Intracranial hypertension after cerebral venous thrombosis—Risk factors and outcomes

Abstract Background and Purpose Cerebral venous thrombosis (CVT) is a special cerebrovascular disease that accounts for around 0.5%–1.0% of all strokes and often occurs in younger adults. Intracranial hypertension is the most frequent symptom of acute CVT due to venous occlusion. This study aimed to ascertain the risk factors for intracranial hypertension after CVT and to investigate whether intracranial hypertension at diagnosis may affect patient outcomes. Methods We performed a retrospective cohort analysis of all patients treated for acute/subacute CVT at our department between 2018 and 2021. Logistic regression analysis was performed to identify potential risk factors associated with intracranial hypertension after CVT and clinical outcomes at the 6‐month follow‐up. Results A total of 293 acute/subacute CVT survivors were eligible for inclusion, with 245 patients (83.60%) experiencing concomitant intracranial hypertension at diagnosis. In the multivariable regression analysis, hereditary thrombophilia (OR 2.210, 95% CI 1.148–4.254, p = 0.018) and thrombosis location of superior sagittal sinus (SSS) and right lateral sinus (LS) (OR 4.115, 95% CI 1.880–9.010, p = 0.000) were independently associated with intracranial hypertension. 83.67% of patients with intracranial hypertension after CVT had favorable functional outcomes (mRS score, 0–2), whereas they more often had residual visual impairment (15.51% vs. 4.17%, p = 0.036) at follow‐up. The risk factors for residual visual impairment were papilledema (OR 2.971, 95% CI 1.231–7.170, p = 0.015) and visual disturbances at diagnosis (OR 2.869, 95% CI 1.123–7.327, p = 0.028), thrombosis location (SSS and right LS [OR 10.811, 95% CI 4.208–27.773, p = 0.000]; SSS and left LS [OR 3.139, 95% CI 1.409–6.995, p = 0.005]), and CVT recurrence (OR 4.763, 95% CI 1.556–14.584, p = 0.006). Conclusions Intracranial hypertension is the most common clinical symptom of acute CVT. At follow‐up, patients with intracranial hypertension after CVT were more prone to develop residual visual impairment.


| INTRODUC TI ON
Cerebral venous thrombosis (CVT) is a special cerebrovascular disease caused by thrombosis of the dural sinuses and/or intracranial veins, 1-3 which accounts for around 0.5%-1.0% of all strokes. 4,5 This disease occurs more frequently in young and middle-aged adults, with a sex ratio heavily skewed toward females. [1][2][3] The clinical manifestation of CVT is highly variable, depending on the predominant site of venous occlusion. Approximately 60% of patients have CVT involving multiple dural venous sinuses, with the superior sagittal sinus (SSS) being the most frequently affected. CVT can also lead to intracranial hypertension due to impaired cerebral venous drainage and absorption of cerebrospinal fluid (CSF). Moreover, in isolated intracranial hypertension cases, patients may suffer from headaches (often accompanied by nausea), papilledema, visual field disturbances, and tinnitus. 1 The risk factors and causes of CVT are complicated and diverse, involving sex-specific factors such as oral contraceptive use, pregnancy, puerperium, hereditary thrombophilia, infections, and neurosurgical procedures. 6,7 The International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) found that up to 85% of adult patients have at least one risk factor 8 ; some of the risk factors are also the leading triggers for intracranial hypertension, thus affecting the overall outcome and quality of life. 9 Furthermore, patients with acute/subacute CVT may present predominantly with clinical features of intracranial hypertension, such as headache, blurred vision, transient visual obscuration, diplopia, and/or papilledema. 4,10 Previous studies have addressed the relationship between CVT and intracranial hypertension. This retrospective study aimed to investigate underlying risk factors for intracranial hypertension after CVT and to estimate the correlation between intracranial hypertension at diagnosis and clinical outcomes by analysis of a large cohort of CVT patients from our institution.

| Patient enrollment
In this retrospective cohort study, CVT patients were identified from a prospective stroke registry in Xuanwu Hospital, Capital Medical University. Patients experiencing first-episode acute/subacute CVT were enrolled consecutively between January 2018 and June 2021.
Based on the interval from symptom onset to a confirmed diagnosis, the acute phase (0-7 days) and the subacute phase (8-15 days) were defined. 11 Intracranial pressure was measured by lumbar puncture (LP) in the left lateral decubitus position, and a CSF opening pressure of 250 mmH 2 O or more was identified as intracranial hypertension. 12,13 We categorized visual outcomes into 2 conditions: residual visual impairment and non-residual visual impairment. Visual impairment was defined as severe papilledema (Frisen grade ≥3), visual field defect or fading eyesight (more than 2 lines with Snellen visual chart). 14,15 All patients were strictly selected with the following inclusion criteria: (1) age ≥18 years; (2) acute/subacute CVT diagnosed by MRI + MRV, CT + CTV, or DSA; (3) neuro-ophthalmological examination and color fundus photography performed at admission and 6-month follow-up; and (4) available valid information on functional outcomes and residual visual outcomes at 6-month follow-up. There were no restrictions regarding sex, and patients with malignancies were not included because the malignancies could be the direct cause of death or affect the outcomes. All participants signed informed consent forms before enrollment and data acquisition. This study was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University ([2020]098).

| Data collection
The demographics, epidemiological data, radiological characteristics, treatments, and clinical outcomes of all patients were collected. Etiology and risk factors for CVT included sex-specific factors (use of estrogen-progesterone, puerperium, oral contra-

K E Y W O R D S
cerebral venous thrombosis, cerebrovascular disease, intracranial hypertension, raised intracranial pressure, residual visual impairment sinus) and parenchymal changes (venous infarction and hemorrhage). Additionally, neuro-ophthalmological examination and color fundus photography results at admission and follow-up, treatments (heparin, endovascular treatment) in the acute phase, use of anticoagulant therapy at discharge, modified Rankin scale (mRS) score on admission and discharge, whether interventional thrombectomy was selected, and CVT recurrence during follow-up were recorded. The patient data reporting followed the STROBE guideline. 16

| Treatment protocol
Patients with CVT were treated with a standard treatment protocol immediately after diagnosis according to the current guidelines. 17 Each patient received subcutaneous low-molecular-weight heparin in adjusted doses for 10 to 14 days, followed by oral anticoagulants (warfarin or dabigatran, if warfarin was used, PT-INR was maintained between 2.0 and 3.0) for 3-6 months or longer. The use of endovascular treatment (local thrombectomy/thrombolysis) was reserved for patients who are still progressing with adequate anticoagulant therapy. Short-term therapy with mannitol or furosemide was administrated to patients with progressive visual loss or cerebral herniation due to intracranial hypertension, acetazolamide, decompressive craniectomy, ventriculoperitoneal shunt or hematoma evacuation, optic nerve sheath decompression was selected by physicians according to current guidelines. 17

| Follow-up and clinical outcomes
Regular follow-up was conducted 6 months after discharge.
Follow-up and outcome data were collected through clinical outpatient visits with a standardized questionnaire. Residual symptoms, such as headache, residual visual impairment, and current work status, were evaluated according to the proposed criteria. 9,18 Brain and ophthalmological characteristics were assessed using radiological imaging modalities. mRS score at the 6-month follow-up after discharge was used as the primary endpoint of efficacy. An mRS score ≤2 was defined as a relatively favorable outcome, whereas an mRS score ≥3 indicated a poor prognosis.

| Statistics
Values of the measured parameters were checked for conformity to a normal distribution by means of the Kolmogorov-Smirnov test prior to statistical analysis. Continuous variables are expressed as the mean ± standard deviation (SD) or median with interquartile range (IQR), and categorical variables are expressed as percentages. Bivariate analysis with the t test or Mann-Whitney U test for continuous variables and the chi-square test for categorical variables were used to identify the potential variables associated with intracranial hypertension at diagnosis (or residual visual impairment).
Bivariate logistic regression models were used to examine the associations between each of the potential risk factors and intracranial hypertension at diagnosis (or residual visual impairment) in all CVT survivors. First, with p ≤ 0.15 in the univariate analysis, etiologic and neuroimaging data were entered as dependent variables.
Then, we checked collinearity among these potential predictors using the tolerance and variance inflation factors test. However, no significant collinearity was detected among any of the potential predictors. Next, all the retained predictors, together with age and sex as covariates, and intracranial hypertension at diagnosis (or residual visual impairment) as the dependent variable, were entered into the regression model. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for the retained variables. A two-sided p value ≤0.05 was considered significant. SPSS 22.0 for Windows (IBM Corp) was used to analyze all data.

| RE SULTS
We identified 306 patients with diagnosed acute/subacute CVT.  , and 62.50% were female). Figure 1 depicts the study flow chart.

| Risk factors for intracranial hypertension in all CVT survivors
Bivariate logistic analysis was performed to identify independent risk factors for intracranial hypertension in all CVT survivors. However, no significant collinearity was detected among any of the potential pre-  Table 2.

| Risk factors for patients with residual visual impairment
Using multivariate logistic regression analysis, papilledema at diag-  Table 3.  cause selection bias and limit the generalizability of the results.
Moreover, we cannot absolutely exclude that the absence of an association between residual visual impairment and intracranial hypertension after CVT is due to the limited sample size. A prospective, multicenter, large-sample trial is needed to verify our findings. Second, there was a lack of baseline characteristics, such as height and weight at admission, that could have underpowered the study and biased the results because obesity is also a risk factor for poor visual outcomes in CVT. 27

ACK N OWLED G M ENTS
None.

FU N D I N G I N FO R M ATI O N
This study was supported by grants from National Natural Science Foundation of China (82271311) and the Pharmaceutical Collaboration Project of Beijing Science and Technology Commission (Z181100001918026).

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that they have no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Anonymized raw data are available upon request from the corresponding author.