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

2. Cerebral Vein Thrombosis
< 2% of all strokes
Predominantly affects young adults and children
Male: uniform age distribution
Females: 61% CVT in 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

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
Impaired absoption of CSF through the arachnoid villai

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 Dutch study (de Bruijn) (Lancet 352 (9124) p 326)
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 %
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: )
(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 %, 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
- Compared to other inflammatory conditions such as RA, and coeliac disease

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 Tissue Factor bearing microvesicles
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 (7) )

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)
headache (can mimick migraine or chronic daily headache), progressive with no other neurological symptoms – exception of diplopia due to involvement of 6th cranial nerve, papilloedema

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
Mannitol, surgical evacuation of clot or decompressive craniectomy

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:
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 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)
Miscarriages in those not anticoagulated not

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: )
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
0/44 patients without thrombophilia or idiopathic clot
3/51 with thrombophilia or idiopathic had a clot