TROMBOSIS VENOSA CEREBRAL LECCIONES DEL ISCVT

Transcription

1 TROMBOSIS VENOSA CEREBRAL LECCIONES DEL ISCVT José M. Ferro Department of Neurociences Hospital de Santa Maria, CHLN University of Lisbon Lisboa, Portugal

2 TROMBOSIS VENOSA CEREBRAL ISCVT LECCIONES DEL ISCVT Rational and design Main contributions Advances on cerebral venous thrombosis after ISCVT ISCVT 2 Purpose and design

3 WHY CEREBRAL VENOUS THROMBOSIS?

4 CEREBRAL VENOUS THROMBOSIS A SINGLE CENTRE CASE SERIES 8 cases of CVT Retrospective observational study Data retrieved from file review

5 CEREBRAL VENOUS THROMBOSIS status before ISCVT Variable clinical presentation Difficulty in establishing diagnosis Infection and puerperium important causes Unpredictable prognosis High mortality Management uncertainity and variability

6 VENOPORT National multicentre observational study 142 adult patients with CVT admitted to 20 hospitals in Portugal retrospective series patients prospective series 6/95-6/88 91 patients Mean follow up 12 months (3-36) Ferro et al, Cerebrovasc Dis 2001;11: ;13: ;14: ;15:78-83

7 Incidence and prevalence Autopsies: 1-9% Hospital bases series Portugal: 0.22/ /year (IC 95% = 0-47) Population based studies Netherlands: 1.32/ /year Stroke registries India: 6% of 1014 strokes Pregnancy CEREBRAL VENOUS THROMBOSIS: EPIDEMIOLOGY 11.6/ deliveries in USA Infants & children <18 years in Canada 0.64/

8 CEREBRAL VENOUS THROMBOSIS: UNDERDIAGNOSED?

9 ISCVT: PHRASING THE RESEARCH CLINICAL QUESTION In PATIENTS with cerebral vein and dural sinus thrombosis In a multicentre, multinational, observational, cohort study (DESIGN) Managed following each site best practice (INTERVENTION) What is the OUTCOME, defined as death or dependency at least 6 months after onset

10 INTERNATIONAL STUDY ON CEREBRAL VEIN AND DURAL SINUS THROMBOSIS U.S.A 10 Mexico 53 Canada 5 Peru 1 Chile 6 Belgium 23 France 132 United Kingdom 10 Portugal 126 Spain 39 Uruguay 1 Germany 53 Italy 54 Sweden 11 The Netherlands 30 Austria 8 Luxembourg 2 Brazil 48 India 1 Australia adult cases 89 centres, 21 countries mean age=39, female/male=2,9 79% caucasians median follow up 16 months Ferro et al Stroke 2004 China 3

11 A DIFFICULT BALANCE Internal validity How precise are the definitions and procedures? Reliability Same results under the same circunstances External validity Same results under different circunstances

12 ISCVT DESIGN Diagnosis of CVT by MR, angiography (any type), surgery or autopsy Simple and short admission and follow up forms Diagnostic work up and treatment left to the local investigator Follow up at 6 months and year 1,2 and 3 Main outcome - death and disability (mrs)

13 CVT: PRESENTING SYNDROMES Isolated intracranial hypertension syndrome Headache, nausea/vomiting, papilloedema, visual disturbances, diplopia/vi nerve palsy, tinnitus Isolated headache Focal syndrome Focal deficits: mono/hemiparesis, aphasia Seizures Encephalopathy Multifocal signs Mental status changes Decreased alertness, stupor/coma

14 CVT: LESS COMMON PRESENTING SYNDROMES Cavernous sinus syndrome Subarachnoid haemorrhage Generalised, basal Localised, convexity Pulsating tinnitus Cranial nerve palsies VII Collet-Sicard syndrome

15 CVT: PRESENTING SYMPTOMS & SYNDROMES Variable with: Interval onset-presentation Age of the patient Location of vein or sinus occlusion Parenchymal lesions Underlying disease

16 CVT: TYPE OF PRESENTATION Isolated ICH OTHERS % ACUTE SUBACUTE CHRONIC

17 PRESENTING SYMPTOMS in patients aged 65 or more >64 years <65 years Isolated Intracranial hypertension %; -22 to -5 Mental status disorder %; 20 to 43 GCS< %; 5 to 30 Papilloedema %;-23 to -3 Visual loss %;-14 to 0 Headache %;- 40 to -14 % Ferro et al Stroke 2006

18 CVT: PARENCHYMAL LESIONS Hemorrhage "Infarct" No lesion % I IHS Aphasia Paresis GCS<14 Seizure Straight Sinus Deep Veins Ferro et al 2010

19 VENOUS INFARCTS FLAIR DWI ADC

20 VENOUS INFARCT Increased permeability of the BBB Brain edema Thrombus Collateral circulation ADC Anatomy Thrombosis Lesion Venous Infarction Hemorrhage Destruction of the BBB Inflammation Prothrombotic state and endothelial dysfunction Secondary injury potentiated by physiological processes

21 VENOUS INFARCT hypothesis In CVT, disruption of the BBB is followed by an inflammatory response Elevation of markers of BBB disruption, inflammatory markers and prothrombotic markers is associated with a higher degree of secondary lesion Progression of the parenchymal lesions and functional prognosis is associated with the levels of MMP-9, IL-6 and sp-sel over time Aguiar de Sousa D PhD thesis

22 Methods Admission Worsening 0 48h 1S 1M 3M CVT Only in patients with parenchymal lesion

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24 INTEROBSERVER AGREEMENT ON THE LOCALISATION OF CVT High interobserver agreement for the majority of dural sinus and cerebral veins (K > 0,80) Higher diagnostic agreement for the thrombosis of the right jugular vein and lateral sinus than for their left counterparts Low agreement for the diagnosis of cortical vein thrombosis Higher agreement when there are parenchymal lesions located near the occluded veins or sinus Ferro et al Eur J Neurol 2007

25 Idbaih A et al Stroke 2006 MRI: T2*SW SEQUENCES T2*SW cortical vein thrombosis

26 TVC: D-DIMERS Are DD < 500 ng/ml a good screening test for CVT? Meta-analysis of 14 studies with 1134 patients Sensitivity 93.9%; specificity 89.7% Risk factors for false negative D-Dimers Isolated headache Limited extent of CVT Longer duration of symptoms Ongoing M Arnold s (Berne) study D-dimers; FXIII-AP Dentali et al, 2012

27 THE CAUSES OF CVT Associated conditions Condition found in association with CVT Risk factors Condition that increases the risk of CVT Cause Causality requests are fulfilled Necessary Sufficient Contributory

28 CVT ASSOCIATED CONDITIONS 13% no associated condition 44% > 1 associated condition 41% - genetic prothrombotic mutation Nº associated conditions

29 IATROGENIC CVT: ISCVT (11%) Ferro and Canhão, 2013

30 Gouveia and Canhão, 2010; Marjot et al Stroke 2011; Lauw et al, 2014 CVT & THROMBOPHILIA Significant associations OR Prothrombin G20210A 6.1 Factor V Leiden 2.9 Antihtrombin deficiency 3.8 Protein S deficiency 6.5 Protein C deficiency 8.4 High homocystein 3.0

31 Gouveia and Canhão, 2010; Marjot et al Stroke 2011; Lauw et al, 2014 CVT & THROMBOPHILIA Not associated MTHFR polymorphisms PAI-1 polymorphisms Protein Z/G79A Not estimable/uncertain JK-2/V617 (more frequent in MPS with CVT) Factor VIII

32 RISK FACTORS world regions * 50 % * * * * * 0 Contraceptives Only contraceptives Pregnancy Genetic Prothrombotic Haematologic Iatrogenic * p < 0.05

33 CVT: ASSOCIATED CONDITIONS IN A PAKINSTAN-MIDDLE EAST COHORT Prothrombotic state Malignancy 4 7 Infections Pregnancy/puerperium Oral contraceptives PAK-M.EAST ISCVT % Khealani et al Stroke 2008

34 CONTRACEPTIVES (54%) Estrogens OR 5.59 CVT IR/100000/y IRR Levonorgestrel Norgestimate Desogestrel Contraceptive patch Dentali et al, 2006; Jick and Jick, 2006

35 OTHER GENDER SPECIFIC CAUSES Vaginal rings Case reports Emergency (day after) contraception Case report In-vitro fertilization Case report Hormonal replacement therapy

36 CVT ASSOCIATED CONDITIONS Permanent Hereditary thrombophilia Chronic conditions associated with a prothrombotic state (e.g. APS, malignancy) Transient Oral contraceptives Pregnancy/puerperium Infections Both permanent and transient None (cryptogenic CVT)

37 CVT? MR with T2*SW sequences MR-Venography Search the cause... Meningitis? Isolated intracranial hypertension Contraceptives Pregnancy / Puerperium ENT, face & neck infections Systemic inflammatory diseases Malignancy Haematological diseases Other rare causes Prothrombotic screening Lupus anticoagulant Anticardiolipin antibodies Antiβ2 glycoprotein antibd Antithrombin Protein C and S Factor V Leiden Prothrombin G20210 A Homocystein Lumbar puncture

38 CRYPTOGENIC CVT? 13% in ISCVT, 88% with complete prothrombotic screening CVT preciding a systemic disease Anti-phospholip syndrome Essential thrombocythemia and policythemia Inflammatory diseases (IBD, B D) Malignancy

39 OUTCOME AT FINAL FOLLOW UP 624 patients, median follow up: 16 months 79 % 57, ,5 8,3 0,6 1,6 2,9 7,5 death/dependency Compete recovery Rankin 6 Rankin 5 Rankin 4 Rankin 3 Rankin 2 Rankin 1 Rankin 0 Direct f up: 57% Ferro et al Stroke 2004

40 DECLINING MORTALITY IN CVT Coutinho et al, Stroke,2014

41 LAST FOLLOW UP DEATH/DEPENDENCY (n=32) PROGNOSTIC FACTOR HR 95%CI CNS infection Any malignancy Deep venous system thrombosis Haemorrhage on CT/MR GCS score < Mental status disorder Age > Male gender Accuracy: 85% area under the ROC curve 0.79

42 Ferro et al Cerebrovasc Dis 2009 Sensitivity CVT PROGNOSIS External validation Validation sample: VENOPORT and 5 ISCVT centres 1,0 0,8 0,6 ROC Curve Accuracy: 84 and 86% 0,2 Area under the ROC 0,0 curve: 0.69 and ,0 0,2 0,4 0,6 0,8 1,0 1 - Specificity 0,4 Diagonal segments are produced by ties.

43 CVT: RECOVERY IN THE ELDERLY Elderly patients mrs 0-1 mrs 3-6 Young-middle aged mrs 0-1 mrs disch 6 month last f up disch 6 month last f up Ferro et al Stroke 2006

44 CVT:PROGNOSIS IN WOMEN mrs GSRF GSRF+ GSRF No GSRF Coutinho et al Stroke 2009

45 CVT: PROGNOSIS IN PATIENTS WITH PARENCHYMAL LESIONS mrs 0-2 mrs 3-6 acute death % hemorrhage "infarct" no lesion Ferro et al Cerebrovas Dis 2010

46 ISOLATED HEADACHE: PROGNOSIS 100 CVT patients with isolated headache 52 diagnosed 7 days from onset (early diagnosis) 48 diagnosed > 7 days from onset (delayed diagnosis) Clinical worsening Early diagnosis: 23% Delayed diagnosis: 8% Decreased alerteness, focal defect, seizure, < visual acuity Long-term outcome 89% complete recovery, similar in the 2 groups Gameiro et al, 2012

47 TREATMENTS IN ISCVT Large sample size, wide spectrum of severity, manifestations and risk factors Case series of infrequent treatments (IV thrombolysis, shunting) Treatments choiced by treating MD Variability between centres and countries Non randomised treatment comparisons, adjusted by prognostic factors (steroids, acetazolamide, heparins, AEDs)

48 CVT: COMPLICATIONS OF HEPARIN TREATMENT Low risk of intracranial haemorrhage (8%) Low risk of systemic haemorrage (1.8%) Such haemorrages do not influence outcome Safe to use in patients with intracranial haemorrhages, either intracerebral or subarachnoid

49 IV or LMW Heparin? % France Portugal Italy Mexico Germany Brasil Spain Netherlands Belgium IV Hep LMWH No

50 ISCVT* IV UFH or LMW Heparin? LMW Heparin (28%) vs IV heparin 302 (72%) In favour of LMWH (after adjusting for prognostic factors) More patients independent at 6 months OR 2.4 (95% CI 1.0 to 5.7) Less new intracerebral hemorrhages OR 0.29 (95% CI 0.07 to 1.3) No difference in complete recovery and mortality RCT in India 32 IV heparin vs 34 LMWH Death 6 vs 0, Complete recovery 20 vs 30 LMWH seems preferable over IV UF heparin Coutinho et al (ISCVT) Stroke 2010; Misra et al 2012

51 TREATMENT UNCERTAINTY ACO 12 M ACO 6 M ACO 3 M AED LESION AED LMWH HEPARIN YES % Coutinho J et al, Cerebrovasc 2011

52 ISCVT 2 from observational to experimental studies Safety of anticoagulation in the acute phase Prospective study of decompressive surgery Optimal duration of AC after CVT Effectiveness of AEDs to prevent early and remote seizures after CVT Safety and management of pregnancy after CVT

53 SAFETY OF ANTICOAGULATION IN ACUTE CVT Recent publications raising concerns on the safety of AC in the acute phase Multicentre study with retrospective retrieval of information Centres with CVT registries Follow up cerebral imaging Intracerebral haemorrhage, symptomatic or not Systemic haemorrhage, serious

54 DECOMPRESSIVE SURGERY DECOMPRESS 2: objectives To describe in a prospective registry the vital and functional outcome of CVT patients treated by decompressive surgery To identify subgroups of CVT patients who benefit most from this surgery To describe the psychosocial outcomes after decompressive surgery in acute CVT 18 pt included 9/62 centers To perform an updated systematic review

55 PREVENTION OF RECURRENT VENOUS THROMBOEMBOLISM Risk of recurrence of venous thrombotic events CVT: 2-12% per 100 person-years Other VT: 7-15% per 100 person-years Risk factors for recurrence of venous thrombotic events in adults Male gender Policythemia/thrombocythemia Severe thrombophilia (DVT and PE) Previous VTE EFNS and AHA/ASA Guidelines 3 months (transient risk factors) to lifetime, depending on thrombophilia grading International survey 3 months -13% 6 months 64% 12 months 20% Miranda et al Stroke 2010; Martinelli et al Circulation 2010; Coutinho et al, 2011; Dentali et al 2012

56 PREVENTION OF RECURRENT VENOUS THROMBOEMBOLISM CVT related to a transient risk factor 3 or 3-6 months CVT idiopathic or related to mild thrombophilia 6-12 CVT related to combined, severe thrombophilia or recurrent CVT permanent EFNS guideline (Eur J Neurol 2010) Good practice point AHA/ASA guideline (Stroke 2011) Class IIb, level of evidence C

57 EXCOA-CVT clustered randomised trial To compare the efficacy and safety of a short (3 months to 6 months) and longterm (12 months) oral anticoagulation (any type) policy for the prevention of venous thromboembolic events (VTEs) after 1 st CVT Follow up: 24 months Multicentre, multinational Cluster allocation design

58 EX-COA TRIAL clustered randomised trial AC POLICY ANY ANTICOAGULANT Policy preference 3-6 or 12 months Uncertain? Randomised 3-6 or 12 months

59 Inclusion criteria Patients aged > 18 years with acute symptomatic and confirmed CVT CVT diagnosis <1 month before randomisation Patient must be clinically stable and able to stop parenteral anticoagulation in order to initiate oral anticoagulation Written informed consent

60 Exclusion criteria Systemic life-threatening or major bleeding while on anticoagulants during the acute phase of CVT or during the 6 months prior to randomisation General contraindications for anticoagulant therapy Life expectancy < 2 years due to a pre-existing condition (including any malignancy) Child bearing potential without proper contraceptive measures, pregnancy or breast feeding Other conditions judged by the investigator to be an absolute indication for prolonged oral anticoagulation such as antiphospholipid syndrome, known severe thrombophilia (antithrombin, protein C or protein S deficiency, homozygous factor V Leiden or prothrombin G20210A mutation or combined abnormalities)

61 SAFETY OUTCOMES: BLEEDINGS, ALL DEATHS EX-COA TRIAL clustered randomised trial AC POLICY 3-6 MONTHS 12 MONTHS EXCLUSIONS 12 MONTHS TREATMENT 24 MONTHS FOLLOW UP PRIMARY EFFICACY OUTCOME FATAL OR NONFATAL VTE

62 EXCOA-CVT sample size 50% decrease in the risk of recurrent CVT, deep venous thrombosis or pulmonary embolism from a basal risk of 10% to 5% α error of 0.05, 80% power Estimated cluster size (median ISCVT) 7 patients Estimated intracluster correlation coefficient clusters per intervention group (198 centers) 3% dropout rate patients

63 Estimated sample size 1428 patients 198 centers

64 EXCOA-CVT relevant clinical questions What is the most effective and safe duration of AC treatment after CVT? Is it safe to stop AC, one year after CVT? Does AC really prevents TVE in high-risk (excluded) patients? Are NOACs safe and effective after CVT?* Prevention of seizures Outcome of pregnancies *Geisbüsch C et al, 2014

65 PREGNANCY AFTER CVT? 10 studies Case series, only 2 prospective 5 venous thrombotic events/181 pregnancies 2.76% ( ) 2 CVT recurrences/207 pregnancies 0.97% ( ) Low absolute (but uncertain) risks

66 PREGNANCY AFTER CVT ISCVT pregnancy study 10 y follow up of 314 (currently 111) women in fertile age included in ISCVT Outcome of pregnancies (currently 64) Antithrombotic management 51% ISCVT investigators response rate Database to be closed 1st trimester 2015 Results to be presented at EAN Congress Berlin June 2015

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68 ISCVT A TEAM WORK MG Bousser, J Stam, F Barinagarrementeria Patrícia Canhão Marisa Costa All the ISCVT investigators The patients FCT (Fundação para a Ciência e Tecnologia) Competitive grant

69 ISCVT 2 threats & opportunities Funding (IMM) Low cost study electronic CRF and data transmission EXCOA-CVT cluster design no experimental drug distribution Participating centres Benefits from participation, payment for patient inclusion and follow up, competitive studies Ethics and local administrations