Jonathan M. Coutinho

Cerebral Venous and Sinus Thrombosis in Women

Background and Purpose— Little is known about the gender-specific manifestations of cerebral venous and sinus thrombosis, a disease that is much more common in women than men. Methods— We used data of the International Study on Cerebral Vein and Dural sinus Thrombosis (ISCVT), a multicenter prospective observational study, to analyze gender-specific differences in clinical presentation, etiology, and outcome of cerebral venous thrombosis. Results— Four hundred sixty-five of a total of 624 patients were women (75%). Women were significantly younger, had less often a chronic onset of symptoms, and had more often headache at presentation. There were no gender differences in ancillary investigations or treatment. A gender-specific risk factor (oral contraceptives, pregnancy, puerperium, and hormonal replacement therapy) was present in 65% of women. Women had a better prognosis than men (complete recovery 81% versus 71%l P=0.01), which was entirely due to a better outcome in female patients with gender-specific risk factors. Women without gender-specific risk factors are similar to men in clinical presentation, risk factor profile, and outcome. Logistic regression analysis confirmed that the absence of gender-specific risk factors is a strong and independent predictor of poor outcome in women with sinus thrombosis (OR, 3.7; CI, 1.9 to 7.4). Conclusions— Our study identified important differences between women and men in presentation, course, and risk factors of cerebral venous and sinus thrombosis and showed that women with a gender-specific risk factor have a much better prognosis than other patients.

Decompressive Surgery in Cerebrovenous Thrombosis A Multicenter Registry and a Systematic Review of Individual Patient Data

Background and Purpose— Herniation attributable to unilateral mass effect is the major cause of death in cerebral venous thrombosis (CVT). Decompressive surgery may be lifesaving in these patients. Methods— Retrospective registry of cases of acute CVT treated with decompressive surgery (craniectomy or hematoma evacuation) in 22 centers and systematic review of all published cases of CVT treated with decompressive surgery. The primary outcome was the score on the modified Rankin Scale (mRS) score at last follow-up, dichotomized between favorable (mRS score, 0–4) and unfavorable outcome (mRS score, 5 or death). Secondary outcomes were complete recovery (mRS score 0–1), independence (mRS score, 0–2), severe dependence (mRS score, 4–5), and death at last available follow-up. Results— Sixty-nine patients were included and 38 were from the registry. Decompressive craniectomy was performed in 45 patients, hematoma evacuation was performed in 7, and both interventions were performed in 17 patients. At last follow-up (median, 12 months) only 12 (17.4%) had un unfavorable outcome. Twenty-six (37.7%) had mRS score 0 to 1, 39 (56.5%) had mRS score 0 to 2, 4 (5.8%) were alive with mRS score 4 to 5, and 11 (15.9%) patients died. Three of the 9 patients with bilateral fixed pupils recovered completely. Comatose patients were less likely to be independent (mRS score 0–2) than noncomatose patients (45% versus 84%; P=0.003). Patients with bilateral lesions were more likely to have unfavorable outcomes (50% versus 11%; P=0.004) and to die (42% versus 11%; P=0.025). Conclusions— In CVT patients with large parenchymal lesions causing herniation, decompressive surgery was lifesaving and often resulted in good functional outcome, even in patients with severe clinical conditions.

The Incidence of Cerebral Venous Thrombosis A Cross-Sectional Study

Background and Purpose— The purpose of this study was to determine the incidence of adult cerebral venous thrombosis. Methods— A retrospective cross-sectional study was conducted among all 19 hospitals located in 2 Dutch provinces serving 3.1 million people. Adult cerebral venous thrombosis cases diagnosed between January 1, 2008, and December 31, 2010, were identified using the Dutch financial coding system for hospital care and the International Classification of Diseases, 9th Revision. Medical records of potential patients were hand searched to identify cerebral venous thrombosis cases. The Dutch National Bureau for Statistics provided population figures of the 2 provinces during 2008 to 2010. Results— Among 9270 potential cases, we identified 147 patients diagnosed with cerebral venous thrombosis. Of these, 53 patients did not meet the inclusion criteria; therefore, 94 patients were included in the analysis. The overall incidence was 1.32 per 100 000 person-years (95% CI, 1.06–1.61). Among women between the ages of 31 and 50 years, the incidence was 2.78 (95% CI, 1.98–3.82). Conclusions— The incidence of cerebral venous thrombosis among adults is probably higher than previously believed.

Clinical characteristics and outcome of brain abscess Systematic review and meta-analysis

Objective: To define clinical characteristics, causative organisms, and outcome, and evaluate trends in epidemiology and outcome of brain abscesses over the past 60 years. Methods: We performed a systematic review and meta-analysis of studies on brain abscesses published between 1970 and March 2013. Studies were included if they reported at least 10 patients with brain abscesses, included less than 50% extra-axial CNS infections (empyema) without brain abscess, and did not solely report on brain abscesses caused by a single pathogen. Results: We identified 123 studies including 9,699 patients reported between 1935 and 2012. There was a male predominance of 2.4 to 1, and the mean age of patients with brain abscesses was 34 years. The most common causative microorganisms were Streptococcus and Staphylococcus species, comprising 2,000 (34%) and 1,076 (18%) of 5,894 cultured bacteria. Geographical distribution of causative microorganisms over continents was similar and did not substantially change over the past 60 years. Predisposing conditions were present in 8,134 of 9,484 patients (86%) and mostly consisted of contiguous or metastatic foci of infection. The classic triad of fever, headache, and focal neurologic deficits was present in 131 of 668 (20%) of patients. Case fatality rate decreased from 40% to 10% over the past 5 decades, while the rate of patients with full recovery increased from 33% to 70%. Conclusions: The prognosis of patients with brain abscesses has gradually improved over the past 60 years. Important changes over time were the modality of cranial imaging, neurosurgical technique, and antimicrobial regimen.

Unfractionated or Low–Molecular Weight Heparin for the Treatment of Cerebral Venous Thrombosis

Background and Purpose— There is no consensus whether to use unfractionated heparin or low-molecular weight heparin for the treatment of cerebral venous thrombosis. We examined the effect on clinical outcome of each type of heparin. Methods— A nonrandomized comparison of a prospective cohort study (the International Study on Cerebral Vein and Dural Sinus Thrombosis) of 624 patients with cerebral venous thrombosis. Patients not treated with heparin (n=107) and those who sequentially received both types of heparin (n=99) were excluded from the primary analysis. The latter were included in a secondary analysis, allocated according to the type of heparin given first. The primary end point was functional independency at 6 months (modified Rankin scale score ≤2). Secondary end points were complete recovery (modified Rankin scale score 0 to 1), mortality, and new intracranial hemorrhages. Results— A total of 119 patients received low-molecular weight heparin (28%) and 302 received unfractionated heparin (72%). Significantly more patients treated with low-molecular weight heparin were functionally independent after 6 months, both in univariate analysis (odds ratio, 2.1; CI, 1.0 to 4.2) and after adjustment for prognostic factors and imbalances (odds ratio, 2.4; CI, 1.0 to 5.7). In the secondary analysis, there was a similar, nonsignificant trend (odds ratio, 1.7; CI, 0.80 to 3.6). Low-molecular weight heparin was associated with less new intracerebral hemorrhages (adjusted odds ratio, 0.29; CI, 0.07 to 1.3), especially in patients with intracerebral lesions at baseline (adjusted odds ratio, 0.19; CI, 0.04 to 0.99). There was no difference in complete recovery and mortality. Conclusions— This nonrandomized study in patients with cerebral venous thrombosis suggests a better efficacy and safety of low-molecular weight heparin over unfractionated heparin. Low-molecular weight heparin seems preferable above unfractionated heparin for the initial treatment of cerebral venous thrombosis.

Decompressive hemicraniectomy in cerebral sinus thrombosis: consecutive case series and review of the literature

Background and Purpose— Thirteen percent of patients with cerebral venous and sinus thrombosis (CVST) has a poor clinical outcome. In patients with a poor prognosis, endovascular thrombolysis can be considered, but this procedure does not appear to be beneficial in patients with impending transtentorial herniation because of large hemorrhagic venous infarcts. Therefore, halfway through 2006, we changed our policy to decompressive hemicraniectomy in these patients. Methods and Results— Patients with CVST and impending herniation attributable to venous infarcts were eligible for surgical intervention. Since 2006 we consecutively treated 3 patients with decompressive hemicraniectomy. Two patients had an excellent outcome. The third patient, who had been comatose for at least 12 hours before surgery, died despite intervention. Conclusions— Our data suggest that decompressive hemicraniectomy can be life-saving and can result in an excellent outcome in patients with severe CVST.

Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis: Rationale and Design of the TO-ACT Trial

Rationale Endovascular thrombolysis, with or without mechanical clot removal, may be beneficial for a subgroup of patients with cerebral venous sinus thrombosis (CVT) who have a poor prognosis despite treatment with heparin. Published experience with endovascular thrombolysis is promising but only based on case series and not on controlled trials. Aim The objective of the Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TO-ACT) trial is to determine if endovascular thrombolysis improves the functional outcome of patients with a severe form of CVT. Design The TO-ACT trial is a multicenter, prospective, randomized, open-label, blinded endpoint trial. Patients are eligible if they have a radiologically proven CVT, a high probability of poor outcome (defined by presence of one or more of the following risk factors: mental status disorder, coma, intracranial hemorrhagic lesion, or thrombosis of the deep cerebral venous system), and if the responsible physician is uncertain if endovascular thrombolysis or standard anticoagulant treatment is better. One hundred sixty-four patients (82 in each treatment arm) will be included to detect a 50% relative reduction (from 40% to 20%) of poor outcomes. Study Patients will be randomized to receive either endovascular thrombolysis or standard therapy (therapeutic doses of heparin). Endovascular thrombolysis is composed of local application of rt-plasminogen activator (PA) or urokinase within the thrombosed sinuses, mechanical thrombosuction, or a combination of both. Patients randomized to endovascular thrombolysis will be treated with heparin before and after the interventional procedure, according to international guidelines. Outcomes The primary endpoint is the modified Rankin score (mRS) at 12 months, with a score ≥2 defined as poor outcome. Secondary outcomes are six-months mRS, mortality, and recanalization rate. Major intracranial and extracranial hemorrhagic complications within one-week after the intervention are the principal safety outcomes. Results will be analyzed according to the ‘intention-to-treat’ principle. Blinded assessors not involved in the treatment of the patient will assess endpoints with standardized questionnaires.

Combined Intravenous Thrombolysis and Thrombectomy vs Thrombectomy Alone for Acute Ischemic Stroke: A Pooled Analysis of the SWIFT and STAR Studies

Importance Mechanical thrombectomy (MT) improves clinical outcomes in patients with acute ischemic stroke (AIS) caused by a large vessel occlusion. However, it is not known whether intravenous thrombolysis (IVT) is of added benefit in patients undergoing MT. Objective To examine whether treatment with IVT before MT with a stent retriever is beneficial in patients undergoing MT. Design, Setting, and Participants This post hoc analysis used data from 291 patients treated with MT included in 2 large, multicenter, prospective clinical trials that evaluated MT for AIS (Solitaire With the Intention for Thrombectomy performed from January 1, 2010, through December 31, 2011, and Solitaire Flow Restoration Thrombectomy for Acute Revascularization from January 1, 2010, through December 31, 2012). An independent core laboratory scored the radiologic outcomes in each trial. Interventions Patients were treated with IVT with tissue plasminogen activator followed by MT (IVT and MT group) with the use of a stent retriever or MT with a stent retriever alone (MT group). Main Outcomes and Measures Successful reperfusion, functional independence (modified Rankin Scale score of 0-2) and mortality at 90 days, symptomatic intracranial hemorrhage, emboli to new territory, and vasospasm were compared. Results Of 291 patients included in the analysis, 160 (55.0%) underwent IVT and MT (mean [SD] age, 67 [13] years; 97 female [60.6%]), and 131 (45.0%) underwent MT alone (mean [SD] age, 69 [12] years; 71 [55.7%] female). Median Alberta Stroke Program Early CT Score at baseline was lower in the IVT and MT group (8 vs 9, P = .04). There was no statistically significant difference in the duration from symptom onset to groin puncture (254 minutes for the IVT and MT group vs 262 minutes for the MT group, P = .10). The number of passes, rate of successful reperfusion, functional independence at 90 days, mortality at 90 days, and emboli to new territory were also similar among groups. Symptomatic intracranial hemorrhage (1% vs 4%) and parenchymal hemorrhages type 1 (1% vs 3%) or type 2 (1% vs 2%) did not differ significantly (P = .25). Vasospasm occurred more often in patients who received IVT and MT vs MT alone (27% vs 14%, P = .006). In multivariate analysis, no statistically significant association was observed between IVT and MT vs MT alone for any of the outcomes. Conclusions and Relevance The results indicate that treatment of patients experiencing AIS due to a large vessel occlusion with IVT before MT does not appear to provide a clinical benefit over MT alone. A randomized clinical trial seems warranted. Trial Registration clinicaltrials.gov Identifiers: NCT01054560 and NCT01327989

Declining Mortality in Cerebral Venous Thrombosis A Systematic Review

Background and Purpose— Cerebral venous thrombosis (CVT) is nowadays considered a disease with a good outcome in most cases, but in the past, these patients were thought to have a grave prognosis. We systematically studied the apparent decline in mortality of patients with CVT over time. Methods— A systematic review of the literature (MEDLINE and EMBASE) was performed. Studies with ≥40 patients with CVT that reported mortality at discharge or follow-up were eligible. Duplicate publications based on the same patient cohort were excluded. Studies were ranked according to the year halfway the period of patient inclusion. Two of the authors independently screened all eligible studies. Results— We screened 4585 potentially eligible studies, of which 74 fulfilled the selection criteria. The number of patients per study varied from 40 to 706 (median, 76). Data from 8829 patients with CVT, included from 1942 to 2012, were analyzed. The average age was 32.9 years, and 64.7% were women. There was a significant inverse correlation between mortality and year of patient recruitment (Pearson correlation coefficient, −0.72; P<0.001). In a sensitivity analysis, the correlation remained significant after exclusion of studies published before 1990, retrospective studies, or single-center studies. Both the frequency of focal neurological deficits and coma also decreased significantly over time (correlation coefficient, −0.50 and −0.52). Conclusions— There is a clear trend in declining mortality among patients with CVT over time. Possible explanations are improvements in treatment, a shift in risk factors, and, most importantly, the identification of less severe cases by improved diagnostic methods.

How to treat cerebral venous and sinus thrombosis

Summary.  Cerebral venous and sinus thrombosis (CVT) is a rare form of thrombosis, with many different clinical manifestations. Better imaging techniques have greatly improved the diagnosis, but as a result of the paucity of controlled trials, choosing the optimal treatment for each patient often remains a challenge. Heparin is generally considered the mainstay of treatment, supported by data from a few small trials. More invasive treatment options are available, such as endovascular thrombolysis and – in more severe cases – decompressive hemicraniectomy. Furthermore, CVT is often accompanied by various neurological complications, such as seizures and intracranial hypertension, which require specific treatment. In this review we summarize the available treatment options for CVT and suggest which therapy should be reserved for which patients.