Presentation on theme: "A Case of Cerebral Venous Sinus Thrombosis (CVST)"— Presentation transcript:
1 A Case of Cerebral Venous Sinus Thrombosis (CVST) McGill Stroke RoundsChenjie Xia (R2)Wednesday, April 28th, 2010
2 Outline Case introduction Overview of CVST Anticoagulation in CVST Role of steroids in CVSTManagement of seizures in CVST
3 Outline Case introduction Overview of CVST Anticoagulation in CVST Role of steroids in CVSTManagement of seizures in CVST
4 Mr. GC ID: PMHx: FMHx: Meds: Habits: 38M, right handed originally from Australia, now works as oceanography researcher in HonoluluPMHx:Nilno known previous clotting d/oFMHx:DVT in maternal grand-motherMeds:Nil at homeHabits:non-smoker, occasional EtOH
5 Mr. GCHPI:July 19th 2009: flight of 10hrs on from Honolulu to Montreal for oceanography conferenceDrank ½ litre of wine prior to flight (slightly unusual consumption)Slight HA and nausea for 3 days PTAPTA: 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
6 Mr. GCHPI (continued):July 20th: brought to MGH by EMS with sudden onset GTC seizure lasting 1 minute at the conferenceRepeated GTC seizure while in the MGH ERCourse at MGH:O/E : expressive aphasia, Rt hemiplegiaCT head: left frontal 24 x 35mm ICH with edema, mild mass effect, no midline shiftGiven Dilantin load and Ativan PRN for seizure controlTransferred to MNH NICUGTC seizure with witnessed loss of consciousness, foaming at mouth, post-ictal duration unclear.
7 Mr. GC O/E at MNH (July 21st): Neck supple, afebrile, vitals normal Mental statusSevere expressive aphasia (answers mostly limited to yes/no, < 4 words sentences, good repetition, able to read without difficulty)Follows first-second order commandCNs:pupils b/l reactive 4mm, fundi right normal, left not well seen, VFs normalright facial droop (UMN distribution)rest of the CNs unremarkableGeneral exam:135/80, HR 65, afebrileOverall unremarkable
8 Mr. GC O/E at MNH (July 21st): Motor: tone Right UE and b/l LEsDense right hemiplegia, normal left side strengthreflexes (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 RAMGeneral exam:135/80, HR 65, afebrileOverall unremarkable
9 Mr. GCCT head (July 20th)MRI T2 FLAIR (July 21st)
11 Mr. GC Imaging: CT head: MRI/MRV: left frontal hematoma at high convexity with +++ edemaThickening / hyperdensity of SSS, suspicion of venous thrombosisMRI/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 thrombosisMRV reveals thrombosis of anterior and mid portion of the SSS
12 Outline Case introduction Overview of CVST Anticoagulation in CVST Role of steroids in CVSTManagement of seizures in CVST
13 CVST - Epidemiology3-4 cases / million in adults; 7 cases / million in children; 5-8 cases / year in a tertiary care centre75% of adults are women, M:F = 1.5/5Peak incidence in third decade in adultsHighly variable symptoms and clinical course> 80% have good neurologic outcomeIn contrast to arterial strokes: rare, women dominate, peak in young adulthood, relatively good outcome
14 CVST - Pathogenesis Mechanisms: 1) Thombosis of cerebral veins localized edema and venous infarctioncombination of cytotoxic and vasogenic edema2) Thrombosis of major venous sinuses venous pressure and impaired CSF absorption intracranial hypertensionNo pressure between subarachnoid spaces at surface of the brain and ventricles no hydrocephalus
15 CVST - PathogenesisJan Stam. Thrombosis of the cerebral veins and sinuses. The New England Journal of Medicine, April 28, 2005.
16 CVST – Causes and Risk Factors Prothrombotic risk factor (genetic or acquired)DehydrationHead traumaNeurosurgical proceduresObstetrical delivery (12 / deliveries)OCPsLPInfections (otitis, mastoiditis, paranasal sinusitis, orbit or facial infections)43% of patients will have > 1 RF43% of patients will have > 1 RF (important to keep looking for additional RF, especially thrombophilias, even when 1 RF already found)OCPs (increasing incidence in women of childbearing age since advent of OCPs)LP (through ICP with downward brain movement and traction of sinuses leading to prothrombotic states)Infectionsotitis, mastoiditis sigmod or transverse sinusesparanasal sinusitis, orbit or facial infections cavernous sinus thrombosis
17 CVST – Clinical Manifestations Headachemost common, 90% of all casesFocal neurological signsmotor, sensory deficits, aphasia, hemianopsiaSeizuresBehavioural problemsAmnesia, personality changeThalamic lesionsStupor or comafrom herniation, seizures, bilateral thalamic involvementIsolated intracranial hypertension20-40%Headache, n/v, papilledema, diplopiaSeizures (40% of patients, far outnumber frequency in arterial strokes)Behavioural problems (delirium, amnesia, mutism) in thalamic lesions
18 CVST - Diagnosis Delay from onset of Sx to Dx: Diagnostic modalities: Average = 7 daysDiagnostic modalities:MRI, MRVbest tools for Dx and F/uCT, CTVCan be used for Dxlimited for F/u (radiation, contrast)Conventional angioPrevious gold standardMay be useful in cases of isolated thrombosis of cortical veins without sinus thrombosis
19 CVST - Treatment Acute management of patients with impaired LOC Role of anticoagulation (controversial…)Role of thrombolysisControl of seizuresChronic intracranial hypertension managementDifferent aspects of management of patients with CVSTPatients with acutely impared LOCStabilize; prevent or reverse cerebral herniationIV mannitol, surgical removal of hemorrhagic infarct, decompressive hemicraniectomyAnticoagulationControversialRCTs demonstrating non-significant trend toward better outcomeISCVT demonstrates safety even in those with prior ICHLMWH may be less likely to cause major bleeding complication than UFH (from studies looking at DVTs)Duration of A/C unclearThrombolysisAdministration of thrombolytic enzyme (urokinase) into the sinusOnly case reports and uncontrolled studies available, needs more RCTsCurrently should be restricted to patients with poor prognosisIntracranial hypertensionRepeated LPs, acetazolamide, shunt, fenestration
21 Mr. GC Course of hospitalization: Initial decision made not to A/C for now given hemorrhagePlan repeat MRI/MRV in 1 week, then reconsider A/C1 week later…Increasing strength of right hemibody (especially proximal muscles)
22 Mr. GCCT head (July 27th)MRI T2 FLAIR (July 27th)
23 Mr. GC Imaging: CT head: MRI/MRV: Evidence of edema causing significant mass effect with right midline deviation of 6 mm.The left lateral ventricle is compressedno interval change in the size of left frontal hemorrhage.more conspicuously seen edema and mass effectMRI/MRV:increased surrounding edema, midline shift to the rightfurther compression of the lateral ventricleno evidence of recent hemorrhageAgain demonstrated is hyperintensity in the two anterior thirds of the SSS in keeping with thrombosisMRV does not demonstrate any significant change
24 Mr. GC July 27: Clinical progress Increasing ease in word-findingStart to form short complete sentencesIncreasing strength of right hemibodyAgain, decision made not to A/C due to clinical stability / improvement.Plan: repeat imaging in one week and then reevaluate need for A/C…
26 Outline Case introduction Overview of CVST Anticoagulation in CVST Role of steroids in CVSTManagement of seizures in CVST
27 A/C in CVST – The Controversy Not a new problem…Hugo Krayenbuhl, Swiss neurosurgeon ( ) 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.”
28 A/C in CVST – The Controversy Rationale FOR use of A/C in CVSTAvoid thrombus extensionFavour spontaneous thrombus resolutionPrevent pulmonary embolismRationale AGAINST use A/C in CVSTPromote or worsen ICHPromote extracerebral bleeding complications
29 A/C in CVST – The Evidence Einhaupl et al. Lancet 1991 2 groups of 10 patients each average delay to treatment 10 daysUFH groupControl groupBetter outcome at 3 mos (8 recovered completely)Worse outcome at 3 mosNo new ICH (25% at baseline)2 new ICHsNo death2 deathsNo PE1 fatal (probable) PEOnly 2 RCTs available for analysis:Delay to Dx may reflect delay to proper diagnosis or reflect recruitment of patients who had deterioration following an initial period where A/C was not given because they initially looked clinically well
30 A/C in CVST – The Evidence 2) De Bruijn et al. Stroke 1999 2 groups of 30 patients each average delay to treatment 4 weeksLMWH (nadroparin) groupControl groupBetter outcome at 3 months (ARR = 11%, non significant)Worse outcome at 3 months1 major GI bleed1 case of fatal PENo new ICH (40% at baseline)
31 A/C in CVST – The Evidence Cochrane review: primary outcome (death)Stam et al. Anticoagulation for cerebral sinus thrombosis (Review). The Cochrane Collaboration, 2008
32 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
33 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
34 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
35 A/C in CVST – The Evidence Is A/C safe in patients with CVST complicated by hemorrhage?Fink et al. Neurology, 2001Starting points:Increasing evidence heparin is safe for CVST with hemorrhageUncertainties about safety of heparin in presence of large hemorrhages
36 A/C in CVST – The Evidence Fink et al. Neurology, 2001Findings25 cases of CVT: 14 with ICH, 9 of which > 4cm37/9 ICH patients treated with heparin:0/7 had significant recurrent ICH or clinical deterioration3/9 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
37 A/C in CVST – The Evidence Fink et al. Neurology, 2001ConclusionsHeparin is safe in CVT with large hemorrhageDe novo recurrent ICH (i.e. in different vascular territory) occurred only in those not treated with heparin & subsequent improvement occurred only if heparin was institutedLimitations of study: retrospective, non-randomized
38 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 countries624 consecutive adult patients with symptomatic CVT (recruited from May 1998 to May 2001)Dx confirmed by angio, CTV, MRV, surgery or autopsyChoice of treatment left up to treating physician (i.e. no randomization)
39 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 heparin¾ 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
40 A/C in CVST – The Evidence Girot et al. Predictors of outcome in patients with cerebral venous thrombosis and intracerebral hemorrhage. Stroke, 2007.
41 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 equipoiseMay still be reasonable to collect more data from cohort series or case-control studies to estimate A/C-related risk
42 A/C in CVST – The Conclusion EFNS (European Federation of Neurological Societies) 2010 guidelines:Level B recommendation for use of A/CConcomitant ICH is not a contraindicationLMWH may be preferableStudies with DVT shows risk for extracerebral bleed with LMWH compared to UFH
43 A/C in CVST – The Consensus? Letters to the editor, Archives of Neurology 2008:AGAINST (Walsay et al.)Good natural history without treatmentNo statistically significant from RCTsPhysicians choose to A/C because “they find it extremely difficult to do nothing.”AMBIVALENT (Roach)Data favoring A/C is suggestive, but not compellingMore RCTs needed?FOR (Stam)A/C corrects underlying mechanism of hemorrhage: thrombosis capillary pressure local cerebral edema petechial hemorrhageCannot ignore the ARR of 13% found in RCT (p = 0.08) from meta-analysis
44 A/C in CVST – Long-term Long-term oral anticoagulation Recanalization Occurs within first 4 months irrespective of further OATEven if incomplete or no recanalization, CVST recurrence rareCVST RecurrenceRisk may be lower than in extracerebral VTEISCVT: during 16 months f/u 2.2% recurrenceDespite above…Most still offer long-term OATISCVT: at 6 months, 80% of patients were on OAT; median time on OAT = 7.7 monthsEven murkier waters than acute A/C
46 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.”
48 Mr. GC July 27: Clinical progress Increasing ease in word-findingStart to form short complete sentencesIncreasing strength of right hemibodyAgain, decision made not to A/C due to clinical stability / improvement…Plan: repeat imaging in one week and then reevaluate need for A/C
50 Mr. GC Imaging of August 4th: size and density of the left frontal hematoma have diminished significantlysurrounding vasogenic edema has diminished slightlyleft frontal horn is starting to reexpandmidline shift has improved
51 Mr. GC Withhold A/C and wait another week…? August 4th: Plan: Pleuritic chest pain (no cough, SOB, desat or hemoptysis)Already on heparin sc for DVT prophylaxisCXR: small left pleural effusionCT-angio shows LLL PE with small area of pulm. parenchyma infarctionLeg Doppler: no evidence of DVTPlan:in view of PE: UFH started, then bridged to tinzaparin
52 Mr. GC August 7th: August 22th: Significant clinical improvement Began using laptopAble to speak incomplete sentences, still some difficulty finding low-frequency wordsStrength: 2+ at shoulder and hip, 3+ at elbow and knee, 2+ distallyAugust 22th:Ambulates independently in BRD/Ced to Australia on tinzaparin, to be followed by hematology and neurology in Australia
53 Mr. GC In search of hypercoagulability risk factor: Thrombophilic w/u: fibrinogen and FVIII reactive as per hemeotherwise normal FVL, pothrombin 21020A, MTHFR, homocysteine, anticardiolipin, ANA, potein C/S, antithrombin, antiphospholipid ab, lupus anticoagulant screen all normalMalignancy w/u:Tumour markers, SPEP normalPan CT, bone scan normalPET scan increased sigmoid uptake C-scope with removal of small polyp at hepatic flexure (tubular adenoma); normal sigmoid mucosa
55 Mr. GCCT head (July 27th)MRI T2 FLAIR (July 27th)
56 Mr. GCRecall previously mentioned significant vasogenic edema on patient’s CT/MRI …DexamethasoneJuly 21st – August 10th 4mg PO qidAugust 10th and onward gradual taper in view of improving edema on imagingWhat is the evidence for use of steroids in CVST?
57 Outline Case introduction Overview of CVST Anticoagulation in CVST Role of steroids in CVSTManagement of seizures in CVST
58 CVST – Use of Steroids Rationale for use of steroids Recall CVT associated with combination of vasogenic and cytotoxic edemaFOR steroids:can vasogenic edemacan ICPAGAINST steroids:prothrombotic propertiesproducing severe complications (GI bleed, infection, avascular necrosis, hyperglycemia)
59 CVST – Use of Steroids ISCVT, Stroke 2007: 24% of patients treated with steroidshigh variability across different centresVariability not affected by patient characteristicsMedian duration: 11 daysSteroids was not associated with better outcome in any subgroup of patients (including comparison b/w patients with and without ICP)
60 CVST – Use of SteroidsCanhao et al. Are steroids useful to treat cerebral venous thrombosis? Stroke, 2007.
61 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-randomizedtype and route and dose not specifiedno information on complications associated with treatmentsmall sample size, inadequate power
63 Mr. GCOn August 4thincreasing LFTs (ALT/GGT peaking at 1600 and 1200)W/u for liver dz all unremarkable:Serologies for autoimmune liver diseaseSerologies for viral hepatitis, CMV, EBVHepatic U/S to r/o portal vein or hepatic artery thrombosisEchocardiogram to r/o hepatic congestionLiver biopsy:changes c/w drug-effectinvolving < 30% of liver
64 Mr. GC Recall: Dx: Dilantin-induced hepatitis August 5th: Initially presented with GTC seizureGiven load of Dilantin 1g on presentationReceived Dilantin 200mg PO bid thereafterDx: Dilantin-induced hepatitisAugust 5th:Dilantin Keppra 500mg PO bidPrompt decrease in LFTs seen thereafterHow necessary were the AEDs in this case?
65 Outline Case introduction Overview of CVST Anticoagulation in CVST Role of steroids in CVSTManagement of seizures in CVST
66 CVST – Management of Seizures ISCVT data:Presenting seizuresPrevalence: 39.3%Risk factors: supratentorial lesion, cortical vein thrombosis, SSS thrombosis, puerperial CVTEarly seizures (w/i first 2 wks)Prevalence: 6.9%Risk factors: supratentorial lesion, presenting seizures60% of those with early seizures had presenting seizures.
67 CVST – Management of Seizures Patients with supratentorial lesion and presenting seizures were BOTH the most likely to have early and/or recurrent seizures as well as the most likely to benefit from AED treatment.Ferro et al. Early seizures in cerebral vein and dural sinus thrombosis – Risk factors and role of antiepileptics, Stroke, 2008.
68 CVST – Management of Seizures ISCVT data regarding AED use:those with presenting seizures and supratentorial lesion benefited significantly from AED useSeizures were not an independent predictor of death and/or dependencyLimitations:case-control study, it may overestimate AED effects.AED type, dosage, duration, compliance not specified
69 CVST – Management of Seizures EFNS 2010 guidelines:No data regarding prophylactic use of AEDsRFs associated with seizures:focal deficitsfocal edema / infarct, ICHcortical vein thrombosisRisk for residual seizures (i.e. after acute phase)5-10%, most occur within first yearStrongest predictor: hemorrhage on initial CT scan
70 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 headoptimal duration unclear, but reasonable to continue for 1 year in those with early seizures and hemorrhagic lesion on admission CT
71 Take Home MessagesIn contrast to arterial strokes, CVST occurs predomainly in young female adults, with HA, seizures, and intracranial hypertension as common presenting sxIt has an overall relatively good prognosisMRI/MRV are currently the best tests for Dx and subsequent F/ULook aggressively for underlying risk factors, especially thrombophilias
72 Take Home MessagesAnticoagulation in acute setting is safe in CVST, even in patients presenting with associated ICHLong-term anticoagulation may be reasonable, with duration tailored to underlying risk factorsSteroids should not be used, especially when no intraparenchmal lesions are seenIt seems reasonable to treat seizures with antiepileptics, although there’s no data available regarding the type and duration of treatment.
73 ReferencesCanhao 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, (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, 2008Wasay 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