Case 129 – Summary

This weeks case was based around Cerebral venous sinus thrombosis (CVST). Thanks for everyone’s help really lovely that so many of you contributed your thoughts.

Incidence:

This is a rare disorder affecting 2-4/million of the adult population a year but is becoming increasingly common with more widespread availability of MRI scanning.

It is more common in females (accounting for up to 75% of cases), particularly in pre-menopausal women.

Risk factors for CVST :

  • Hormonal contraceptives/Pregnancy
  • Inherited Thrombophillias
  • Acquired Prothrombotic states: Malignancy, Nephrotic syndrome, Myeloproliferative disorders, TTP, PNH etc
  • Head Injury
  • ENT and CNS infections
  • PEG Aspariginase in ALL therapy

Presentation:

This case illustrates that not all cases of CVST will present in the same way. The majority of patients will have headaches, however they are not always localised and of gradual onset and there are case reports of CVST mimicking Subarachnoid haemorrhage as in our case. Other important presentations not to miss include encephalopathy, generalised seizures and even new cranial nerve palsies.  Therefore it is important that a clinician remains alert to this in a differential diagnosis particularly in pre-menopausal women who are the highest risk group.

Pathophysiology:

The pathophysiology of CVST helps explain the varied clinical presentations that are seen:

  1. The thrombosis can occur at any site within the dural vein network.
  2. Initially in CVST collateral venous pathways and capillary dilation mitigates the effects, however these systems can be rapidly overwhelmed.
  3. The thrombosis obstructs the blood drainage from brain parenchyma. This increase in pressure leads to high venous and capillary back pressure causing oedema as plasma leaks into the interstitial space. The extra pressure then causes capillaries to rupture leading to local haemorrhage formation.
  4. Increased pressure in the venous system results in increased intravascular pressure causing a reduction in cerebral profusion which can cause ischaemic infarction.
  5. There is also a loss of CSF reabsorption that leads to elevated intracranial pressure and the symptoms and signs associated with this such as vomiting, visual loss, papilloedema and cranial nerve palsies.

Understanding these mechanisms can help to understand why anticoagulation is recommended even in the presence of cerebral haemorrhage.

Initial Management:

Initial management is with either unfractionated or more commonly LMWH. Evidence for recommendations are weak and based on the findings of a 2011 Cochrane review that looked at 79 patients in two RCT and it concluded

Based upon the limited evidence available, anticoagulant treatment for cerebral venous sinus thrombosis appeared to be safe and was associated with a potentially important reduction in the risk of death or dependency which did not reach statistical significance”.

The European Stroke organisation guidelines recommend treatment with heparin in acute setting even with those who have intracerebral haemorrhage at baseline. BSH guidelines are in agreement with the european guidelines and also suggest duration of initial LMWH should be for at least 7 days

Thrombolysis is generally not recommended unless clinical deterioration despite anticoagulation and it is clear this is deterioration isn’t related to new intra-cranial bleed. Surgical decompression is also an option in raised ICP with risk of herniation.

Our patient had an elevated BMI and therefore it is important to follow local trust protocol or summary of product characteristics of the LMWH for safe prescribing. Generally the advice is use a weight based therapeutic dose but split dose (to reduce bleeding risk). Anti-Xa monitoring should occur to ensure therapeutic levels are reached. Initial monitoring should be 3-4 hours after third dose.  In renal impairment unfractionated heparin would be a suitable alternative.

Long term anticoagulation:

Oral anticoagulation is to be avoided until patient is stable. There is no recommendation to re-evaluate with imaging but if concerns this could be considered especially if ongoing symptoms. In some centres this is done routinely prior to moving to long term anticoagulation. As with all Haemostasis and thrombosis situations the plan needs to be based on the specifics of the case and there is a lack of trial data to support decision making.

Recommendations for duration of longer term anticoagulation are based on the individual precipitating features for the CVST.

If there was a clear transient provoking factor then European stroke guidelines suggest 3-12 months of anticoagulation is sufficient. BSH guidance also suggests at least 3 months anticoagulation should be used. This guidance is based on two important observations:

  1. Recurrence of CVST is generally low between 1.5% to 4.4% based on retrospective studies.
  2. There is also evidence to show the majority of patients even those without anticoagulation do recanalise following thrombosis by 4 months.

 

Practically speaking patients with clear provoking factors generally have 3-6 months anticoagulation and unprovoked events may be anticoagulated up to 12 months or even longer term depending on perceived risks and benefits. Patients with recurrent CVST should be considered for long term anticoagulation.

Thrombophillia screens are generally not recommended in the guidelines and are unlikely to alter management unless strong family history of thrombosis. A young female patient with unprovoked event who may be contemplating pregnancy should have anticardiolipin antibodies checked as a minimum in line with RCOG Green top 37a guidance. It should also be pointed out that thrombophillia screening should not occur during acute phase of thrombosis or be performed on anticoagulation. Patients who have been deemed appropriate for long term anticoagulation should not have thrombophillia screening as unlikely to alter management in these cases.

At present warfarin is recommended as the anticoagulant of choice for longer term anticoagulation. However, in context of active malignancy LMWH may be a more appropriate choice at preventing recurrent VTE. In pregnancy again LMWH should be continued.

In our patients case Direct oral anticoagulants are not suitable given the patients elevated BMI. There are however new studies that have been preformed looking at the possible safety of Dabigatran and other DOACs in CVST. Most of the evidence prior to 2019 had been based on single centre observational studies with less than 20 patients which concluded that Rivaroxaban and Dabigatran appeared safe.

The RE-SPECT CVT study which was a prospective randomised open-label trial with a blinded end-point adjudication reported in JAMA neurology in 2019. It recruited 120 patients in 9 countries across 51 sites. It found that Dabigatran and Warfarin were associated with low risk of recurrent VTEs (No VTE in both arms over 6 months follow up)  and that risk of bleeding was similar (1 Intestinal bleed on Dabigatran and 2 ICH in warfarin group) . The authors therefore conclude that “Dabigatran may be safe and effective in preventing recurrent VTEs”.  This trial was published after the European stroke guidelines were released as yet in Europe this approach has yet to be adopted into practice. It should be highlighted that DOACs are not recommended if thrombosis in context of antiphospholipid syndrome.

In summary CVST is an interesting condition with varied presentation and clinical course. Generally it has low recurrence rates and can be managed with short term anticoagulation. The mainstay of therapy is anticoagulation and haemorrhage associated with CVST is not a contraindication to therapy. In the future there may be a role for use of DOACs in the management of CVST but this remains the subject of clinical trials and is yet to be adopted by the guidance in UK and Europe.

The end of our case 129….

With all this evidence in mind our patient was reviewed in clinic. Her history revealed she had several possible risk factors for the CVST she has an elevated BMI and was on the COCP at the time of the event. She also had a finding of an isolated lupus anticoagulant at presentation without anticardiolipin or beta 2 glycoprotein 1 antibodies. Her antibodies were repeated while on anticoagulation and were negative at 12 week time point. She had no family history of VTE or personal history of thrombosis. She reported no issues on warfarin therapy and had been established on therapy for 8 months. She reported no neurological sequale or headaches.

She was clear she wished to become pregnant and that she wanted to stop her warfarin therapy. She was now 8 months from initial diagnosis and not on COCP so this was agreed. After discontinuing warfarin therapy her APTT was normal and her DRVVT was within normal range. The positive DRVVT at diagnosis of CVST was transient and not present on repeat sampling therefore she did not fulfil the criteria for Antiphospholipid syndrome (which would require two or more positive lupus anticoagulant tests more than 12 weeks apart in presence of VTE).

She was counselled about dietary advice as it was explained that high BMI was a modifiable risk factor for VTE. She was informed of the need to avoid hormone based contraceptives in future given the CVST. She was encouraged to address her lifestyle first before trying to conceive as this would improve her chances of a successful pregnancy outcome. It was explained to her that given her history of VTE while on hormonal contraception and her elevated BMI she would require thromboprophylaxis throughout her pregnancy and 6 weeks postpartum in line with RCOG Green top guidelines 37a.

Thanks for your help with the case and please feel free to post any comments.

References:

UpToDate cerebral venous sinus thrombosis section.

Coutinho  J, de Bruijn  SFTM, deVeber  G, Stam  J. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No.: CD002005.

Ferro et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis – endorsed by the European Academy of Neurology. European Journal of neurology 2017; 24 (10) 1203-1213.

https://onlinelibrary.wiley.com/doi/full/10.1111/ene.13381

Miyakis S et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of thrombosis and haemostasis.2006;4 (2) pp295-206.

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2006.01753.x

RCOG Green Top Guideline 37a. reducing the risk of VTE during pregnancy and puerperum. April 2015.

https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf

Tait C et al. Guidelines on the investigation and management of venous thrombosis at unusual sites.BJHaem 2012;159 (1) 28-38.

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2012.09249.x

Ferro et al. Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis A Randomized Clinical Trial. JAMA Neurol 2019;76(12) 1457-1465.

https://jamanetwork.com/journals/neur/articlepdf/2749167/jamaneurology_ferro_2019_oi_190070.pdf

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