thrombosis in at least two different sinuses. The superior sagittal sinus was the most common location for CVSTs (79%), followed by the transverse sinus (57.5%). Twenty-nine cases (89%) were managed with anticoagulation alone and one case had a mechanical thrombectomy. We have performed a comprehensive review of cases that had the simultaneous occurrence of SAH and CVST and have identified their peculiarities and the challenges to management. Further research is needed in order to identify a causal relationship and to serve as a basis for the development of a standard management guideline across the board.

K E Y W O R D S
anticoagulation, cerebral venous sinus thrombosis, CVST, SAH, subarachnoid hemorrhage

| INTRODUCTION
Although the leading causes of subarachnoid hemorrhage (SAH) are aneurysm rupture and arteriovenous malformations, cerebral venous sinus thrombosis (CVST) can, in rare cases, be associated with SAH. 1 This phenomenon is an uncommon presentation, with less than a hundred cases reported based on our review of the literature. CVST itself typically presents with headache, nausea, vomiting, weakness, loss of vision, and seizure. 2 Because of its rarity, a high index of suspicion is important in making the diagnosis. 3 CVST accounts for 1% of all strokes 4,5 and has a mortality as high as 30% with the annual incidence ranging from 0.22 to 1.57 per 100,000. It is more common in women than men. 6,7 Multiple reversible and irreversible factors are associated with CVST and include surgery, thrombophilia, antiphospholipid syndrome, cancer, inflammatory bowel disease, use of the oral contraceptive pill, infection, and pregnancy. 8 The reason why SAH might occur together with CVST is still debated. In some cases, they could be coincidental. However, there are many hypotheses with regards a causal relationship between the two entities; hence, there is a need to review all the cases in the existing literature to see the similarities and differences across these rare cases and presentations. The purpose of this review is to highlight what is known regarding these cases, how they are managed and to highlight the need for further studies that will serve as a basis for the development of a standard management guideline across board. In this article, we systematically reviewed all such published cases of CVST and SAH occurring concurrently, noting their common characteristics, imaging findings, treatment, and outcomes.

| Source of information and search
We followed the PRISMA guidelines for conducting systematic reviews. To identify potentially relevant papers, the following databases were searched: PubMed and Ovid Embase. A complementary search of Google Scholar and African Journal Online (AJOL) was done. Gray literature search was also conducted on the Google search engine for any additional relevant papers. The results were exported into an excel document and duplicates were removed. The search strategy is presented in Table A1 in Appendix 1.

| Selection criteria
We identified cases where SAH and CVST occurred together. We included case reports and case series, which included the aforementioned. We excluded posters, abstract-only papers, reviews, meta-analyses, commentaries, and letters to the editor. We excluded articles that were not written in the English language.

| Selection of sources of evidence
Three reviewers working independently evaluated the titles, abstracts, and then full text of all cases identified by our searches for relevant papers. We resolved disagreements on study selection and data extraction by consensus where necessary. The process is summarized in Figure 1.

| Data extraction
A data-charting form was jointly developed by the three authors to determine which data to extract. The reviewers then read each article extensively and populated the data extraction form with relevant details. The authors continually discussed the results and continuously updated the data-charting form in an iterative process. We extracted data on the characteristics of each patient/case (Age, gender, symptoms at presentation and their duration), diagnostic modalities for the subarachnoid hemorrhage and CVST, the location of the SAH and CVSTs, possible etiology (presence of aneurysms, trauma, coagulation disorders), the treatment modalities and the outcomes. We were able to extract data regarding 33 cases from 29 identified studies. A summary of the case studies is seen in Table A2 in Appendix 1.

| Investigated patient characteristics
The mean age was 46.6 ± 14.08. 17 (51.5%) of the cases were female, and the female-to-male ratio was 1.1:1. One case had hyperhomocysteinemia while another had C667T mutations (Heterozygous for methylenetetrahydrofolate reductase). Only one case had a recent use of antiplatelets (Clopidogrel) prior to the diagnosis of CSVT and SAH.

| Clinical symptoms and Imaging
Headache was by far the commonest symptom, occurring in 82% of cases followed by seizures in 42% of cases. Four patients (12%) had loss of consciousness while 5 patients (15%) had some form of focal neurologic deficit. Other symptoms included dizziness, nausea, vomiting, gait disturbance and ataxia. The diagnostic modalities used included a non-contrast computed tomography (CT) scan, computed tomography angiography (CTA), computed tomography venography (CTV), magnetic resonance imaging (MRI), magnetic resonance venography (MRV), and digital subtraction angiography (DSA). Twentyfive (75.7%) of the studies had an MRI done, while only 17 (51.5%) of them had a further MRV done to confirm the venous thrombosis. Twenty-seven of the cases had a non-contrast CT scan done which showed evidence of subarachnoid hemorrhage. Four patients later had a CTA, while another three had a magnetic resonance angiography (MRA) done to exclude an aneurysmal cause. Only one patient had a CTV done.

| Diagnosis, treatment, and outcomes
Twenty patients (60.6%) had cerebral venous sinus thrombosis in at least two different sinuses. Of the different locations for the CVSTs, the superior sagittal sinus was the most common location (79%), followed by the transverse sinus (57.5%). Only one case of CVST and SAH had an accompanying intracerebral hemorrhage (ICH). The locations of the subarachnoid hemorrhage were more diverse, ranging from the perimesencephalic areas and cerebral convexities to the Sylvian fissures and interhemispheric fissures. Twenty-five of them involved the cerebral convexities while 7 of them involved the subarachnoid cisterns. Most of the subarachnoid hemorrhages were non-aneurysmal. Only one patient had an aneurysmal rupture; the location of the aneurysm was in the anterior communicating artery. Twenty-nine cases (89%) were managed with anticoagulation alone and one case had a mechanical thrombectomy first prior to anticoagulation. One case was managed with dehydration, scavenging free radicals, and nerve protective therapy, while another was managed with hydration and osmotic diuresis (with an eventual decompressive craniectomy for persistent raised ICP). The only case of the aneurysm was managed with coil embolization. All 28 cases that discussed the status at discharge and a few weeks after reported different ranges of improvement; recovery ranged from improvement in symptoms and partial recanalization to full recovery and full recanalization of the vessels.

| DISCUSSION
Subarachnoid hemorrhage should be considered in the event of a sudden worsening headache. 9 The diagnostic modality of choice for subarachnoid hemorrhage in the initial stages is a non-contrast CT scan. 9,10 With an equivocal result, a lumbar puncture is advised; however, given the increased sensitivity of a non-contrast CT scan within the six-hour timeframe, the choice to undertake a lumbar puncture should be through a shared decision-making process. 9 As aneurysms are a common cause of SAH, CTA F I G U R E 1 Prisma flow chart scans are important in demonstrating a causative aneurysm. 9 A non-contrast CT scan is also a useful diagnostic modality for diagnosing a CVST as it can show findings that include, but are not limited to, venous sinus or deep vein hyper-density. 11,12 CT venography and/or MR venography are recommended diagnostic modalities of choice, as recommended by the European Stroke Organization. 13 Transverse sinuses, superior sagittal sinuses, and the sigmoid sinus are the most common sites of CVSTs, and in most cases, multiple sinuses are affected. [14][15][16] This is consistent with the findings of our review study, which showed that multiple sinuses were frequently affected with the superior sagittal sinus and the transverse sinus being the commonest sites. In cases with a coexisting cerebral venous sinus thrombosis, the perimesencephalic region is a common location for non-aneurysmal SAH. 17,18 The most common locations for aneurysms are in the circle of Willis, particularly the anterior communicating artery and the internal carotid artery. 19,20 A third of CVST cases might present with intracerebral hemorrhage. 21 However, there is a paucity of literature on how common it is for CVST to occur with subarachnoid hemorrhage. One hypothesis of why SAH may occur simultaneously with CVST is that the blood from the ensuing hemorrhagic infarct (resulting from the venous thrombosis) may extend into the subarachnoid space. 22 This may certainly be the case in some of our findings where there was parenchymal hemorrhage besides the presence of CVST and SAH; however, its absence (also seen in many of the cases identified) may suggest a more direct causal relationship. A leading hypothesis supporting this stipulates that when CVST occurs, the ensuing secondary venous hypertension could be transmitted to the cortical veins, leading to the dilation and rupture of the fragile thin-walled cortical veins in the subarachnoid space. 17,23 Sometimes, the occurrence of both entities together could be coincidental, as seen in instances with an aneurysmal cause of the SAH, like in some of the identified cases.
Regardless of etiology, the treatment of a patient with SAH and CVST occurring concurrently can pose a dilemma. The risk of rebleeding in SAH is high, and in the absence of immediate surgical intervention for aneurysmal SAH, antifibrinolytics have been advised. 24 This is in sharp contrast to the standard treatment of CVSTs, which involves rapid anticoagulation and the stoppage of any prothrombotic medications. 11 Using systemic anticoagulation where simultaneous subarachnoid hemorrhage exists might worsen the hemorrhage. In cases of simultaneous CVST and ICH, endovascular interventional therapy has been beneficial. 25 There is a possibility that such interventions may also yield positive results when used in cases of CVST occurring with SAH. Interestingly, in our study, despite the SAH, most of the patients were treated with anticoagulant therapy with good outcomes reported. Despite our comprehensive review, this study was not without limitations. Because we excluded articles that were not in the English Language, we could have potentially missed relevant literature. There was also heterogeneity in the way the case reports were reported which meant some relevant data could have been missed. Regardless, this review will contribute to the growing body of work on this occurrence.

| CONCLUSION
We have performed a comprehensive review of cases that had the simultaneous occurrence of SAH and CVST and have identified their peculiarities and the challenges to management. Further research is needed in order to identify a causal relationship and to serve as a basis for the development of a standard management guideline across the board.

AUTHOR CONTRIBUTIONS
D.J involved in conceptualization, methodology, software, validation, formal analysis, investigation, resources, data collection, data curation, writing-original draft, writing-review and editing, project administration, supervision, submission, and correspondence. O.O and T.M involved in conceptualization, methodology, software, validation, formal analysis, investigation, resources, data collection, data curation, writing-original draft, writing-review and editing.

CONFLICT OF INTEREST
The authors hereby declare that there are no competing interests.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

CONSENT
As this was a review of cases in already literature, no individual consent was required. Consent was however obtained by the individual case reports used in this review in accordance with the journal's patient consent policy.