A Case of Cerebral Venous Sinus Thrombosis CVST

A Case of Cerebral Venous Sinus Thrombosis (CVST) Mc. Gill Stroke Rounds Chenjie Xia (R 2) Wednesday, April 28 th, 2010

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

Mr. GC • ID: – 38 M, 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 Et. OH

Mr. GC • HPI: – July 19 th 2009: flight of 10 hrs 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 20 th: 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 35 mm 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 21 st): – 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 4 mm, 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 21 st): – 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 20 th) MRI T 2 FLAIR (July 21 st)

Mr. GC MRV (July 20 th)

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 • – CT, CTV • • – best tools for Dx and F/u 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 27 th) MRI T 2 FLAIR (July 27 th)

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 ? Member. ID=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 (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 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 No new ICH (40% at baseline) 1 case of fatal PE

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 > 4 cm 3 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, nonrandomized

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 (heterozygous FVL, Severe thrombophilia (antithrombin mutation, heterozygous prothrombin G 20210 A mutation, high VIII) protein C/S deficiency, homozygous FVL mutation, homozygous prothrombin G 20210 A 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 4 th)

Mr. GC • Imaging of August 4 th: – 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 4 th: – 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 7 th: – 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 22 th: – 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 21020 A, 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 27 th) MRI T 2 FLAIR (July 27 th)

Mr. GC • Recall previously mentioned significant vasogenic edema on patient’s CT/MRI … • Dexamethasone – July 21 st – August 10 th 4 mg PO qid – August 10 th 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 4 th – – 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 1 g on presentation – Received Dilantin 200 mg PO bid thereafter • Dx: Dilantin-induced hepatitis • August 5 th: – Dilantin Keppra 500 mg 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