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
• Case introduction
• Overview of CVST
• Anticoagulation in CVST
• Role of steroids in CVST
• Management of seizures in CVST
 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
• Case introduction
• Overview of CVST
• Anticoagulation in CVST
• Role of steroids in CVST
• Management of seizures in CVST
 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
• Case introduction
• Overview of CVST
• Anticoagulation in CVST
• Role of steroids in CVST
• Management of seizures in CVST
 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 Evidence
1) 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 Worse outcome at 3 mos

(8 recovered completely)
No new ICH (25% at 2 new ICHs
baseline)
No death 2 deaths
No PE 1 fatal (probable) PE
 A/C in CVST – The Evidence
2) 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 Worse outcome at 3 months
(ARR = 11%, non significant)
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)

Stam et al. Anticoagulation for cerebral sinus thrombosis (Review).

The Cochrane Collaboration, 2008
 A/C in CVST – The Evidence
• Cochrane review: secondary outcome (new or recurrent
intracerebral hemorrhage)  CI = 0-9%

Stam et al. Anticoagulation for cerebral sinus thrombosis (Review).

The Cochrane Collaboration, 2008
 A/C in CVST – The Evidence
• Cochrane review: secondary outcome (extracerebral
hemorrhage)

Stam et al. Anticoagulation for cerebral sinus thrombosis (Review).

The Cochrane Collaboration, 2008
 A/C in CVST – The Evidence
• 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
 A/C in CVST – The Evidence
• 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
 A/C in CVST – The Evidence
• 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
 A/C in CVST – The Evidence
• 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)
 A/C in CVST – The Evidence
• 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
A/C in CVST – The Evidence

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 Severe thrombophilia

(heterozygous FVL, (antithrombin mutation,
heterozygous protein C/S deficiency,
prothrombin G20210A homozygous FVL mutation,
mutation, high VIII) 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
• Case introduction
• Overview of CVST
• Anticoagulation in CVST
• Role of steroids in CVST
• Management of seizures in CVST
 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)
 CVST – Use of Steroids
• 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)
CVST – Use of Steroids

Canhao et al. Are steroids useful to treat cerebral venous

thrombosis? Stroke, 2007.
 CVST – Use of Steroids
• 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
• Case introduction
• Overview of CVST
• Anticoagulation in CVST
• Role of steroids in CVST
• Management of seizures in CVST
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
CVST – Management of Seizures

Ferro et al. Early seizures in cerebral vein and dural sinus thrombosis –
Risk factors and role of antiepileptics, Stroke, 2008.
CVST – Management of Seizures
• 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
CVST – Management of Seizures
• 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
CVST – Management of Seizures
• 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