A Case of Cerebral Venous Sinus Thrombosis (CVST) McGill Stroke Rounds Chenjie Xia (R2) Wednesday, April 28 th, 2010

A Case of Cerebral Venous Sinus Thrombosis (CVST)

McGill Stroke Rounds

Chenjie Xia (R2)

Wednesday, April 28th, 2010

Outline

• Case introduction• Overview of CVST• Anticoagulation in CVST• Role of steroids in CVST• Management of seizures in CVST

Outline


Mr. GC• ID:

– 38M, right handed– originally from Australia, now works as oceanography researcher

in Honolulu• PMHx:

– Nil– no known previous clotting d/o

• FMHx: – DVT in maternal grand-mother

• Meds: – Nil at home

• Habits: – non-smoker, occasional EtOH

Mr. GC

• HPI:– July 19th 2009: flight of 10hrs on from Honolulu to

Montreal for oceanography conference– Drank ½ litre of wine prior to flight (slightly unusual

consumption)– Slight HA and nausea for 3 days PTA– PTA: no fever or other malaise, no focal neurological

signs (aphasia, visual changes, motor or sensory changes), no recent infection/fever/weight loss or other constitutional symptoms

Mr. GC

• HPI (continued):– July 20th: brought to MGH by EMS with sudden onset

GTC seizure lasting 1 minute at the conference– Repeated GTC seizure while in the MGH ER– Course at MGH:

• O/E : expressive aphasia, Rt hemiplegia• CT head: left frontal 24 x 35mm ICH with edema, mild mass

effect, no midline shift• Given Dilantin load and Ativan PRN for seizure control

– Transferred to MNH NICU

Mr. GC

• O/E at MNH (July 21st):– Neck supple, afebrile, vitals normal– Mental status

• Severe expressive aphasia (answers mostly limited to yes/no, < 4 words sentences, good repetition, able to read without difficulty)

• Follows first-second order command

– CNs: • pupils b/l reactive 4mm, fundi right normal, left not well seen,

VFs normal• right facial droop (UMN distribution)• rest of the CNs unremarkable

Mr. GC

• O/E at MNH (July 21st):– Motor:

• tone Right UE and b/l LEs• Dense right hemiplegia, normal left side strength• reflexes (3+ at right arm and bilateral legs, right

ankle 4-5 bts clonus, equivocal toes)

– Sensory exam (normal to LT, T and vibration)– Cerebellar: normal left UE FTN and RAM

Mr. GC

CT head (July 20th) MRI T2 FLAIR (July 21st)

Mr. GC

MRV (July 20th)

Mr. GC

• Imaging:– CT head:

• left frontal hematoma at high convexity with +++ edema• Thickening / hyperdensity of SSS, suspicion of venous

thrombosis– MRI/MRV:

• left frontal intraparenchymal bleed (with focal mass effect and effacement of subarachnoid spaces, minimal compression of the left lateral ventricle)

• Signal void involving the anterior and middle portions of the SSS, highly compatible with sinus thrombosis

• MRV reveals thrombosis of anterior and mid portion of the SSS

Outline


CVST - Epidemiology

• 3-4 cases / million in adults; 7 cases / million in children; 5-8 cases / year in a tertiary care centre

• 75% of adults are women, M:F = 1.5/5• Peak incidence in third decade in adults• Highly variable symptoms and clinical

course• > 80% have good neurologic outcome

CVST - Pathogenesis

• Mechanisms:1) Thombosis of cerebral veins

• localized edema and venous infarction• combination of cytotoxic and vasogenic edema

2) Thrombosis of major venous sinuses• venous pressure and impaired CSF absorption

intracranial hypertension• No pressure between subarachnoid spaces at

surface of the brain and ventricles no hydrocephalus

CVST - Pathogenesis

Jan Stam. Thrombosis of the cerebral veins and sinuses. The New England Journal of Medicine, April 28, 2005.

CVST – Causes and Risk Factors

• Prothrombotic risk factor (genetic or acquired)• Dehydration• Head trauma• Neurosurgical procedures • Obstetrical delivery (12 / 100 000 deliveries)• OCPs • LP • Infections (otitis, mastoiditis, paranasal

sinusitis, orbit or facial infections)• 43% of patients will have > 1 RF

CVST – Clinical Manifestations

• Headache – most common, 90% of all cases

• Focal neurological signs – motor, sensory deficits, aphasia, hemianopsia

• Seizures • Behavioural problems

– Amnesia, personality change– Thalamic lesions

• Stupor or coma – from herniation, seizures, bilateral thalamic involvement

• Isolated intracranial hypertension – 20-40%– Headache, n/v, papilledema, diplopia

CVST - Diagnosis

• Delay from onset of Sx to Dx: – Average = 7 days

• Diagnostic modalities:– MRI, MRV

• best tools for Dx and F/u– CT, CTV

• Can be used for Dx• limited for F/u (radiation, contrast)

– Conventional angio • Previous gold standard• May be useful in cases of isolated thrombosis of cortical veins

without sinus thrombosis

CVST - Treatment

• Acute management of patients with impaired LOC

• Role of anticoagulation (controversial…)• Role of thrombolysis• Control of seizures• Chronic intracranial hypertension

management

Back to our case…

Mr. GC

• Course of hospitalization:– Initial decision made not to A/C for now given

hemorrhage– Plan repeat MRI/MRV in 1 week, then

reconsider A/C– 1 week later…

Mr. GC

CT head (July 27th) MRI T2 FLAIR (July 27th)

Mr. GC

• Imaging:– CT head:

• Evidence of edema causing significant mass effect with right midline deviation of 6 mm.

• The left lateral ventricle is compressed• no interval change in the size of left frontal hemorrhage.• more conspicuously seen edema and mass effect

– MRI/MRV: • increased surrounding edema, midline shift to the right • further compression of the lateral ventricle• no evidence of recent hemorrhage• Again demonstrated is hyperintensity in the two anterior thirds

of the SSS in keeping with thrombosis• MRV does not demonstrate any significant change

Mr. GC

• July 27:– Clinical progress

• Increasing ease in word-finding• Start to form short complete sentences• Increasing strength of right hemibody

– Again, decision made not to A/C due to clinical stability / improvement.

– Plan: repeat imaging in one week and then reevaluate need for A/C…

What is the role of anticoagulation in CVST?

Outline


A/C in CVST – The Controversy

• Not a new problem…– Hugo Krayenbuhl, Swiss

neurosurgeon (1902-1985) said in his 1966 summary of 73 patients with CVST:

“We have no proof that cerebral hemorrhages occur more often and are more severe in anticoagulated cases. The group without any treatment has the highest mortality.”

http://www.societyns.org/society/bio.aspx?MemberID=14400

A/C in CVST – The Controversy

• Rationale FOR use of A/C in CVST– Avoid thrombus extension– Favour spontaneous thrombus resolution– Prevent pulmonary embolism

• Rationale AGAINST use A/C in CVST– Promote or worsen ICH– Promote extracerebral bleeding

complications

A/C in CVST – The Evidence1) Einhaupl et al. Lancet 1991

2 groups of 10 patients each

average delay to treatment 10 days

UFH group Control group

Better outcome at 3 mos (8 recovered completely)

Worse outcome at 3 mos

No new ICH (25% at baseline)

2 new ICHs

No death 2 deaths

No PE 1 fatal (probable) PE

A/C in CVST – The Evidence2) De Bruijn et al. Stroke 1999

2 groups of 30 patients each

average delay to treatment 4 weeks

LMWH (nadroparin) group Control group

Better outcome at 3 months (ARR = 11%, non significant)

Worse outcome at 3 months

1 major GI bleed 1 case of fatal PE

No new ICH (40% at baseline)

A/C in CVST – The Evidence

• Cochrane review: primary outcome (death)

Stam et al. Anticoagulation for cerebral sinus thrombosis (Review). The Cochrane Collaboration, 2008

A/C in CVST – The Evidence• Cochrane review: primary outcome (death or

dependency)



• Cochrane review: secondary outcome (new or recurrent intracerebral hemorrhage) CI = 0-9%



• Cochrane review: secondary outcome (extracerebral hemorrhage)



• Is A/C safe in patients with CVST complicated by hemorrhage?

• Fink et al. Neurology, 2001– Starting points:

• Increasing evidence heparin is safe for CVST with hemorrhage

• Uncertainties about safety of heparin in presence of large hemorrhages


• Fink et al. Neurology, 2001– Findings

• 25 cases of CVT: 14 with ICH, 9 of which > 4cm3• 7/9 ICH patients treated with heparin:

– 0/7 had significant recurrent ICH or clinical deterioration

• 3/9 patients were initially not treated with heparin: – 2/3 had recurrent ICH in different vascular territory (1

eventually died)– 1/3 was subsequently treated with heparin and clinical

deficits resolved completed


• Fink et al. Neurology, 2001– Conclusions

• Heparin is safe in CVT with large hemorrhage • De novo recurrent ICH (i.e. in different vascular

territory) occurred only in those not treated with heparin & subsequent improvement occurred only if heparin was instituted

– Limitations of study: retrospective, non-randomized


• ISCVT (International Study on Cerebral Vein and Dural Sinus Thrombosis):– prospective multinational observational study

involving 89 centres in 21 countries– 624 consecutive adult patients with symptomatic CVT

(recruited from May 1998 to May 2001)– Dx confirmed by angio, CTV, MRV, surgery or autopsy– Choice of treatment left up to treating physician (i.e.

no randomization)


• ISCVT (cont’d):– 83% of patients received UFH or LMWH in the

acute phase reflects general consensus among neurologists re: A/C in acute CVST?

– Safety of heparin• ¾ with early ICH were treated with therapeutic heparin

(rate similar to non-ICH patients)• Heparin associated with better outcome (all delayed ICH

patients who had good outcome were treated with heparin)• Limitation: use of heparin was not randomized nor blinded


Girot et al. Predictors of outcome in patients with cerebral venous

thrombosis and intracerebral hemorrhage. Stroke, 2007.

A/C in CVST – The Conclusion

• Cochrane review 2008:– “A/C treatment for CSVT appeared to be safe and

was associated with potentially important reduction in risk of death or dependency which did not reach statistical significance”

– Future RCTs with A/C vs placebo may be difficult to initiate due to lack of equipoise

– May still be reasonable to collect more data from cohort series or case-control studies to estimate A/C-related risk

A/C in CVST – The Conclusion

• EFNS (European Federation of Neurological Societies) 2010 guidelines:

– Level B recommendation for use of A/C– Concomitant ICH is not a contraindication– LMWH may be preferable

• Studies with DVT shows risk for extracerebral bleed with LMWH compared to UFH

A/C in CVST – The Consensus?

• Letters to the editor, Archives of Neurology 2008:– AGAINST (Walsay et al.)

• Good natural history without treatment• No statistically significant from RCTs• Physicians choose to A/C because “they find it extremely difficult

to do nothing.”– AMBIVALENT (Roach)

• Data favoring A/C is suggestive, but not compelling• More RCTs needed?

– FOR (Stam)• A/C corrects underlying mechanism of hemorrhage: thrombosis

capillary pressure local cerebral edema petechial hemorrhage

• Cannot ignore the ARR of 13% found in RCT (p = 0.08) from meta-analysis

A/C in CVST – Long-term

• Long-term oral anticoagulation– Recanalization

• Occurs within first 4 months irrespective of further OAT• Even if incomplete or no recanalization, CVST recurrence

rare– CVST Recurrence

• Risk may be lower than in extracerebral VTE• ISCVT: during 16 months f/u 2.2% recurrence

– Despite above…• Most still offer long-term OAT• ISCVT: at 6 months, 80% of patients were on OAT; median

time on OAT = 7.7 months

A/C in CVST – Long-term

• EFNS guidelines– Optimal duration unclear, target INR 2-3

3-months 6-12 months Indefinite

Provoked CVST Idiopathic CVST Recurrent CVST

Transient RF Mild thrombophilia (heterozygous FVL, heterozygous prothrombin G20210A mutation, high VIII)

Severe thrombophilia (antithrombin mutation, protein C/S deficiency, homozygous FVL mutation, homozygous prothrombin G20210A mutation, APLA, combined abnormalities)

A/C in CVST – Final Words

• Still the same problem:

– Hugo Krayenbuhl (1966):

“We have no proof that cerebral hemorrhages occur more often and are more severe in anticoagulated cases. The group without any treatment has the highest mortality.”

Again, back to our case…

Mr. GC

• July 27:– Clinical progress

• Increasing ease in word-finding• Start to form short complete sentences• Increasing strength of right hemibody

– Again, decision made not to A/C due to clinical stability / improvement…

– Plan: repeat imaging in one week and then reevaluate need for A/C

Mr. GC

CT head (August 4th)

Mr. GC

• Imaging of August 4th:– size and density of the left frontal

hematoma have diminished significantly– surrounding vasogenic edema has

diminished slightly– left frontal horn is starting to reexpand– midline shift has improved

Mr. GC

• Withhold A/C and wait another week…?

• August 4th:– Pleuritic chest pain (no cough, SOB, desat or

hemoptysis) – Already on heparin sc for DVT prophylaxis– CXR: small left pleural effusion– CT-angio shows LLL PE with small area of pulm.

parenchyma infarction– Leg Doppler: no evidence of DVT

• Plan: – in view of PE: UFH started, then bridged to tinzaparin

Mr. GC• August 7th:

– Significant clinical improvement• Began using laptop• Able to speak incomplete sentences, still some

difficulty finding low-frequency words• Strength: 2+ at shoulder and hip, 3+ at elbow and

knee, 2+ distally

• August 22th: – Ambulates independently in BR– D/Ced to Australia on tinzaparin, to be followed

by hematology and neurology in Australia

Mr. GC

• In search of hypercoagulability risk factor:– Thrombophilic w/u:

• fibrinogen and FVIII reactive as per heme• otherwise normal FVL, pothrombin 21020A, MTHFR,

homocysteine, anticardiolipin, ANA, potein C/S, antithrombin, antiphospholipid ab, lupus anticoagulant screen all normal

– Malignancy w/u:• Tumour markers, SPEP normal• Pan CT, bone scan normal• PET scan increased sigmoid uptake C-scope with

removal of small polyp at hepatic flexure (tubular adenoma); normal sigmoid mucosa

Going back to some of the imagings…

Mr. GC

CT head (July 27th) MRI T2 FLAIR (July 27th)

Mr. GC

• Recall previously mentioned significant vasogenic edema on patient’s CT/MRI …

• Dexamethasone– July 21st – August 10th 4mg PO qid– August 10th and onward gradual taper in view of

improving edema on imaging

• What is the evidence for use of steroids in CVST?

Outline


CVST – Use of Steroids

• Rationale for use of steroids– Recall CVT associated with combination of

vasogenic and cytotoxic edema– FOR steroids:

• can vasogenic edema• can ICP

– AGAINST steroids: • prothrombotic properties• producing severe complications (GI bleed,

infection, avascular necrosis, hyperglycemia)


• ISCVT, Stroke 2007:– 24% of patients treated with steroids

• high variability across different centres• Variability not affected by patient characteristics

– Median duration: 11 days– Steroids was not associated with better

outcome in any subgroup of patients (including comparison b/w patients with and without ICP)


Canhao et al. Are steroids useful to treat cerebral venous thrombosis? Stroke, 2007.


• ISCVT, Stroke 2007 (cont’d):– Use of steroids was associated with worse outcome

in patients without intraparenchymal lesions (may be a false positive result though due to small sample size)

– Limitations: • non-randomized• type and route and dose not specified• no information on complications associated with treatment• small sample size, inadequate power

One last learning point from Mr. GC…

Mr. GC

• On August 4th

– increasing LFTs (ALT/GGT peaking at 1600 and 1200)

– W/u for liver dz all unremarkable:• Serologies for autoimmune liver disease• Serologies for viral hepatitis, CMV, EBV• Hepatic U/S to r/o portal vein or hepatic artery thrombosis• Echocardiogram to r/o hepatic congestion

– Liver biopsy: • changes c/w drug-effect• involving < 30% of liver

Mr. GC

• Recall: – Initially presented with GTC seizure– Given load of Dilantin 1g on presentation– Received Dilantin 200mg PO bid thereafter

• Dx: Dilantin-induced hepatitis• August 5th:

– Dilantin Keppra 500mg PO bid– Prompt decrease in LFTs seen thereafter

• How necessary were the AEDs in this case?

Outline


CVST – Management of Seizures

• ISCVT data:– Presenting seizures

• Prevalence: 39.3% • Risk factors: supratentorial lesion, cortical vein

thrombosis, SSS thrombosis, puerperial CVT

– Early seizures (w/i first 2 wks) • Prevalence: 6.9%• Risk factors: supratentorial lesion, presenting

seizures


Ferro et al. Early seizures in cerebral vein and dural sinus thrombosis –

Risk factors and role of antiepileptics, Stroke, 2008.


• ISCVT data regarding AED use: – those with presenting seizures and supratentorial

lesion benefited significantly from AED use – Seizures were not an independent predictor of death

and/or dependency– Limitations:

• case-control study, it may overestimate AED effects. • AED type, dosage, duration, compliance not specified


• EFNS 2010 guidelines:– No data regarding prophylactic use of AEDs– RFs associated with seizures:

• focal deficits• focal edema / infarct, ICH• cortical vein thrombosis

– Risk for residual seizures (i.e. after acute phase)• 5-10%, most occur within first year• Strongest predictor: hemorrhage on initial CT scan


• EFNS 2010 guidelines:– Overall recommendations:

• prophylactic AED may be given to those with focal deficits and supratentorial lesion on admission CT head

• optimal duration unclear, but reasonable to continue for 1 year in those with early seizures and hemorrhagic lesion on admission CT

Take Home Messages

• In contrast to arterial strokes, CVST occurs predomainly in young female adults, with HA, seizures, and intracranial hypertension as common presenting sx

• It has an overall relatively good prognosis• MRI/MRV are currently the best tests for Dx

and subsequent F/U• Look aggressively for underlying risk

factors, especially thrombophilias

Take Home Messages

• Anticoagulation in acute setting is safe in CVST, even in patients presenting with associated ICH

• Long-term anticoagulation may be reasonable, with duration tailored to underlying risk factors

• Steroids should not be used, especially when no intraparenchmal lesions are seen

• It seems reasonable to treat seizures with antiepileptics, although there’s no data available regarding the type and duration of treatment.

References• Canhao et al. Are steroids useful to treat cerebral venous thrombosis? Stroke, 2007.• Einhaupl et al. EFNS guideline on the treatment of cerebral venous and sinus

thrombosis in adult patients, European Journal of Neurology, 2010. • Ferro et al. Early seizures in cerebral vein and dural sinus thrombosis – Risk factors

and role of antiepileptics, Stroke, 2008. (p = 0.01 was used to avoid errors)• Ferro et al. Prognosis of cerebral vein and dural sinus thrombosis – Results of the

International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke, 2003.

• Fink et al. Safety of Anticoagulation for cerebral venous thrombosis associated with intracerebral hematoma, Neurology, 2001.

• Girot et al. Predictors of outcome in patients with cerebral venous thrombosis and intracerebral hemorrhage. Stroke, 2007.

• Stam, Jan. Thrombosis of the cerebral veins and sinuses. The New England Journal of Medicine, April 28, 2005.

• Stam et al. Anticoagulation for cerebral sinus thrombosis (Review). The Cochrane Collaboration, 2008

• Wasay et al. Anticoagulation in cerebral venous sinus thrombosis – Are we treating ourselves?; Roach E.S. Cerebral Venous Sinus Thrombosis – To treat or not to treat?: Stam. J. Sinus thrombosis should be treated with anticoagulation. Archives of Neurology, 2008

Documents

A Case of Cerebral Venous Sinus Thrombosis (CVST) McGill Stroke Rounds Chenjie Xia (R2) Wednesday, April 28 th, 2010