CEREBRAL VENOUS THROMBOSIS

Cerebral Venous Thrombosis

DR.SRIRAMA ANJANEYULU

Introduction

• Uncommon compared to arterial stroke• Significant morbidity• Recognised early and more commonly

with newer imaging techniques

Incidence• 0.5% of all strokes.• In 1973, Towbin reported CVT in 9% of

182 autopsies.• In 1995, Daif reported a frequency in

Saudi Arabia of 7 cases per 100,000 hospital patients.

• Venous to arterial strokes-1:62.5.• Towbin A.  Stroke. May-Jun 1973;4(3):419-30.• Daif A, Awada A, al-Rajeh S, et al. Stroke. Jul 1995;26(7):1193-5. 

Mortality &morbidity• Mortality in untreated CVT- 13.8-48%.

• Analyzed 91 consecutively admitted patients from 1995 to 1998 over a mean 1-year follow-up interval.

• 7% died in the acute phase• 1% died during the one year follow-up• 82% recovered completely• 1% were dependent• 59% developed thrombotic events during the follow-up• 10% had seizures• 11% complained of severe headaches• 1 patient experienced severe visual loss.

• Ferro JM, Lopes MG, Rosas MJ, et al. results of the venoport study. Cerebrovasc Dis. 2002;13(4):272

• series of 34 patients with confirmed cerebral venous thrombosis.

• 10 patients (30%) -episodic headaches• 3 patients (8.8%) - seizures• 4 patients (11.7%) -pyramidal signs• 2 (5.9%) - visual deficits• Mild nonfluent aphasia in 3 patients• Working memory deficit and depression of mood

in 6 patients (17.6%)• Buccino G, Scoditti U, Patteri I, et al.  Acta Neurol Scand. May 2003;107(5):330-

5. 

SEX&AGE• In a series of 110 cases, Ameri and

Bousser found a female-to-male ratio of 1.29:1.

• 61% of women with CVT were aged 20-35 years.

• Ameri A, Bousser MG.  Neurol Clin. Feb 1992;10(1):87-111

Mechanisms Leading to the Clinical Manifestations

• The occlusion of a cerebral vein -localized brain edema and venous infarction.

• HPE- swollen veins, edema, ischemic neuronal damage and petechial hges that can merge - large hg.

• Cytotoxic edema by local ischemia damages the energy-dependent cellular membrane pumps and induce intracellular swelling.

• Vasogenic edema by disruption in the BBB and leakage of plasma into the interstitial space is reversible .

• The occlusion of a major sinus - development of intracranial hypertension due to impaired absorption of CSF.

• Stam J. Adv Neurol 2003;92:233-40.  

Headache• MC symptom of CVT

• Stretching of nerve fibres in the walls of the occluded sinus and local inflammation .

1.Headache of unusual type that started a few days or wks earlier with other CNS symptoms.

2.In a context of isolated intracranial hypertension. 3.Only symptom , in the absence of intracranial

hypertension, SAH or meningitis.

• Isolated headache is sometimes of the thunderclap type, mimicking a subarachnoid hemorrhage

Isolated focal neurological deficits

• long-lasting focal neurological deficits due to stroke (either venous ischemia or intra-cerebral hemorrhage) or edema.

• Transient focal neurological deficits mimicking transient ischemic attacks.

Diffuse encephalopathies with seizures

• In patients with parenchymal lesions, the clinical picture is more severe and may include at various degrees:

• Coma• motor deficits or aphasia • seizures (focal or generalized seizures,

including status epilepticus). • Seizures - more common in sagittal sinus

and cortical vein thrombosis.

Other clinical presentations

• Attacks of migraine with aura• Isolated psychiatric disturbances• Pulsatile tinnitus• Isolated or multiple cranial nerve

involvement

Clinical manifestations and the site of venous occlusion

• Cortical veins -motor or sensory deficits, seizures or both. • Sagittal sinus- motor deficits that are alternating or

bilateral,seizures and rarely isolated intracranial hypertension. • Lateral sinus -isolated intracranial hypertension, associated

with aphasia when the left transverse sinus is occluded. • Deep cerebral veins -severe clinical presentation with coma,

delirium and bilateral motor deficits, symptoms may be of milder if the thrombosis is limited.

• Cavernous sinus- orbital pain, chemosis, proptosis and oculomotor palsies.

• Leys D, Cordonnier C. Ann Indian Acad Neurol 2008 ;11:79-87.

Specificities of clinical manifestations in the elderly

• In ISCVT, 8.2% of patients were aged 65 years or over.

• Isolated intracranial hypertension -less frequent

• Impaired consciousness and mental status impairment-more frequent .

• CVT-DD for impaired consciousness in elderly • Cancers more frequently found as the cause

than in younger CVT pts. • Ferro JM, Canhao P, Bousser MG, Stam J, Barinagarrementeria F; ISCVT Investigators. Stroke

2005;36:1927-32.  

I. Gosk-Bierska etal, Neurology 2006;67;814-819

Laboratory Studies

• Diagnosis made on cl. presentation and imaging studies.

• For determining the possible causes of CVT.• CBC -polycythemia,PC decreased in TTP; leukocytosis in

sepsis. • Antiphospholipid and anticardiolipin antibodies .• protein S, protein C, antithrombin III, lupus anticoagulant, and

Leiden factor V mutation.• Sickle cell preparation or hemoglobin electrophoresis .• ESR,ANA-systemic lupus erythematosus, Wegener

granulomatosis, and temporal arteritis.• Urine protein –NS.• LFT-cirrhosis.

D-Dimers• 18 pts with CVT, Tardy et al reported that D-dimer levels < 500 ng/mL

had a negative predictive value for ruling out the diagnosis in pts with acute headache.

• 54 consecutive pts with headache suggestive of CVT, Lalive found that 12 had CVT and, of those, 10 had D-dimer levels >500 ng/mL.

• Kosinski et al (2004) -343 pts with symptoms s/o CVT.• The diagnosis was confirmed in 35, with 34 of these pts showing

elevated D-dimer levels > 500 mcg/L. • Of the 308 pts not having CVT, 27 had positive values. • Sensitivity was 97.1%, with a negative predictive value of 99.6%. • Specificity was 91.2%, with a positive predictive value of 55.7%.

• Tardy B, Tardy-Poncet B, Viallon A, et al.  Am J Med. Aug 15 2002;113(3):238-41.• Lalive PH, de Moerloose P, Lovblad K, et al. Neurology. Oct 28 2003;61(8):1057-60. • Kosinski CM, Mull M, Schwarz M, et al.  Stroke. Dec 2004;35(12):2820-5. 

Imaging Studies MRI

Infarct that does not follow the distribution of an expected arterial occlusion.

Show absence of flow void in the normal venous channels. MRV is an excellent method of visualizing the dural venous

sinuses and larger cerebral veins. Single-slice phase-contrast angiography (SSPCA) takes less

than 30 seconds and provides rapid and reliable information. Procedure of choice in diagnosing cerebral venous thrombosis.

In a study of 21 patients, Adams demonstrated a specificity and sensitivity of 100% for SSPCA when compared to alternative imaging techniques.

– Adams WM, Laitt RD, Beards SC, et al. Eur Radiol. 1999;9(8):1614-9. 

MRI• Very early stage of an acute thrombosis, MRI alone is limited by

flow artefacts that can lead to false positives and the lack of hyperintense signal on T1- and T2-w images.

• During the first 3-5 days, the thrombosed sinus appears as an isointense signal on T1-w sequences and a hypointense signal on T2-w sequences: it can, therefore be very difficult to differentiate it from normal veins.

• The diagnostic yield of MRV alone is limited ,cannot differentiate between an occluded sinus and hypoplasia, particularly for lateral sinuses.

• Even with the combination of MRI and MRV, the diagnosis can still remain difficult, particularly for isolated cortical vein thrombosis: if the characteristic cord sign is not present on noncontrast-enhanced CT- or MRI-scan, a conventional angiography may sometimes still be required.

Magnetic resonance venogram - axial view; A = transverse sinus;

B = sigmoid sinus; C = confluence of sinuses; D = superior sagittal sinus.

Magnetic resonance venogram - sagittal view; A = lateral (transverse) sinus; C = confluence of sinuses; D = superior sagittal sinus; and E = straight sinus.

Contrast-enhanced MRI showing lack of filling of left transverse sinus.

Axial view of MR venogram demonstrating lack of flow in transverse sinus.

Coronal view of MR venogram demonstrating lack of flow in the left transverse and sigmoid sinuses.

CT

CT - often the first imaging study obtained. infarction that does not correspond to an arterial distribution.

In the absence of a hemorrhagic component, demonstration of the infarct may be delayed up to 48-72 hours.

Useful in ruling out other conditions such as neoplasm and in evaluating coexistent lesions such as subdural empyema.

CT of the sinuses is useful in evaluating sinusitis; CT of the mastoids may be helpful in lateral sinus thrombosis.

Empty delta sign appears on contrast scans as enhancement of the collateral veins in the superior sagittal sinus (SSS) walls surrounding a nonenhanced thrombus in the sinus.

Early division of the SSS can give a false delta sign. The dense triangle sign formed by fresh coagulated blood in the SSS

and the cord sign representing thrombosed cortical vein are extremely rare.

Empty delta sign in a patient with superior sagittal sinus thrombosis. Transverse contrast-enhanced CT image reveals low-attenuating thrombus (arrow) within the superior sagittal

sinus, surrounded by a triangular area of enhancement.

DENSE TRIANGLE SIGN

PROGNOSISPredictors of 30-day case fatality • Impaired consciousness• Mental status disorder• Thrombosis of the deep venous system• Posterior fossa lesions

• The main cause of death is transtentorial herniation, secondary to a large hemorrhagic lesion, multiple lesions or diffuse brain edema.

• Other causes of acute death include status epilepticus, medical complications and pulmonary embolism.

• Deterioration after admission occurs in approximately 23% pts.• Mortality after the acute phase is prominently associated with the

underlying cause, especially cancer.

Out comeThe predictors of poor long-term outcomes • Infection of CNS• Cancer• Deep venous system thrombosis• Intracranial hemorrhage• GCS score at admission >9• Mental status disorder• Age >37 yrs • Male gender• The overall outcome is better than that of arterial stroke as 2/3 pts

recover without sequelae. • In elderly pts, most frequent cause is a carcinoma, the outcome is

worse, 49% of patients being dead or dependent at the end of follow-up.

GENERAL MANAGEMENT• Pts with altered mental status or hemiplegia should be

given NBM.• IVF should not be hypotonic solutions. • NS @ 1000 mL in 24 hrs. • To decrease ICP the head elevated 30-40° at all times.• Seizures –Fosphenytoin in those patients who require a

parenteral formulation. • Phenobarbital or sodium valproate inj , if the pt has

allergy to phenytoin. • Diazepam or lorazepam to treat SE, pt should be given

an AED with a longer duration of action to prevent recurrent szs.

Heparin & procedures of recanalization

• The aims of heparin therapy in CVT (i) to prevent the extension of the

thrombus(ii) to treat the underlying prothrombotic

state(iii) to prevent venous thrombosis in other

parts of the body or PE(iv) to prevent the recurrence of CVT

• The German trial that compared iv unfractionated heparin with placebo was stopped after the recruitment of 10 pts in each arm because the interim analysis showed a significant benefit .

• Another analysis, based on more usual scales of stroke outcome, failed to show any statistically significant difference between the two groups but showed just a clear tendency.

• The Dutch trial compared fixed high-dose of SC nadroparin with placebo in 60 pts. • Failed to show any statistically significant difference between groups. • Imbalance at baseline that favored the placebo group.

• The Indian trial compared the effect of IV unfractionated heparin with placebo in 57 Indian women with puerperal sinus thrombosis in whom the diagnosis had not been confirmed by MRI or angiography.

• Showed an insignificant tendency for a benefit of anticoagulant treatment .

• A meta-analysis of these 3 trials showed a insignificant reduction in the relative risk of death or dependency of 0.46 (95% CI, 0.16-1.31).

• Based on these 3 trials and the meta-analysis, most neurologists now start treatment with heparin as soon as the diagnosis is confirmed, even in the presence of hemorrhagic infarcts.

• Einhaupl KM et al. Lancet 1991;338:597-600.  • de Bruijn SF, Stam J. Stroke 1999;30:484-8.  • Nagaraja D, Rao B, Taly A, NIMHANS J 1995;13:111-5.  

HEPARIN• Increases the action of antithrombin III, leading to inactivation

of coagulation enzymes thrombin, factor Xa, and factor Ixa.• Initial infusion: 18 U/kg/h IV• aPTT checked in 6 h and q6h after any dosage change, as well

as every am• adjust dose according to aPTT

aPTT ; <1.2 times : 80 U/kg bolus with increase of 4 U/kg/haPTT : 1.2-1.5 times : 40 U/kg bolus with increase of 2 U/kg/haPTT : 1.5-2.3 times : No change in infusion rate aPTT : 2.3-3 times : Decrease infusion rate by 2 U/kg/haPTT : > 3 times : Hold infusion for 1 h and decrease rate by 3 U/kg/h

THROMBOLYTIC THERAPY

– Infusion of a thrombolytic agent into the dural venous sinus utilizing microcatheter technique.

– Limited to specialized centers ,should be considered for patients with significant deficit.

– Rheolytic catheter device in pts who fails to responded to microcatheter instillation of urokinase.

– The rheolytic catheter was designed for use in the coronary circulation and delivers 6 high-velocity saline jets through a halo device at the tip of the catheter.

– leads to breaks up the thrombus. – Particulate debris is directed into an effluent lumen for

collection into a disposable bag.

• Alteplase • 1 mg/cm infused via venous sinus catheter

throughout clot, then 1-2 mg/h• Urokinase • 250,000 U/h instilled directly or via venous sinus

catheter; additional doses of 50,000 U; total dose 1,000,000 U over 2 h

• Streptokinase • Loading dose: 1000-3000 IU/kg; followed by

infusion of 1000-1500 IU/kg/h; in CVT, administered by direct infusion via catheter

ORAL ANTICOAGULANTS• After acute stage, heparin replaced by oral

anticoagulation. • To prevent any recurrence of CVT, any other

venous thrombosis and pulmonary embolism. • Following EBM data and recommendations in deep

venous thrombosis oral anticoagulation is recommended for 6-12 months, aiming at INR 2-3.

• Prolonged oral anticoagulation necessary in pts with inherited or acquired prothrombotic disorders, including APLA.

Warfarin • Interferes with action of vitamin K, a cofactor

essential for converting precursor proteins into factors II, VII, IX, and X.

• 5 mg PO qd; adjust dose by monitoring INR (target, 2.5)

• 0.2 mg/kg PO up to 10 mg,Maintenance: 0.1 mg/kg/d.(paed)

• ginger and Ginkgo biloba should be avoided.• green leafy vegetables have high levels of

vitamin K, which may decrease INR.

Drugs that may decrease anticoagulant effects

• griseofulvin• Carbamazepine• Glutethimide• Estrogens• Nafcillin• Phenytoin• Rifampin• Barbiturates• Cholestyramine• vitamin K• Spironolactone• oral contraceptives• sucralfate

Medications that may increase anticoagulant effects

• Phenylbutazone• Salicylates• Sulfonamides• chloral hydrate• Clofibrate• Diazoxide• anabolic steroids• Ketoconazole• ethacrynic acid• Miconazole• nalidixic acid• Sulfonylureas• Allopurinol• Chloramphenicol• Cimetidine• Disulfiram• Metronidazole• phenylbutazone• Phenytoin• Sulfonamides• acetaminophen• sulindac

Holger Allroggen, Richard J Abbott,Postgrad Med J 2000;76:12–15

Thank you