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A Case of Cerebral Venous Sinus Thrombosis (CVST)

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Presentation on theme: "A Case of Cerebral Venous Sinus Thrombosis (CVST)"— Presentation transcript:

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

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

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

4 Mr. GC ID: PMHx: FMHx: Meds: Habits: 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

5 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

6 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 GTC 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 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 General exam: 135/80, HR 65, afebrile Overall unremarkable

8 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 General exam: 135/80, HR 65, afebrile Overall unremarkable

9 Mr. GC CT head (July 20th) MRI T2 FLAIR (July 21st)

10 Mr. GC MRV (July 20th)

11 Mr. GC Imaging: CT head: MRI/MRV:
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

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

13 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 In 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 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

15 CVST - Pathogenesis Jan 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) Dehydration Head trauma Neurosurgical procedures Obstetrical delivery (12 / deliveries) OCPs LP Infections (otitis, mastoiditis, paranasal sinusitis, orbit or facial infections) 43% of patients will have > 1 RF 43% 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) Infections otitis, mastoiditis  sigmod or transverse sinuses paranasal sinusitis, orbit or facial infections  cavernous sinus thrombosis

17 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 Seizures (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 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

19 CVST - Treatment Acute management of patients with impaired LOC
Role of anticoagulation (controversial…) Role of thrombolysis Control of seizures Chronic intracranial hypertension management Different aspects of management of patients with CVST Patients with acutely impared LOC Stabilize; prevent or reverse cerebral herniation IV mannitol, surgical removal of hemorrhagic infarct, decompressive hemicraniectomy Anticoagulation Controversial RCTs demonstrating non-significant trend toward better outcome ISCVT demonstrates safety even in those with prior ICH LMWH may be less likely to cause major bleeding complication than UFH (from studies looking at DVTs) Duration of A/C unclear Thrombolysis Administration of thrombolytic enzyme (urokinase) into the sinus Only case reports and uncontrolled studies available, needs more RCTs Currently should be restricted to patients with poor prognosis Intracranial hypertension Repeated LPs, acetazolamide, shunt, fenestration

20 Back to our case…

21 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… Increasing strength of right hemibody (especially proximal muscles)

22 Mr. GC CT 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 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

24 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…

25 What is the role of anticoagulation in CVST?

26 Outline Case introduction Overview of CVST Anticoagulation in CVST
Role of steroids in CVST Management 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 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

29 A/C in CVST – The Evidence
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 Only 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 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)

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, 2001 Starting points: Increasing evidence heparin is safe for CVST with hemorrhage Uncertainties about safety of heparin in presence of large hemorrhages

36 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

37 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

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 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)

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 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

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 equipoise May 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/C Concomitant ICH is not a contraindication LMWH may be preferable Studies 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 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

44 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 Even murkier waters than acute A/C

45 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) Mainly inspired from guidelines pertaining to DVT studies

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.”

47 Again, back to our case…

48 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

49 Mr. GC CT head (August 4th)

50 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

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 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

52 Mr. GC August 7th: August 22th: 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

53 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

54 Going back to some of the imagings…

55 Mr. GC CT head (July 27th) MRI T2 FLAIR (July 27th)

56 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?

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

58 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)

59 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)

60 CVST – Use of Steroids Canhao 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-randomized type and route and dose not specified no information on complications associated with treatment small sample size, inadequate power

62 One last learning point from Mr. GC…

63 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

64 Mr. GC Recall: Dx: Dilantin-induced hepatitis August 5th:
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?

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

66 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 60% 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 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

69 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

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

71 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

72 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.

73 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, (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


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