Radiosurgical, neurosurgical, or no intervention for cerebral cavernous malformations: A decision analysis

Introduction We aimed to evaluate the preferred treatment strategy for patients with symptomatic cerebral cavernous malformations (CCM). Methods In a decision model, we compared neurosurgical, radiosurgical, and conservative management. A literature review yielded the risks and outcomes of interventions, intracerebral hemorrhage (ICH), and seizures. Patients with CCM rated their quality of life to determine utilities. We estimated the expected number of quality-adjusted life years (QALYs) and the ICH recurrence risk over five years, according to mode of presentation and CCM location (brainstem vs. other). We performed analyses with a time horizon of five years. Results Using the best available data, the expected number of QALYs for brainstem CCM presenting with ICH or focal neurological deficit was 2.84 (95% confidence interval [CI]: 2.54-3.08) for conservative, 3.01 (95% CI: 2.86-3.16) for neurosurgical, and 3.03 (95% CI: 2.88-3.18) for radiosurgical intervention; those for non-brainstem CCM presenting with ICH or focal neurological deficit were 3.08 (95% CI: 2.85-3.31) for conservative, 3.21 (95% CI: 3.01-3.36) for neurosurgical, and 3.19 (95% CI: 2.98-3.37) for radiosurgical intervention. For CCM presenting with epilepsy, QALYs were 3.09 (95% CI: 3.03-3.16) for conservative, 3.33 (95% CI: 3.31-3.34) for neurosurgical, and 3.27 (95% CI: 3.24-3.30) for radiosurgical intervention. Discussion and conclusion For the initial five years after presentation, our study provides Class III evidence that for CCM presenting with ICH or focal neurological deficit conservative management is the first option, and for CCM presenting with epilepsy CCM intervention should be considered. More comparative studies with long-term follow-up are needed

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations

BACKGROUND: We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM). METHODS: The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location. RESULTS: Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01–0.66]; P=0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01–1.07]; P=0.067). CONCLUSIONS: Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM

A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups

Supplemental materials for a systematic review of stereotactic radiosurgery for cerebral cavernous malformations

Supplementary data in support of manuscript: "Stereotactic radiosurgery for cerebral cavernous malformations: a systematic review".Poorthuis, Michiel; Rinkel, Leon. (2019). Supplemental materials for a systematic review of stereotactic radiosurgery for cerebral cavernous malformations, [dataset]. University of Edinburgh. Centre for Clinical Brain Sciences. https://doi.org/10.7488/ds/2571

Stereotactic radiosurgery for cerebral cavernous malformations: a systematic review and meta-analysis

Objective The efficacy of stereotactic radiosurgery (SRS) for the treatment of cerebral cavernous malformations (CCMs) is uncertain, so we set out to quantify clinical outcomes after SRS for CCM and compare them to microsurgical excision or conservative management. Methods We searched Ovid Medline and Ovid EMBASE from inception until June 1, 2018, for peer-reviewed publications describing clinical outcomes after SRS for >= 10 people with CCM in cohorts with or without a comparison group treated with neurosurgical excision or conservative management. Two reviewers independently extracted data from the included studies to quantify cohort characteristics and the incidence of the primary outcome (death attributable to CCM or its treatment) and secondary outcomes (incident nonfatal symptomatic intracerebral hemorrhage [ICH] and incident nonhemorrhagic persistent focal neurologic deficit [FND]). We assessed whether comparative studies showed a dramatic association (meaning the conventionally calculated probability comparing 2 differently managed patient groups from the same population was Results We included 30 cohort studies involving a total of 1,576 patients undergoing SRS for CCM. Four nonrandomized studies compared SRS to other treatment strategies, but did not demonstrate dramatic associations. During a median follow-up of 48 (interquartile range 35-62) months after SRS, the annual incidences (95% confidence interval) of outcomes were death 0.18% (0.10-0.31), ICH 2.40% (2.05-2.80), FND 0.71% (0.53-0.96), and the composite of death, ICH, or FND 3.63% (3.17-4.16). Outcomes did not differ by CCM location or type of SRS. Conclusion After SRS for CCM, the annual incidences of death, ICH, and FND ar

Association between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage from Cerebral Cavernous Malformations

Background: We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM). Methods: The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location. Results: Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01-0.66]; P=0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01-1.07]; P=0.067). Conclusions: Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM

Meta-analysis of timing of endovascular aneurysm treatment in subarachnoid haemorrhage : inconsistent results of early treatment within 1 day

BACKGROUND AND PURPOSE: To systematically review and meta-analyse the data on impact of timing of endovascular treatment in aneurysmal subarachnoid haemorrhage (SAH) to determine if earlier treatment is associated with improved clinical outcomes and reduced case fatality. METHODS: We searched MEDLINE, Cochrane database, EMBASE and Web of Science to identify studies for inclusion. The measures of effect utilised were unadjusted/adjusted ORs. Effect estimates were combined using random effects models for each outcome (poor outcome, case fatality); heterogeneity was assessed using the I2index. Subgroup and sensitivity analyses were performed to account for heterogeneity and risk of bias. RESULTS: 16 studies met the inclusion criteria. Treatment 1 day (OR=0.40 (95% CI 0.28 to 0.56; I2=0%)) but not when compared with treatment at 1-3 days (OR=1.16 (95% CI 0.47 to 2.90; I2=81%)). Treatment at <2 days and at <3 days were associated with similar odds of poor outcome compared with later treatment (OR=1.20 (95% CI 0.70 to 2.05; I2=73%; OR=0.71 (95% CI 0.36 to 1.37; I2=71%)). Early treatment was associated with similar odds of case fatality compared with later treatment, regardless of how early/late treatment were defined (OR=1.80 (95% CI 0.88 to 3.67; I2=34%) for treatment <1 day vs days 1-3; OR=1.71 (95% CI 0.72 to 4.03; I2=54%) for treatment <2 days vs later; OR=0.90 (95% CI 0.31 to 2.68; I2=48%) for treatment <3 days vs later). CONCLUSIONS: In only 1 of the analyses was there a statistically significant result, which favoured treatment <1 day. The inconsistent results and heterogeneity within most analyses highlight the lack of evidence for best timing of endovascular treatment in SAH patients

Hemorrhage rates in patients with acute ischemic stroke treated with intravenous alteplase and thrombectomy versus thrombectomy alone

BACKGROUND: Intravenous alteplase treatment (IVT) for acute ischemic stroke carries a risk of intracranial hemorrhage (ICH). However, reperfusion of an occluded vessel itself may contribute to the risk of ICH. We determined whether IVT and reperfusion are associated with ICH or its volume in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN)-NO IV trial.METHODS: The MR CLEAN-NO IV trial randomized patients with acute ischemic stroke due to large vessel occlusion to receive either IVT followed by endovascular treatment (EVT) or EVT alone. ICH was classified according to the Heidelberg bleeding classification on follow-up MRI or CT approximately 8 hours-7 days after stroke. Hemorrhage volume was measured with ITK-snap. Successful reperfusion was defined as extended Thrombolysis In Cerebral Infarction (eTICI) score of 2b-3. Multinomial and binary adjusted logistic regression were used to determine the association of IVT and reperfusion with ICH subtypes.RESULTS: Of 539 included patients, 173 (32%) developed ICH and 30 suffered from symptomatic ICH (sICH) (6%). Of the patients with ICH, 102 had hemorrhagic infarction, 47 had parenchymal hematoma, 44 had SAH, and six had other ICH. Reperfusion was associated with a decreased risk of SAH, and IVT was not associated with SAH (eTICI 2b-3: adjusted OR 0.45, 95% CI 0.21 to 0.97; EVT without IVT: OR 1.6, 95% CI 0.91 to 2.8). Reperfusion status and IVT were not associated with overall ICH, hemorrhage volume, and sICH (sICH: EVT without IVT, OR 0.96, 95% CI 0.41 to 2.25; eTICI 2b-3, OR 0.49, 95% CI 0.23 to 1.05).CONCLUSION: Neither IVT administration before EVT nor successful reperfusion after EVT were associated with ICH, hemorrhage volume, and sICH. SAH occurred more often in patients for whom successful reperfusion was not achieved.</p

Long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis

Background: Antithrombotic (anticoagulant or antiplatelet) therapy is withheld from some patients with cerebral cavernous malformations, because of uncertainty around the safety of these drugs in such patients. We aimed to establish whether antithrombotic therapy is associated with an increased risk of intracranial haemorrhage in adults with cerebral cavernous malformations. Methods: In this population-based, cohort study, we used data from the Scottish Audit of Intracranial Vascular Malformations, which prospectively identified individuals aged 16 years and older living in Scotland who were first diagnosed with a cerebral cavernous malformation during 1999–2003 or 2006–10. We compared the association between use of antithrombotic therapy after first presentation and the occurrence of intracranial haemorrhage or persistent or progressive focal neurological deficit due to the cerebral cavernous malformations during up to 15 years of prospective follow-up with multivariable Cox proportional hazards regression assessed in all individuals identified in the database. We also did a systematic review and meta-analysis, in which we searched Ovid MEDLINE and Embase from database inception to Feb 1, 2019, to identify comparative studies to calculate the intracranial haemorrhage incidence rate ratio according to antithrombotic therapy use. We then generated a pooled estimate using the inverse variance method and a random effects model. Findings: We assessed 300 of 306 individuals with a cerebral cavernous malformation who were eligible for study. 61 used antithrombotic therapy (ten [16%] of 61 used anticoagulation) for a mean duration of 7·4 years (SD 5·4) during follow-up. Antithrombotic therapy use was associated with a lower risk of subsequent intracranial haemorrhage or focal neurological deficit (one [2%] of 61 vs 29 [12%] of 239, adjusted hazard ratio [HR] 0·12, 95% CI 0·02–0·88; p=0·037). In a meta-analysis of six cohort studies including 1342 patients, antithrombotic therapy use was associated with a lower risk of intracranial haemorrhage (eight [3%] of 253 vs 152 [14%] of 1089; incidence rate ratio 0·25, 95% CI 0·13–0·51; p<0·0001; I2=0%). Interpretation: Antithrombotic therapy use is associated with a lower risk of intracranial haemorrhage or focal neurological deficit from cerebral cavernous malformations than avoidance of antithrombotic therapy. These findings provide reassurance about safety for clinical practice and require further investigation in a randomised controlled trial. Funding: UK Medical Research Council, Chief Scientist Office of the Scottish Government, The Stroke Association, Cavernoma Alliance UK, and the Remmert Adriaan Laan Foundation

Role of intravenous alteplase on late lesion growth and clinical outcome after stroke treatment

Several acute ischemic stroke mechanisms that cause lesion growth continue after treatment which is detrimental to long-term clinical outcome. The potential role of intravenous alteplase treatment (IVT), a standard in stroke care, in cessing the physiological processes causing post-treatment lesion development is understudied. We analyzed patients from the MR CLEAN-NO IV trial with good quality 24-hour and 1-week follow-up Non-Contrast CT scans. We delineated hypo- and hyper-dense regions on the scans as lesion. We performed univariable logistic and linear regression to estimate the influence of IVT on the presence (growth > 0 ml) and extent of late lesion growth. The association between late lesion growth and mRS was assessed using ordinal logistic regression. Interaction analysis was performed to evaluate the influence of IVT on this association. Of the 63/116 were randomized to included patients, IVT. Median growth was 8.4(-0.88-26) ml. IVT was not significantly associated with the presence (OR: 1.24 (0.57-2.74, p = 0.59) or extent (beta = 5.1(-8.8-19), p = 0.47) of growth. Late lesion growth was associated with worse clinical outcome (aOR: 0.85(0.76-0.95), p < 0.01; per 10 ml). IVT did not influence this association (p = 0.18). We did not find evidence that IVT influences late lesion growth or the relationship between growth and worse clinical outcome. Therapies to reduce lesion development are necessary