Anil Can

Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties.

Pharmacological targeting of spreading depression in migraine

Migraine, particularly with aura, is a genetically heterogeneous disorder of ion channels, pumps or transporters associated with increased cortical excitability. Spreading depression, as one reflection of hyperexcitability, is the electrophysiological event underlying aura symptoms and a trigger for headache. Endogenous (e.g., genes and hormones) and exogenous factors (e.g., drugs) modulating migraine susceptibility have also been shown to modulate spreading depression susceptibility concordantly, suggesting that spreading depression can be a relevant therapeutic target in migraine. In support of this, several migraine prophylactic drugs used in clinical practice have been shown to suppress spreading depression susceptibility as a probable mechanism of action, despite belonging to widely different pharmacological classes. Hence, susceptibility to spreading depression can be a useful preclinical model with good positive and negative predictive value for drug screening.

Migraine Prophylaxis, Ischemic Depolarizations, and Stroke Outcomes in Mice

Background and Purpose— Migraine with aura is an established stroke risk factor, and excitatory mechanisms such as spreading depression (SD) are implicated in the pathogenesis of both migraine and stroke. Spontaneous SD waves originate within the peri-infarct tissue and exacerbate the metabolic mismatch during focal cerebral ischemia. Genetically enhanced SD susceptibility facilitates anoxic depolarizations and peri-infarct SDs and accelerates infarct growth, suggesting that susceptibility to SD is a critical determinant of vulnerability to ischemic injury. Because chronic treatment with migraine prophylactic drugs suppresses SD susceptibility, we tested whether migraine prophylaxis can also suppress ischemic depolarizations and improve stroke outcome. Methods— We measured the cortical susceptibility to SD and ischemic depolarizations, and determined tissue and neurological outcomes after middle cerebral artery occlusion in wild-type and familial hemiplegic migraine type 1 knock-in mice treated with vehicle, topiramate or lamotrigine daily for 7 weeks or as a single dose shortly before testing. Results— Chronic treatment with topiramate or lamotrigine reduced the susceptibility to KCl-induced or electric stimulation-induced SDs as well as ischemic depolarizations in both wild-type and familial hemiplegic migraine type 1 mutant mice. Consequently, both tissue and neurological outcomes were improved. Notably, treatment with a single dose of either drug was ineffective. Conclusions— These data underscore the importance of hyperexcitability as a mechanism for increased stroke risk in migraineurs, and suggest that migraine prophylaxis may not only prevent migraine attacks but also protect migraineurs against ischemic injury.

Large-scale identification of patients with cerebral aneurysms using natural language processing

Objective: To use natural language processing (NLP) in conjunction with the electronic medical record (EMR) to accurately identify patients with cerebral aneurysms and their matched controls. Methods: ICD-9 and Current Procedural Terminology codes were used to obtain an initial data mart of potential aneurysm patients from the EMR. NLP was then used to train a classification algorithm with .632 bootstrap cross-validation used for correction of overfitting bias. The classification rule was then applied to the full data mart. Additional validation was performed on 300 patients classified as having aneurysms. Controls were obtained by matching age, sex, race, and healthcare use. Results: We identified 55,675 patients of 4.2 million patients with ICD-9 and Current Procedural Terminology codes consistent with cerebral aneurysms. Of those, 16,823 patients had the term aneurysm occur near relevant anatomic terms. After training, a final algorithm consisting of 8 coded and 14 NLP variables was selected, yielding an overall area under the receiver-operating characteristic curve of 0.95. After the final algorithm was applied, 5,589 patients were classified as having aneurysms, and 54,952 controls were matched to those patients. The positive predictive value based on a validation cohort of 300 patients was 0.86. Conclusions: We harnessed the power of the EMR by applying NLP to obtain a large cohort of patients with intracranial aneurysms and their matched controls. Such algorithms can be generalized to other diseases for epidemiologic and genetic studies.

Effect of Vascular Anatomy on the Formation of Basilar Tip Aneurysms

BACKGROUND The pathogenesis of intracranial aneurysms is multifactorial and includes genetic, environmental, and anatomic influences. Hemodynamic stress plays a particular role in the formation of intracranial aneurysms, which is conditioned by the geometry and morphology of the vessel trees. OBJECTIVE To identify image-based morphological parameters that correlated with the formation of basilar artery tip aneurysms (BTAs) in a location-specific manner. METHODS Morphological parameters obtained from computed tomographic angiographies of 33 patients with BTAs and 33 patients with aneurysms at other locations were evaluated with Slicer, an open-source image analysis software, to generate 3-dimensional models of the aneurysms and surrounding vascular architecture. We examined the diameters and vessel-to-vessel angles of the main vessels at the basilar bifurcation in patients with and without BTAs. To control for genetic and other risk factors, only patients with at least 1 aneurysm were included. Univariate and multivariate analyses were performed to determine statistical significance. RESULTS Sixty-six patients (33 with BTAs, 33 with other aneurysms) who were evaluated from 2008 to 2013 were analyzed. Multivariate logistic regression revealed that a larger angle between the posterior cerebral arteries (odds ratio, 1.04; P = 1.42 × 10(-3)) and a smaller basilar artery diameter (odds ratio, 0.23; P = .02) were most strongly associated with BTA formation after adjustment for other morphological and clinical variables. CONCLUSION Larger posterior cerebral artery angles and smaller basilar artery diameters are associated with the formation of basilar tip aneurysms. These parameters are easily measurable by the clinician and will aid in screening strategies in high-risk patients.

Micro-heterogeneity of flow in a mouse model of chronic cerebral hypoperfusion revealed by longitudinal Doppler optical coherence tomography and angiography

Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimers disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC)-perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity.

Association of intracranial aneurysm rupture with smoking duration, intensity, and cessation

Objective: Although smoking is a known risk factor for intracranial aneurysm (IA) rupture, the exact relationship between IA rupture and smoking intensity and duration, as well as duration of smoking cessation, remains unknown. Methods: In this case-control study, we analyzed 4,701 patients with 6,411 IAs diagnosed at the Brigham and Womens Hospital and Massachusetts General Hospital between 1990 and 2016. We divided individuals into patients with ruptured aneurysms and controls with unruptured aneurysms. We performed univariable and multivariable logistic regression analyses to determine the association between smoking status and ruptured IAs at presentation. In a subgroup analysis among former and current smokers, we assessed the association between ruptured aneurysms and number of packs per day, duration of smoking, and duration since smoking cessation. Results: In multivariable analysis, current (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.89–2.59) and former smoking status (OR 1.56, 95% CI 1.31–1.86) were associated with rupture status at presentation compared with never smokers. In a subgroup analysis among current and former smokers, years smoked (OR 1.02, 95% CI 1.01–1.03) and packs per day (OR 1.46, 95% CI 1.25–1.70) were significantly associated with ruptured aneurysms at presentation, whereas duration since cessation among former smokers was not significant (OR 1.00, 95% CI 0.99–1.02). Conclusions: Current cigarette smoking, smoking intensity, and smoking duration are significantly associated with ruptured IAs at presentation. However, the significantly increased risk persists after smoking cessation, and smoking cessation does not confer a reduced risk of aneurysmal subarachnoid hemorrhage beyond that of reducing the cumulative dose.

The myocutaneous trapezius flap revisited: A treatment algorithm for optimal surgical outcomes based on 43 flap reconstructions

BACKGROUND Because the vascular anatomy of the trapezius flap is highly variable, choosing the most appropriate flap type and design is essential to optimize outcomes and minimize postoperative complications. The aim of this study was to develop a surgical treatment algorithm for trapezius flap transfers. METHODS The medical files of all consecutive patients with a myocutaneous trapezius flap reconstruction of the head, neck, and upper back area treated at three different university medical centers between July 2001 and November 2012 were reviewed. RESULTS There were 43 consecutive flaps performed in 38 patients with a mean follow-up time of 15 months (range, 1-48 months). Eleven patients had a mentosternal burn scar contracture (12 flaps), 12 patients (13 flaps) presented with cancer, and 15 patients (18 flaps) were suffering from chronic wounds due to failed previous reconstruction (n = 6), osteoradionecrosis (n = 1), chronic infection (n = 3), bronchopleural fistula (n = 3), and pressure sores (n = 2). The mean defect size was 152 cm(2). Sixteen flaps were based on the superficial cervical artery (SCA; type 2), 16 were based on the dorsal scapular artery (DSA; type 3), one was based on the intercostal arteries (type 4), and 10 flaps were based on both the DSA and SCA. Recipient-site complications requiring reoperation occurred in 16.3%, including one total flap failure (2.6%). CONCLUSIONS The trapezius myocutaneous flap is a valuable option to reconstruct various head and neck and upper back defects. Based on our data, a surgical treatment algorithm was developed in an attempt to reduce variation in care and improve clinical outcomes.

Pituitary Dysfunction After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis.

BACKGROUND The prevalence of hypothalamic-pituitary dysfunction after aneurysmal subarachnoid hemorrhage has not been precisely determined, and conflicting results have been reported in the literature. OBJECTIVE To perform a systematic review and meta-analysis investigating the prevalence of pituitary insufficiency after aneurysmal subarachnoid hemorrhage and to focus on basal serum and dynamic test differences. METHODS The prevalence of pituitary dysfunction was quantified at 3 to 6 months and >6 months after aneurysmal subarachnoid hemorrhage. Proportions were transformed with the logit transformation. A subgroup analysis was performed focusing on the differences in outcome between basal serum and dynamic tests for the diagnosis of growth hormone deficiency (GHD) and secondary adrenal insufficiency. RESULTS Overall prevalence of hypopituitarism differed considerably between studies, ranging from 0.05 to 0.45 in studies performed between 3 and 6 months after the event and from 0 to 0.55 in long-term studies (>6 months), with pooled frequencies of 0.31 (95% confidence interval [CI]: 0.22-0.43) and 0.25 (95% CI: 0.16-0.36), respectively. Pooled frequency of GHD at 3 to 6 months was 0.14 (95% CI: 0.08-0.24). At >6 months, GHD prevalence was 0.19 (95% CI: 0.13-0.26) overall, but ranged from 0.15 (95% CI: 0.06-0.33) with the insulin tolerance test to 0.25 (95% CI: 0.15-0.36) using the growth hormone releasing hormone + arginine test. CONCLUSION Hypopituitarism is a common complication in patients with aneurysmal subarachnoid hemorrhage, with GHD being the most prevalent diagnosis. We showed that variations in prevalence rates in the literature are partly due to methodological differences among pituitary function tests. ABBREVIATIONS ACTH, adrenocorticotropic hormoneaSAH, aneurysmal subarachnoid hemorrhageGHD, growth hormone deficiencyGHRH, growth hormone-releasing hormoneGST, glucagon stimulation testIGF, insulin-like growth factor 1ITT, insulin tolerance testSAH, subarachnoid hemorrhage.

Complications of pacemaker therapy in adults with congenital heart disease: A multicenter study

BACKGROUND This study aims to investigate indications and complications of permanent cardiac pacing in adults with congenital heart disease (CHD). METHODS AND RESULTS Two-hundred and seventy-four CHD patients were identified who underwent permanent pacemaker implantation between 1972 and 2009. The indication for pacing was acquired sinus node or AV node conduction disease (63%), sinus node or AV node conduction disease after cardiac surgery (28%), and drug/arrhythmia-related indications (9%). Patients with complex CHD received a pacemaker at younger age (23 versus 31 years, p<0.0001) and more often received an epicardial pacing system (51% versus 23%, p<0.0001) compared to those with simple or moderate CHD. Twenty-nine patients (10.6%) had a periprocedural complication during the primary pacemaker implantation (general population: 5.2%). The most common acute complications were lead dysfunction (4.0%), bleeding (2.6%), pocket infection (1.5%) and pneumothorax (1.5%). During a median follow-up of 12 years, pacemaker-related complications requiring intervention occurred in 95 patients (34.6%). The most common late pacemaker-related complications included lead failure (24.8%), pacemaker dysfunction/early battery depletion (5.1%), pacemaker migration (4.7%) and erosion (4.7%). Pacemaker implantation at younger age (<18 years) was an independent predictor of late pacemaker-related complication (adjusted hazard ratio 1.68, 95% confidence interval 1.07 to 2.63, p=0.023). CONCLUSIONS The risk of periprocedural complications seems higher in the CHD population compared to the general population and more than one-third of CHD patients encountered a pacemaker-related complication during long-term follow-up. This risk increases for those who receive a pacemaker at younger age.