Understanding Cerebral Venous Thrombosis: Rare But Sometimes Fatal

The prognosis of CVT is favorable compared with other types of stroke: almost 80% of patients with CVT recover without functional disability. Nevertheless, 5% to 10% of patients die in the acute phase.

CLINICAL

Cerebral venous thrombosis (CVT) is a rare cause of stroke, with an incidence of approximately 1.3 per 100,000 per year.1 The median age is 37 years and the female-to-male sex ratio is 3:1.2,3 In CVT, a blood clot forms in one or more of the cerebral venous sinuses or veins, blocking drainage of venous blood and cerebral spinal fluid. There is a wide spectrum of signs and symptoms, such as headache, visual disturbances, focal neurologic deficits, seizures, and decreased consciousness. The thrombosis may lead to intracranial hypertension, localized or diffuse brain edema, or intracranial hemorrhage.

Case Vignette

A 34-year-old woman presents to the emergency department with fever and decreased consciousness. Her partner explains that for several days she has suffered from a progressive headache, right-sided earache, and ear effusion. A high fever developed this morning and she became rapidly confused and less reactive. Upon neurologic examination, decreased consciousness is noted with an E3M5V3 on the Glasgow Coma Scale score. No nuchal rigidity is found. Decreased movements of the left arm and leg are observed. Plantar reflexes are pathologic on the left and normal on the right. Bilateral papilledema is seen upon fundoscopy.

A non-contrast enhanced CT of the head shows a right temporal intracerebral hemorrhage and fluid in the right mastoid air cells. Subsequent CT venography of the head shows thrombosis of the superior sagittal sinus, right sigmoid and transverse sinus, and right internal jugular vein. Lumbar puncture is performed, with an increased opening pressure of 50 cm H2O. Cerebrospinal fluid (CSF) shows a neutrophilic pleiocytosis of 7000/μL, total protein of 500 mg/dL, and a glucose of 0.1 mg/dL. The diagnosis is bacterial meningitis and septic cerebral venous thrombosis; she is started on broad spectrum antibiotic treatment and dexamethasone.

Risk factors

A recent meta-analysis assessed risk factors for CVT by pooling all case-control studies on adult CVT.4 As in other types of venous thromboembolism, female-specific risk factors such as oral contraceptive use, pregnancy, and puerperium constitute major risk factors. Other risk factors described were genetic risk factors, systemic diseases, medication use, mechanical causes, and infections. Infections associated with CVT include mainly ear, nose, and throat infections and CNS infections.

Case Vignette cont’d

The patient is admitted to the Intensive Care Unit. The ear, nose, and throat specialist advises continuation of conservative therapy with antibiotics to treat the mastoiditis. Because of the infectious trigger of CVT and the intracranial hemorrhage, no anticoagulant therapy is started. CSF culture reveals Streptococcus pneumoniae and antibiotic therapy is switched to intravenous penicillin. Rapid clinical improvement is observed. At discharge, sensory disturbances of the left arm, mild headache, and mild concentration problems remain.

Current treatment and new developments

In patients with acute CVT, anticoagulation with therapeutic doses of heparin is the primary treatment.5 However, in patients with septic CVT such as the patient in the Case Vignette, the use of anticoagulation is controversial. Patients with septic CVT were not included in the trials that evaluated the efficacy and safety of anticoagulant treatment in CVT, and there are some indications that the risk of intracranial hemorrhage is increased in patients with infections of the CNS.6 In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT)-a large observational cohort of 624 adult CVT patients-patients with CVT associated with an infection of the head or neck more frequently had new intracranial hemorrhages compared with patients without an infection.7 However, similar intracranial hemorrhage rates were seen in patients with head or neck infection who did and did not receive anticoagulation. Furthermore, there were no differences in clinical outcome between patients with and without an infection of the head or neck.

In patients with severe CVT with a high probability of poor outcome, such as those with decreased consciousness, intracranial hemorrhage, or deep venous system thrombosis, endovascular therapy is sometimes performed. The randomized controlled trial TO-ACT (Thrombolysis Or Anticoagulation for Cerebral venous Thrombosis) compared the effect of endovascular thrombolysis with standard therapeutic anticoagulation in patients with severe CVT on functional outcome (modified Rankin Scale) after 1 year.8 After inclusion of 67 patients, the trial was stopped early for futility. In the included patients, the proportion of patients with the primary outcome of a modified Rankin Scale of 0-1 was similar in both treatment groups.9

In CVT patients with parenchymal lesion(s) with impending herniation, decompressive hemicraniectomy can be life-saving.5 The quality of the evidence on this intervention is low because no randomized controlled trials have been performed due to ethical and feasibility reasons. To improve the quality of evidence on this intervention, an ongoing, international, prospective multicenter registry is underway.

Oral anticoagulation with vitamin K antagonists has been the standard treatment for the prevention of recurrent venous thromboembolism after CVT.5 This recommendation is based on the extrapolation of evidence regarding secondary prevention after deep venous thrombosis. With the increasing use of direct oral anticoagulants for secondary prevention after various types of venous thromboembolism , the use of direct oral anticoagulants in CVT has become a topic of debate.10,11

The RE-SPECT CVT trial (A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis) was an explorative randomized controlled trial that compared vitamin K antagonists with dabigatran for the prevention of recurrent venous thromboembolism in 120 patients with CVT. The study was not powered to formally assess non-inferiority or superiority of either treatment, but explorative comparison showed low venous thromboembolism recurrence rates and low hemorrhagic complication rates in both treatment groups after 25 weeks of follow-up.12 The Canadian SECRET trial (Study of Rivaroxaban for Cerebral Venous Thrombosis), currently in its feasibility phase, will compare rivaroxaban to standard of care in CVT.13

Lastly, the recently finished EINSTEIN Jr phase III trial (Oral Rivaroxaban in Children With Venous Thrombosis) was the first RCT to compare a DOAC (namely rivaroxaban) to standard anticoagulation in children with venous thromboembolism.14 The results of this study are expected to be released in the soon.

Conclusion

The prognosis of CVT is favorable compared with other types of stroke: almost 80% of patients with CVT recover without functional disability. Nevertheless, 5% to 10% of patients die in the acute phase due to CVT or an underlying condition. Moreover, a substantial number of patients who survive suffer from chronic sequelae such as chronic headache, fatigue, memory and concentration problems, or epilepsy.15

Large international research collaborations have greatly increased our knowledge of diagnosis, treatment, and prognosis of rare diseases such as CVT. Future studies are needed to improve the treatment of severe CVT, as well as the prevention and treatment of acute and chronic complications.

The authors are with the Department of Neurology, Amsterdam UMC, University of Amsterdam, The Netherlands.

References:

1. Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012;43:3375-3377.

2. Ferro JM, Canhao P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: Results of the international study on cerebral vein and dural sinus thrombosis (ISCVT). Stroke. 2004;35:664-670.

3. Coutinho JM, Ferro JM, Canhao P, et al. Cerebral venous and sinus thrombosis in women. Stroke. 2009;40:2356-2361.

4. Green M, Styles T, Russell T, et al. Non-genetic and genetic risk factors for adult cerebral venous thrombosis. Thromb Res. 2018;169:15-22.

5. Ferro JM, Bousser MG, Canhao P, et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis: endorsed by the European Academy of Neurology. Eur J Neurol. 2017;24:1203-1213.

6. Mook-Kanamori BB, Fritz D, Brouwer MC, et al. Intracerebral hemorrhages in adults with community associated bacterial meningitis in adults: should we reconsider anticoagulant therapy? PloS One. 2012;7:e45271.

7. Zuurbier SM, Coutinho JM, Stam J, et al. Clinical outcome of anticoagulant treatment in head or neck infection-associated cerebral venous thrombosis. Stroke. 2016;47:1271-1277.

8. Coutinho JM, Ferro JM, Zuurbier SM, et al. Thrombolysis or anticoagulation for cerebral venous thrombosis: rationale and design of the TO-ACT trial. Int J Stroke. 2013;8:135-140.

9. Coutinho JM. Thrombolysis or anticoagulation for cerebral venous thrombosis. 2017 European Stroke Organisation Conference; late braking news, oral presentation.

10. Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism. Cochrane Database Syst Rev. 2015:CD010957.

11. Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database Syst Rev. 2015:CD010956.

12. Ferro JM, Coutinho JM, Dentali F, et al. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol. In press.

13. Field TS. Study of rivaroxaban for cerebral venous thrombosis. https://clinicaltrials.Gov/ct2/show/nct03178864. Accessed July 17, 2019.

14. Lensing AWA, Male C, Young G, et al. Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood: design of the EINSTEIN-Jr phase III study. Thromb J. 2018;16:34.

15. Hiltunen S, Putaala J, Haapaniemi E, Tatlisumak T. Long-term outcome after cerebral venous thrombosis: analysis of functional and vocational outcome, residual symptoms, and adverse events in 161 patients. J Neurol. 2016;263:477-484.