Alexander E. Merkler

Recurrent thromboembolic events after ischemic stroke in patients with cancer

Objective: To determine the cumulative rate and characteristics of recurrent thromboembolic events after acute ischemic stroke in patients with cancer. Methods: We retrospectively identified consecutive adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary-care cancer center from 2005 through 2009. Two neurologists independently reviewed all electronic records to ascertain the composite outcome of recurrent ischemic stroke, myocardial infarction, systemic embolism, TIA, or venous thromboembolism. Kaplan-Meier statistics were used to determine cumulative outcome rates. In exploratory analyses, Cox proportional hazard analysis was used to evaluate potential independent associations between a priori selected clinical factors and recurrent thromboembolic events. Results: Among 263 study patients, complete follow-up until death was available in 230 (87%). Most patients had an adenocarcinoma as their underlying cancer (60%) and had systemic metastases (69%). Despite a median survival of 84 days (interquartile range 24–419 days), 90 patients (34%; 95% confidence interval 28%–40%) had 117 recurrent thromboembolic events, consisting of 57 cases of venous thromboembolism, 36 recurrent ischemic strokes, 13 myocardial infarctions, 10 cases of systemic embolism, and one TIA. Kaplan-Meier rates of recurrent thromboembolism were 21%, 31%, and 37% at 1, 3, and 6 months, respectively; cumulative rates of recurrent ischemic stroke were 7%, 13%, and 16%. Adenocarcinoma histology (hazard ratio 1.65, 95% confidence interval 1.02–2.68) was independently associated with recurrent thromboembolism. Conclusions: Patients with acute ischemic stroke in the setting of active cancer (especially adenocarcinoma) face a substantial short-term risk of recurrent ischemic stroke and other types of thromboembolism.

Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis

Background and Purpose— The safety and efficacy of restarting anticoagulation therapy after intracranial hemorrhage (ICH) remain unclear. We performed a systematic review and meta-analysis to summarize the associations of anticoagulation resumption with the subsequent risk of ICH recurrence and thromboembolism. Methods— We searched published medical literature to identify cohort studies involving adults with anticoagulation-associated ICH. Our predictor variable was resumption of anticoagulation. Outcome measures were thromboembolic events (stroke and myocardial infarction) and recurrence of ICH. After assessing study heterogeneity and publication bias, we performed a meta-analysis using random-effects models to assess the strength of association between anticoagulation resumption and our outcomes. Results— Eight studies were eligible for inclusion in the meta-analysis, with 5306 ICH patients. Almost all studies evaluated anticoagulation with vitamin K antagonists. Reinitiation of anticoagulation was associated with a significantly lower risk of thromboembolic complications (pooled relative risk, 0.34; 95% confidence interval, 0.25–0.45; Q=5.12, P for heterogeneity=0.28). There was no evidence of increased risk of recurrent ICH after reinstatement of anticoagulation therapy, although there was significant heterogeneity among included studies (pooled relative risk, 1.01; 95% confidence interval, 0.58–1.77; Q=24.68, P for heterogeneity <0.001). No significant publication bias was detected in our analyses. Conclusions— In observational studies, reinstitution of anticoagulation after ICH was associated with a lower risk of thromboembolic complications and a similar risk of ICH recurrence. Randomized clinical trials are needed to determine the true risk–benefit profile of anticoagulation resumption after ICH.

Cryptogenic Subtype Predicts Reduced Survival Among Cancer Patients With Ischemic Stroke

Background and Purpose— Cryptogenic stroke is common in patients with cancer. Autopsy studies suggest that many of these cases may be because of marantic endocarditis, which is closely linked to cancer activity. We, therefore, hypothesized that among patients with cancer and ischemic stroke, those with cryptogenic stroke would have shorter survival. Methods— We retrospectively analyzed all adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary care cancer center from 2005 through 2009. Two neurologists determined stroke mechanisms by consensus. Patients were diagnosed with cryptogenic stroke if no specific mechanism could be determined. The diagnosis of marantic endocarditis was restricted to patients with cardiac vegetations on echocardiography or autopsy and negative blood cultures. Patients were followed until July 31, 2012, for the primary outcome of death. Kaplan–Meier statistics and the log-rank test were used to compare survival between patients with cryptogenic stroke and patients with known stroke mechanisms. Multivariate Cox proportional hazard analysis evaluated the association between cryptogenic stroke and death after adjusting for potential confounders. Results— Among 263 patients with cancer and ischemic stroke, 133 (51%) were cryptogenic. Median survival in patients with cryptogenic stroke was 55 days (interquartile range, 21–240) versus 147 days (interquartile range, 33–735) in patients with known stroke mechanisms (P<0.01). Cryptogenic stroke was independently associated with death (hazard ratio, 1.64; 95% confidence interval, 1.25–2.14) after adjusting for age, systemic metastases, adenocarcinoma histology, and functional status. Conclusions— Cryptogenic stroke is independently associated with reduced survival in patients with active cancer and ischemic stroke.

Preoperative steroid use and the risk of infectious complications after neurosurgery.

Background and Purpose: The association between preoperative corticosteroid use and infectious complications after neurosurgical procedures is unclear. We aim to determine whether corticosteroids increase the risk of infectious complications after neurosurgery. Methods: We examined the association between preoperative corticosteroid use and postoperative infectious complications in a cohort of adults who underwent a neurosurgical procedure between 2005 and 2010 at centers participating in the National Surgical Quality Improvement Program. Corticosteroid use was defined as at least 10 days of oral or parental therapy in the 30 days prior to surgery. Our primary outcome was a composite of any infectious complications occurring within 30 days of surgery. We used propensity score analysis to examine the independent association between preoperative corticosteroid use and postoperative infections. Results: Among 26 634 neurosurgical procedures, 1228 (4.61%, 95% confidence interval [CI], 4.36-4.86) were preceded by preoperative corticosteroid use and 1469 (5.52%; 95% CI, 5.24-5.79) were followed by postoperative infections. In a propensity score analysis controlling for comorbidities, illness severity, and preexisting preoperative infections, corticosteroid use was independently associated with subsequent postoperative infections (odds ratio, 1.38; 95% CI, 1.11-1.70). Our results were unchanged in sensitivity analyses controlling for central nervous system tumors or active treatment with chemotherapy. Conclusion: Our results suggest that preoperative corticosteroid use is associated with an increased risk of infectious complications after neurosurgery. These findings may aid physicians with preoperative treatment decisions and risk stratification. Future randomized trials are needed to guide preoperative use of corticosteroids in this population.

Direct Invasion of the Optic Nerves, Chiasm, and Tracts by Cryptococcus neoformans in an Immunocompetent Host

Cryptococcus spp is a common fungal infection and frequent cause of meningitis in immunocompromised patients; however, immunocompetent patients are also at risk of infection. Visual loss often occurs via elevated intracranial hypertension but can rarely occur through direct optic nerve, chiasm, or tract invasion. We report a case of a 38-year-old woman who presented with decreased acuity in both eyes. She had generalized visual field constriction in the right eye and temporal hemianopsia in the left eye. Magnetic resonance imaging of the brain and orbits showed multiple areas of ill-defined enhancement in the optic chiasm and tracts as well as in the diaphragmatic sella, prepontine and interpeduncular cisterns, and along cranial nerves VI, VII, and VIII bilaterally. Initial cerebrospinal fluid (CSF) showed 34 white blood cells, hypoglycorrhachia, and negative cryptococcal antigen and bacterial and fungal cultures. A transphenoidal biopsy of the dura and pituitary gland was unremarkable. Empiric steroids resulted in marked improvement in visual acuity in both eyes, but while tapering steroids, she developed rapid visual loss bilaterally. Repeat CSF performed 6 weeks later demonstrated a cryptococcal antigen titer of 1:512. Retroactive staining of the pituitary biopsy was positive for mucicarmine, a component of the polysaccharide capsule of Cryptococcus spp. After induction therapy with amphotericin B and flucytosine and 1 year of fluconazole, her visual acuity was 20/20 in both eyes. In summary, Cryptococcus can affect immunocompetent patients and often presents with insidious, chronic meningitis. Visual loss is common in cryptococcal meningitis but usually results from fulminant papilledema related to elevated intracranial pressure. In rare cases, direct nerve or chiasm infiltration by the fungus results in vision loss.

Safety Outcomes After Percutaneous Transcatheter Closure of Patent Foramen Ovale

Background and Purpose— We sought to evaluate the real-world rate of safety outcomes after patent foramen ovale (PFO) closure in patients with ischemic stroke or transient ischemic attack (TIA). Methods— We performed a retrospective cohort study using administrative claims data on all hospitalizations from 2005 to 2013 in New York, California, and Florida. Using International Classification of Diseases, Ninth Revision, Clinical Modification codes, we identified patients who underwent percutaneous transcatheter PFO closure within 1 year of ischemic stroke or TIA. Our outcome was an adverse event occurring during the hospitalization for PFO closure, defined as in prior studies as atrial fibrillation or flutter, cardiac tamponade, pneumothorax, hemothorax, a vascular access complication, or death. Crude rates were reported with exact confidence intervals. Results— We identified 1887 patients who underwent PFO closure after ischemic stroke or TIA. The rate of any adverse outcome during the hospitalization for PFO closure was 7.0% (95% confidence interval [CI], 5.9%–8.2%). Rates of adverse outcomes varied by age and type of preceding cerebrovascular event. In patients >60 years of age, the rate of adverse outcomes was 10.9% (95% CI, 8.6%–13.6%) versus 4.9% (95% CI, 3.8%–6.3%) in patients ⩽60 years of age. The rate of adverse outcomes was 9.9% (95% CI, 7.3%–12.5%) in patients with preceding ischemic stroke versus 5.9% (95% CI, 4.7%–7.1%) after TIA. Conclusions— Approximately 1 in 14 patients who underwent percutaneous transcatheter PFO closure after ischemic stroke or TIA experienced a serious periprocedural adverse outcome or death. The risk of adverse outcomes was highest in older patients and in those with preceding ischemic stroke.

Demographic Differences in Catheter Ablation After Hospital Presentation With Symptomatic Atrial Fibrillation.

Background Catheter ablation is increasingly used for rhythm control in symptomatic atrial fibrillation (AF), but the demographic characteristics of patients undergoing this procedure are unclear. Methods and Results We used data on all admissions at nonfederal acute care hospitals in California, Florida, and New York to identify patients discharged with a primary diagnosis of AF between 2006 and 2011. Our primary outcome was readmission for catheter ablation of AF, identified using validated International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes. Cox regression models were used to assess relationships between demographic characteristics and catheter ablation, adjusting for Elixhauser comorbidities. We identified 397 612 eligible patients. Of these, 16 717 (4.20%, 95% CI 0.41 to 0.43) underwent ablation. These patients were significantly younger, more often male, more often white, and more often privately insured, with higher household incomes and lower rates of medical comorbidity. In Cox regression models, the likelihood of ablation was lower in women than men (hazard ratio [HR] 0.83; 95% CI 0.80 to 0.86) despite higher rates of AF-related rehospitalization (HR 1.23; 95% CI 1.21 to 1.24). Compared to whites, the likelihood of ablation was lower in Hispanics (HR 0.60; 95% CI 0.56 to 0.64) and blacks (HR 0.68; 95% CI 0.64 to 0.73), even though blacks had only a slightly lower likelihood of AF-related rehospitalization (HR 0.97; 95% CI 0.94 to 0.99) and a higher likelihood of all-cause hospitalization (HR 1.38; 95% CI 1.37 to 1.39). Essentially the same pattern existed in Hispanics. Conclusions We found differences in use of catheter ablation for symptomatic AF according to sex and race despite adjustment for available data on demographic characteristics and medical comorbidities.

Timing of Incident Stroke Risk After Cervical Artery Dissection Presenting Without Ischemia

Background and Purpose— Cervical artery dissection is a common cause of stroke in young people. The temporal profile of stroke risk after cervical artery dissection presenting without ischemia remains uncertain. Methods— We performed a crossover cohort study using administrative claims data on all emergency department visits and acute care hospitalizations from 2005 to 2011 in CA, 2006 to 2013 in NY, and 2005 to 2013 in FL. Using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification codes, we identified patients with a cervical artery dissection and no previous or concurrent stroke or transient ischemic attack diagnosis. We compared the risk of stroke in successive 2-week periods during the 12 weeks after dissection versus the corresponding 2-week period 1 year later. Absolute risk increases were calculated using McNemar test for matched data. In a sensitivity analysis, we limited our population to patients presenting with typical symptoms of cervical artery dissection. Results— We identified 2791 patients with dissection without ischemia. The absolute increase in stroke risk was 1.25% (95% confidence interval, 0.84–1.67%) in the first 2 weeks after dissection compared with the same time period 1 year later. The absolute risk increase was 0.18% (95% confidence interval, 0.02–0.34%) during weeks 3 to 4 and was no longer significant during the remainder of the 12-week postdissection period. Our findings were similar in a sensitivity analysis identifying patients who presented with typical symptoms of acute dissection. Conclusions— The risk of stroke after cervical artery dissection unaccompanied by ischemia at time of diagnosis seems to be limited to the first 2 weeks.

Temporal relationship between infective endocarditis and stroke.

Objective: Stroke frequently complicates infective endocarditis (IE). However, the temporal relationship between these diseases is uncertain. Methods: We performed a retrospective study of adult patients hospitalized for IE between July 1, 2007, and June 30, 2011, at nonfederal acute care hospitals in California. Previously validated diagnosis codes were used to identify the primary composite outcome of ischemic or hemorrhagic stroke during discrete 1-month periods from 6 months before to 6 months after the diagnosis of IE. The odds of stroke in these periods were compared with the odds of stroke in the corresponding 1-month period 2 years earlier, which was considered the baseline risk of stroke. Results: Among 17,926 patients with IE, 2,275 strokes occurred within the 12-month period surrounding the diagnosis of IE. The risk of stroke was highest in the month after diagnosis of IE (1,640 vs 17 strokes in the corresponding month 2 years prior). This equaled an absolute risk increase of 9.1% (95% confidence interval 8.6%–9.5%) and an odds ratio of 96.5 (95% confidence interval 60.1–166.0). Stroke risk was significantly increased beginning 4 months before the diagnosis of IE and lasting 5 months afterward. Similar temporal patterns were seen when ischemic and hemorrhagic strokes were considered separately. Conclusions: The association between IE and stroke persists for longer than previously reported. Most diagnoses of stroke and IE are made close together in time, but a period of heightened stroke risk becomes apparent several months before the diagnosis of IE and lasts for several months afterward.

Neutrophil–Lymphocyte Ratio and Perihematomal Edema Growth in Intracerebral Hemorrhage

Background and Purpose— Although preclinical studies have shown inflammation to mediate perihematomal edema (PHE) after intracerebral hemorrhage, clinical data are lacking. Leukocyte count, often used to gauge serum inflammation, has been correlated with poor outcome but its relationship with PHE remains unknown. Our aim was to test the hypothesis that leukocyte count is associated with PHE growth. Methods— We included patients with intracerebral hemorrhage admitted to a tertiary-care stroke center between 2011 and 2015. The primary outcome was absolute PHE growth during 24 hours, calculated using semiautomated planimetry. Linear regression models were constructed to study the relationship between absolute and differential leukocyte counts (monocyte count and neutrophil–lymphocyte ratio) and 24-hour PHE growth. Results— A total of 153 patients were included. Median hematoma and PHE volumes at baseline were 14.4 (interquartile range, 6.3–36.3) and 14.0 (interquartile range, 5.9–27.8), respectively. In linear regression analysis adjusted for demographics and intracerebral hemorrhage characteristics, absolute leukocyte count was not associated with PHE growth (&bgr;, 0.07; standard error, 0.15; P=0.09). In secondary analyses, neutrophil–lymphocyte ratio was correlated with PHE growth (&bgr;, 0.22; standard error, 0.08; P=0.005). Conclusions— Higher neutrophil–lymphocyte ratio is independently associated with PHE growth. This suggests that PHE growth can be predicted using differential leukocyte counts on admission.