Cerebral Vein & Sinus Thrombosis Dr Anna Kalff Clinical Haematology Registrar

Cerebral Vein & Sinus Cerebral Vein & Sinus ThrombosisThrombosis

Dr Anna KalffDr Anna Kalff

Clinical Haematology RegistrarClinical Haematology Registrar

Cerebral Vein ThrombosisCerebral Vein Thrombosis < 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

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PathogenesisPathogenesis

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

Risk FactorsRisk 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)

Risk Factor: OCPRisk 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

Risk Factor: IBDRisk 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

Risk Factor: IBDRisk Factor: IBD



IBD - PathogenesisIBD - 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

IBDIBD 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)

IBDIBD 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

Clinical PresentationClinical Presentation1. Headache – 90% of adults

usually increases gradually but can mimic a subarachnoid haemorrhage rarely

2. Focal presentationCerebral 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)

DiagnosisDiagnosis

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

TreatmentTreatmentGeneral: 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

TreatmentTreatmentAnticoagulation 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

TreatmentTreatment

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

Prognosis - ISCVTPrognosis - 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



Prognosis ISCVTPrognosis ISCVTImportant 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



Pregnancy and Risk of recurrencePregnancy 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)

Pregnancy related VTE and CVST occurs most frequently during the Puerperium - Pregnancy related VTE and CVST occurs most frequently during the Puerperium - recommend post partum anticoagulationrecommend post partum anticoagulation

Mehraein study: Unable to draw conclusion re need for prophylactic low dose Mehraein study: Unable to draw conclusion re need for prophylactic low dose anticoagulation ante partumanticoagulation ante partum

Evidence of a very low risk of recurrent VTE for women with previous extracerebral 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 venous thrombotic events if no thrombophila present or if the previous VTE was associated with a temporary RF associated with a temporary RF

Risk of recurrence increased if thrombophilia present or prior event was idiopathicRisk of recurrence increased if thrombophilia present or prior event was idiopathic(Brill-Edwards NEJM 2000;343:1439-44)(Brill-Edwards NEJM 2000;343:1439-44)

Decision for prophylactic anticoagulation in women without thrombophilia or Decision for prophylactic anticoagulation in women without thrombophilia or persisting prothrombotic RF may also be based on interval between previous CVST persisting prothrombotic RF may also be based on interval between previous CVST and subsequent pregnancy - 80% relapses within first 2 years 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 although mean time to pregnancy >2 years in 11/14 patients - may contribute to lack of

recurrencerecurrence Further prospective studies are needed to evaluate the need of a temporary Further prospective studies are needed to evaluate the need of a temporary

anticoagulation during pregnancy and puerperium in women with previous CVSTanticoagulation during pregnancy and puerperium in women with previous CVST

Pregnancy and Risk of recurrencePregnancy and Risk of recurrence

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Cerebral Vein & Sinus Thrombosis Dr Anna Kalff Clinical Haematology Registrar