Cerebral Vein & Sinus Thrombosis

1. Cerebral Vein & Sinus Thrombosis Dr Anna Kalff Clinical Haematology Registrar

2. < 2% of all strokes Predominantly affects young adults and children Male: uniform age distribution Females: 61% CVT in 20-35 age group 75% of adult patients are women (ISCVT study) Accounts for up to 50% of strokes during pregnancy and puerperium Incidence 3-4 per 1 million population Cerebral Vein Thrombosis

3. Pathogenesis 1. Thrombosis of cerebral veins - Local effects caused by venous obstruction, oedema of brain (both cytotoxic and vasogenic) and infarction due to elevated venous and capillary pressure - complicated by haemorrhage – may be multiple and bilateral, and not respect arterial vascular territories 2. Thrombosis of major sinuses - obstruction leads to impaired absorption of CSF and intracranial hypertension - no pressure gradient occurs – therefore the ventricles do not dilate 1/5 of patients with sinus thrombosis have intracranial hypertension only without signs of cortical vein thrombosis

4. Risk Factors ISCVT study: International Study on Cerebral Vein & Dural Sinus Thrombosis 43.6% of patients had multiple risk factors Thrombophilia (acquired or inherited) 34.1 % Oral contraceptives 54.3% (in females less then 50) (381/624)

5. Risk Factor: OCP • Increased risk, particularly third-generation oral contraceptives – gestodone, desogestrel • Supported by change in sex ratio of cases of sinus thrombosis over time. • until mid 70’s men and women affected equally • now a significant female predominance among young adults with sinus thrombosis - 70-80% • Dutch study (de Bruijn) (Lancet 352 (9124) p 326) • among those who develop CVST 56% of OCP users were taking third generation products, compared to 38% of population • 2 fold increased risk of CVST for 3rd generation compared with other types of oral contraceptives

6. Risk Factor: IBD • Independent and specific RF for thromboembolism (Meihsler Gut 2004;53:542-548) (Even when adjust for confounding variables of higher number of operations, higher use of contraceptives, more pregnancies and higher incidence of smoking) • 3.6 fold increased risk matched for age and sex • Rate of thromboembolism 1.2 - 6.1%, up to 39% at post mortem examination • In most patients TE, 60% had at least 1 specific IBD factor present at the time of event i.e.: active disease or the presence of complications: stenosis, fistulae or abscess. • Deep vein thrombosis and PE most common, but also unusual sites – central retinal, mesenteric, renal, portal and cerebral veins

7. Risk Factor: IBD

8. IBD - Pathogenesis • Which specific IBD factors promote the development of VTE? • Endotoxins:(Meihsler et al) • Role of endotoxins interacting with IL-1 and TNFa - activating coagulation cascade. • Systemic endotoxaemia detected in active and fistulising crohn’s. • ? Procoagulant effect of endotoxin enhanced by specific IBD factors (when added to control subject’s blood, does not induce clot formation) • Significant abnormalities of fibrinolytic system, platelet count, platelet function and platelet factors, indicating that prothrombotic factors pronounced in active disease (part of acute phase resp) • Anti-TNFa Ab such as infliximab – induces clinical remission but also lead to a decrease in activity of markers of coagulation

9. IBD • Increased platelet activation • CD40 derived from activated platelets - exhibits prothrombotic properties in addition to proinflammatory effects • Soluble CD40 Ligand levels are significantly elevated in IBD pt cf controls • Tissue Factor bearing microvesicles • Complex formed with serine protease FVIIa - initiate coagulation • Expression in the vascular space has only been demonstrated under certain conditions, such as sepsis or on monocytes • In conditions of increased inflammation and increased thrombotic tendency, postulated that increased TNFa activity induces monocyte to express TF-bearing microvesicles • binds to activated platelets and endothelial cell via P-selectin GP ligand 1 and P-selectin allowing transfer onto the activated platelet or endothelial cell surface • Promoting a state of hypercoagulability (SriRajaskanthan EJGH 2005 17(7) 697-700)

10. IBD • Thrombotic event in quiescent disease: ? associated with a thrombophilic disorder • No specific roles found for APC Resistance, Factor V Leiden, Prothrombin gene mutation, Protein C + S deficiency • Conflicting results from multiple trials • Studies analysing the prevalence of the prothrombin G20210A gene mutation in IBD patients and controls have shown no significant difference, although the small number of patients studied has limited the interpretation • Hyperhomocysteinaemia: (VITRO trial) • Vitamin therapy did reduce homocysteine levels, but did not reduce the frequency of recurrent venous thromboembolism. • The relevance of hyperhomocysteinaemia to patients with venous thrombosis, and IBD in particular, remains uncertain

11. Clinical Presentation 1. Headache – 90% of adults • usually increases gradually but can mimic a subarachnoid haemorrhage rarely 2. Focal presentation Cerebral lesions and neurological signs – 50% unilateral hemispheric symptoms (ie: hemiparesis or aphasia) followed by symptoms from the other hemisphere within days (cortical lesions on both sides of the superior sagittal sinus) Seizures – 40% (much more common than in other stroke types) Thrombosis of deep vein system (straight sinus and its branches) centrally located, often bilateral thalamic lesions behavioural symptoms – delirium, amnesia, mutism Compression of diencephalon or brainstem – comatose or die from cerebral herniation 3. Cavernous Sinus Thrombosis (3%) chemosis, proptosis, painful ophthalmoplegia 4. Pseudotumor Cerebri (Isolated Intracranial Hypertension)

12. Diagnosis • consider in young and middle-aged patients with • recent unusual headache • stroke like symptoms in the absence of usual risk factors • intracranial hypertension • CT evidence of haemorrhagic infarcts, especially if not confined to arterial vascular territories • Most sensitive examination: MRI + MR venography

13. Treatment General: supportive, symptomatic Anticoagulation • Arrest the thrombotic process and prevent Pulmonary embolus • Tendency for venous infarcts to become haemorrhagic. • 40% of patients with sinus thrombosis – haemorrhagic infarct prior to anticoagulation commencing • Weak Evidence for anticoagulation • BUT – anticoagulation is safe, even in the setting of ICH • 3 small randomised clinical trials looked at the effectiveness of anticoagulation treatment (NEJM 2005;352:1791-8) • All showed non-significant benefit of anticoagulation as compared with placebo • All included patients who had haemorrhagic infarcts prior to treatment, no increased or new cerebral haemorrhages developed after treatment with heparin, and 2 cases of PE occurred in the placebo groups) ISCVT: non-significant difference in outcome in favour of patients anticoagulated at therapeutic doses in the acute phase

14. Treatment Anticoagulation Cont’d • No data comparing the effect of Unfractionated Heparin with Low molecular weight heparin • Optimal duration of anticoagulation treatment after the acute phase is unknown • Recurrent Sinus thrombosis 2% of patients (ISCVT) • 80% of relapses occurred within first 2 years, mean latency of 10.3 months(Mehraein) • Extra cranial thrombotic event within one year – 4% • Usually, 6 months of anticoagulation with warfarin, or longer in the presence of risk factors Thrombolysis • Should be restricted to patients with a poor prognosis, in centres where the staff have experience in interventional radiology • data limited to case reports • consider if clinical deterioration despite adequate anticoagulation

15. Treatment Intracranial Hypertension alone • rule out other cause • LP if not contraindicated – measure CSF pressure • aim to lower ICP, relieve the headache, reduce papilloedema • Oral acetazolemide • if repeated LP and oral acetazolemide do not control the ICP within 2 weeks, surgical drainage is indicated, usually by a lumboperitoneal shunt

16. Prognosis - ISCVT • Very few patients dependent at 18/12 • death/dependency 13.4% • Complete recovery 79% • Contrast with arterial stroke – proportion of permanently dependent patient ranges between 1-2/3 of survivors

17. Prognosis ISCVT Important prognostic factors for death or dependence • Coma (GCS < 9) • Cerebral Haemorrhage • Malignancy Additional RF identified in ISCVT • Male sex • Age > 37 years • Mental status disorder • Thrombosis of deep cerebral venous system – straight sinus • CNS infection

18. Pregnancy and Risk of recurrence • History of CVST does not preclude a subsequent pregnancy Mehraein, JNNP 2003;74:814-816 • 39 patients of childbearing age – 22 pregnancies and 19 births in 14 patients • no recurrence of CVST and no extracerebral thrombotic complications occurred (including women who presented with pregnancy related CVST = 4) • Mean follow-up 10.25 years (1-20) • Mean interval between CVST and pregnancy 5.3 years • Anticoagulation • Low dose heparin • entire pregnancy = 2 • from 16/40 = 1 • from 36/40 until 2/52 post partum = 2 • no anticoagulation given in 14 other pregnancies (antepartum and puerperium)

19. Pregnancy and Risk of recurrence • Pregnancy related VTE and CVST occurs most frequently during the Puerperium - recommend post partum anticoagulation • Mehraein study: Unable to draw conclusion re need for prophylactic low dose anticoagulation ante partum • Evidence of a very low risk of recurrent VTE for women with previous extracerebral venous thrombotic events if no thrombophila present or if the previous VTE was associated with a temporary RF • Risk of recurrence increased if thrombophilia present or prior event was idiopathic (Brill-Edwards NEJM 2000;343:1439-44) • Decision for prophylactic anticoagulation in women without thrombophilia or persisting prothrombotic RF may also be based on interval between previous CVST and subsequent pregnancy - 80% relapses within first 2 years • although mean time to pregnancy >2 years in 11/14 patients - may contribute to lack of recurrence • Further prospective studies are needed to evaluate the need of a temporary anticoagulation during pregnancy and puerperium in women with previous CVST