Small-vessel disease in the brain.

Cerebral small-vessels are generally located in the brain at branch points from major cerebral blood vessels and perfuse subcortical structures such as the white matter tracts, basal ganglia, thalamus, and pons. Cerebral small-vessel disease (CSVD) can lead to several different clinical manifestations including ischemic lacunar stroke, intracerebral hemorrhage, and vascular dementia. Risk factors for CSVD overlap with conventional vascular risk factors including hypertension, diabetes mellitus, and hypercholesterolemia, as well as genetic causes. As in cardiovascular disease, treatment of CSVD involves both primary and secondary prevention. Aspirin has not been established as a primary prevention strategy for CSVD among the general population; however, long-term antiplatelet therapy with aspirin alone continues to be the mainstay of secondary stroke prevention for non-cardioembolic ischemic stroke and high-risk TIA.

Benefits of an interdisciplinary stroke clinic: addressing a gap in physical therapy at post-stroke neurology follow-up.

BACKGROUND AND PURPOSE: An interdisciplinary stroke clinic (ISC) can improve communication and identify people post-stroke who have not reached their full recovery potential. We describe the characteristics of participants who underwent physical therapy (PT) evaluation in addition to their outpatient neurology evaluation and identify the association of assessment scales that predicted referral for additional rehabilitation. METHODS: Participants' post-stroke seen in the ISC were included in the study. The PT evaluation included the Berg Balance Scale (BBS), Ten-Meter Walk Test (10MWT), Six-Minute Walk Test (6MWT), and Short Form-Stroke Impact Scale (SF-SIS). Multivariable logistic regression analysis was performed to identify factors associated with referral for additional rehabilitation. RESULTS: The study consisted of 148 participants with a mean age of 63 (SD ± 15) years; 58% were women and 76% were Whites. Additional rehabilitation was recommended for 59% of participants. In multivariate analysis, reduced speed on comfortable 10MWT (OR = 0.06; 95%CI = 0.01-0.51) and lower SF-SIS score (OR = 0.76; 95%CI = 0.66-0.87) were significantly associated with referral for additional PT or occupational therapy. CONCLUSION: A significant number of post-acute stroke survivors were found to be appropriate for additional rehabilitation when assessed clinically by a neurologic physical therapist in an ISC. The measures that most closely correlated with this in-person clinical evaluation were 10MWT and SF-SIS.IMPLICATIONS FOR REHABILITATIONAn interdisciplinary stroke clinic can improve communication and identify people post-stroke who have not reached their full recovery potential.In a pilot study, a significant number of post-acute stroke survivors were found to be appropriate for additional rehabilitation when assessed clinically by a neurologic physical therapist in an interdisciplinary stroke clinic.Reduced speed on comfortable Ten-Meter Walk Test and lower Short Form-Stroke Impact Scale scores were associated with referral for additional rehabilitation.

Trends of Acute Ischemic Stroke Reperfusion Therapies from 2012 to 2016 in the United States.

BACKGROUND: American Heart Association/American Stroke Association guidelines recommend endovascular stroke therapy (EST) with recombinant tissue plasminogen activator (rt-PA) for eligible patients in acute ischemic stroke (AIS). Using the National Inpatient Sample database, we evaluated trends in treatment with rt-PA and EST for AIS and their outcomes. METHODS: This is a cross-sectional observational study of patients with AIS admitted in US hospitals from 2012 to 2016. Patients were grouped into those who received rt-PA alone, EST alone, and rtPA+EST. Survey statistical procedures were performed. Multivariable regression analysis with pairwise comparisons of each treatment group with no treatment group was performed for discharge outcomes. RESULTS: The study included 2,290,520 patients with AIS with the mean age of 70.46 years. Treatment rates increased from 2012 to 2016 for rt-PA by 7% per year (5.86%-7.67%, odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.05-1.08) and EST by 38% per year (0.55%-1.75%, OR = 1.38, 95% CI: 1.31-1.45) but not rt-PA+EST (0.54%-0.57%, OR = 1.04, 95% CI: 0.99-1.08). The mean length of stay reduced from 2012 to 2016 for rt-PA (6.07-4.91 days, P < 0.0001) and rt-PA+EST (9.19-7.10 days, P = 0.0067) but not for EST (9.61-8.51 days, P = 0.5074). The odds of patients discharged home increased by 8%, 9%, and 15% among patients who received rt-PA alone, EST alone, and rt-PA+EST, respectively, compared with no treatment group. CONCLUSION: The utilization of rt-PA alone and EST alone increased but that of rt-PA+EST remained unchanged from 2012 to 2016 in the National Inpatient Sample.

A double-blind, randomized, controlled study of two dose strengths of dalfampridine extended release on walking deficits in ischemic stroke.

BACKGROUND: Stroke-induced ischemia affects both cortex and underlying white matter. Dalfampridine extended release tablets (D-ER) enhance action potential conduction in demyelinated axons, which may positively affect post-stroke recovery. OBJECTIVE: Based on promising preliminary data, we compared efficacy of D-ER administered at 7.5 mg or 10 mg with placebo on post-stroke ambulation. Primary study outcome (response) was a ≥20% increase on the 2-minute walk test (2 MinWT) at 12 weeks after first drug administration. METHODS: This was a multicenter, randomized, placebo-controlled, 3-arm, parallel-group, safety and efficacy trial. After obtaining baseline measures of 2 MinWT, Walk-12, and Timed Up and Go, subjects entered a 2-week, single-blind placebo run-in period and were randomized 1:1:1 to receive 7.5 mg D-ER, 10 mg D-ER, or placebo, dosed twice-daily for 12 weeks. Follow-up evaluations occurred at weeks 14 and 16 when subjects were off study drug. RESULTS: The study was terminated early with 377 of planned 540 patients enrolled, due to no treatment effect. At week 12, mean increase in distances walked in 2 minutes were similar among the 3 study groups (14.9±40.0 feet; 19.4±39.6 feet; and 20.4±38.3 feet for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively). The proportion of subjects who showed ≥20% improvement on 2 MinWT at week 12 was 13.5%, 14.0%, and 19.0%, for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively; these were nonsignificant changes from baseline for all groups. CONCLUSIONS: D-ER at either a 7.5-mg or 10-mg dose did not significantly increase performance on the 2 MinWT in stroke survivors with gait impairment, although this study was terminated early before full enrollment. (Clinical Trial # NCT02271217).

Updates in the Management of Cryptogenic Stroke and Patent Foramen Ovale.

BACKGROUND: Stroke is a common neurological disorder and may present with visual symptoms. A thorough workup is warranted to determine the underlying cause of stroke to optimize secondary prevention. Despite a full workup, a high-risk mechanism may not be identified. Optimal treatment in this patient population has been the subject of recent research, particularly with regard to low-risk stroke mechanisms such as patent foramen ovale (PFO). EVIDENCE ACQUISITION: Using PubMed and published stroke guidelines, an evidence-based literature review was performed. RESULTS: In this review, we compare cryptogenic stroke with the newer concept of embolic stroke of undetermined source, summarize the most common causes presumed to underlie these strokes, and review the evidence for optimal antithrombotic management. We also review recent clinical trials demonstrating a benefit for percutaneous closure of PFO for secondary stroke prevention in select patients. CONCLUSIONS: Stroke management is based on evaluation of individual patient-risk factors. Evaluation and treatment is ideally directed by a vascular neurologist to ensure optimal secondary prevention, especially in cases where an underlying etiology is not identified on initial workup.

Predictors of Atrial Fibrillation in Patients With Cryptogenic Stroke.

BACKGROUND AND PURPOSE: Many patients diagnosed with cryptogenic stroke or transient ischemic attack are subsequently found to have atrial fibrillation (AF) on outpatient cardiac telemetry monitoring. Identification of predictive factors for the detection of AF could assist with patient selection to increase the yield of telemetry and hasten initiation of appropriate secondary stroke prevention. METHODS: This was a retrospective cross-sectional study of patients diagnosed with cryptogenic stroke at a comprehensive stroke center and referred for at least 21 days of prolonged outpatient telemetry. Telemetry reports and data from the patient's stroke hospitalization, including imaging studies, electrocardiogram (EKG), echocardiogram, vital signs, and laboratory data, were reviewed. RESULTS: Ten percent of the 121 patients included in the study were diagnosed with AF based on outpatient telemetry. There was a strong association between presence of premature atrial contractions (PACs) on admission EKG and subsequent detection of AF (P = .004). Large left atrial diameter on echocardiogram was correlated with AF detection in males (P = .024). However, there was no association between AF and other echocardiographic measurements. Thyroid-stimulating hormone (TSH) levels were significantly higher in patients with cryptogenic stroke having AF (P = .008), with a TSH greater than 4.20 mIU/L predictive of detection of AF (P < .001). CONCLUSIONS: Atrial fibrillation was found by outpatient monitoring in a notable percentage of patients with cryptogenic stroke. Predictors of occult AF in our study population included PACs and higher TSH levels. Although an association between low TSH and AF has been well established, our results suggest that high TSH may be a predictive factor as well.

STN vs. GPi deep brain stimulation for tremor suppression in Parkinson disease: A systematic review and meta-analysis.

OBJECTIVE: To compare subthalamic nucleus (STN) deep brain stimulation (DBS) with globus pallidus interna (GPi) DBS for tremor suppression in Parkinson disease (PD). BACKGROUND: DBS is an effective surgical therapy that has been shown to provide significant benefit for motor symptoms in PD. Currently, two main structures targeted to treat motor complications in PD are the STN and GPi. Although some groups traditionally favor STN over GPi for tremor suppression, evidence demonstrating superiority in long-term tremor control is limited. METHODS: We performed a systematic review for all randomized trials comparing STN vs GPi DBS in PD that were published before March 2017. Five studies were examined in a random effects model meta-analysis. We conducted moderator variable analysis to determine if there was a treatment effect difference for STN versus GPi. RESULTS: We compared DBS ON versus OFF and found a significant overall standardized difference mean effect: Effect Size = 0.36; 95% CI = 0.316-0.395; P < 0.0001. These findings indicate that DBS reduced tremor symptoms in PD patients with a medium effect size. Moderator variable analysis of STN vs GPI revealed two significant standardized effect sizes: STN effect size = 0.38 and GPi effect size = 0.35. A Z-test showed that effect sizes between the STN and GPi were not significantly different (P = 0.56). CONCLUSIONS: DBS is effective in reducing tremor in PD patients regardless of stimulation target. However, the degree of tremor suppression in STN DBS versus GPi DBS was equivalent.

Management of Blunt Cerebrovascular Injury.

PURPOSE OF REVIEW: This review provides an updated summary of blunt cerebrovascular injury (BCVI) to guide clinicians in its early diagnosis and prevention and treatment of stroke associated with such injury. RECENT FINDINGS: Untreated BCVI causes stroke in 10-40% of patients, but more than half will not present with stroke symptoms initially. Risk of stroke is highest in the first 7 days, with a peak in the first 24 h. Computed tomography (CT) angiography is currently the screening modality of choice, although digital subtraction angiography may still be required in some cases. Antithrombotic therapy is the mainstay of treatment and has proven safety in trauma patients. In carefully selected patients, endovascular intervention may also be beneficial. BCVI is a potentially preventable cause of stroke. A high index of suspicion is needed as emergent screening during initial evaluation can provide a window for stroke prevention. Screening all patients with injuries that would otherwise prompt CT scans of the neck or chest is recommended. Treatment is guided by grade of injury. Early treatment with antithrombotics has been shown to be both effective and safe.

Longitudinal Follow-up of Impedance Drift in Deep Brain Stimulation Cases.

Background: Impedance is an integral property of neuromodulation devices that determines the current delivered to brain tissue. Long-term variability in therapeutic impedance following deep brain stimulation (DBS) has not been extensively investigated across different brain targets. The aim was to evaluate DBS impedance drift and variability over an extended postoperative period across common DBS targets. Methods: Retrospective data from 1,764 electrode leads were included and drawn from 866 DBS patients enrolled in the University of Florida Institutional Review Board-approved INFORM database and analyzed up to 84 months post implantation. An exploratory analysis was conducted to identify trends in impedances using a Mann-Kendall test of trend. Results: There were 866 patients and 1,764 leads available for analysis. The majority of subjects had Parkinson's disease (60.7%). The mean age at implantation was 58.7 years old and the mean follow-up time was 36.8 months. There were significant fluctuations in the mean impedance of all electrodes analyzed that largely stabilized by 6 months except for the subthalamic nucleus (STN) target, in which fluctuations persisted throughout the duration of follow-up with a continued downward trend (p < 0.001). Discussion: The drift in impedance observed primarily within the first 6 months is in keeping with prior studies and is likely due to surgical micro-lesioning effects and brain parenchyma remodeling at the electrode-tissue interface, typically at values approximating 1,000 Ω. The differences in impedance trends over time in the various DBS targets may be due to underlying differences in structure and tissue composition.

Symptomatic Carotid Occlusion Is Frequently Associated With Microembolization.

BACKGROUND AND PURPOSE: Symptomatic carotid artery disease is associated with significant morbidity and mortality. The pathophysiologic mechanisms of cerebral ischemia among patients with carotid occlusion remain underexplored. METHODS: We conducted a prospective observational cohort study of patients hospitalized within 7 days of ischemic stroke or transient ischemic attack because of ≥50% carotid artery stenosis or occlusion. Transcranial Doppler emboli detection was performed in the middle cerebral artery ipsilateral to the symptomatic carotid. We describe the prevalence of microembolic signals (MES), characterize infarct topography, and report clinical outcomes at 90 days. RESULTS: Forty-seven patients, 19 with carotid occlusion and 28 with carotid stenosis, had complete transcranial Doppler recordings and were included in the final analysis. MES were present in 38%. There was no difference in MES between those with carotid occlusion (7/19, 37%) compared with stenosis (11/28, 39%; P=0.87). In patients with radiographic evidence of infarction (n=39), 38% had a watershed pattern of infarction, 41% had a nonwatershed pattern, and 21% had a combination. MES were present in 40% of patients with a watershed pattern of infarction. Recurrent cerebral ischemia occurred in 9 patients (19%; 6 with transient ischemic attack, 3 with ischemic stroke). There was no difference in the rate of recurrence in those with compared to those without MES. CONCLUSIONS: Cerebral embolization plays an important role in the pathophysiology of ischemia in both carotid occlusion and stenosis, even among patients with watershed infarcts. The role of aggressive antithrombotic and antiplatelet therapy for symptomatic carotid occlusions may warrant further investigation given our findings.

Diagnostic Yield of Echocardiography in Transient Ischemic Attack.

BACKGROUND: Echocardiography is often performed to identify a cardiac source of embolism (CSE) causing transient ischemic attack (TIA). However, the diagnostic yield of echocardiography in TIA remains uncertain, and its role in routine evaluation of TIA is controversial. METHODS: Patients with acute TIA were prospectively enrolled at 4 stroke centers. A CSE was defined using the Causative Classification of Stroke system; patent foramen ovale was considered a relevant CSE only if the patient underwent closure or was placed on anticoagulation. Patients with a known CSE at time of admission were excluded from analysis of the yield of echocardiography. RESULTS: A total of 869 patients were enrolled at stroke centers, and 129 had a known CSE at presentation. Of the 740 remaining patients, 603 (81%) underwent echocardiography. A potential CSE was identified in 60 (10%) of these patients. The most common CSEs noted on echocardiography were complex aortic arch atherosclerosis and patent foramen ovale. History of coronary artery disease (P < .001), lack of prior stroke or TIA (P = .007), and presence of acute infarction on magnetic resonance imaging (MRI) (P < .001) were predictors of CSE on echocardiography. The yield of echocardiography was 29% in patients with both history of coronary artery disease and acute infarction on MRI, 14% with one of these features, and 5% with neither of these features (P < .0001). A CSE identified by echocardiography prompted initiation of anticoagulation in 15 of the 603 (2.5%) subjects. CONCLUSIONS: Echocardiography demonstrates a relevant CSE in a significant portion of patients with TIA. However, changes in antithrombotic therapy resulting from echocardiography are infrequent.

Social interaction and social withdrawal in rodents as readouts for investigating the negative symptoms of schizophrenia.

Negative symptoms (e.g., asociality and anhedonia) are a distinct symptomatic domain that has been found to significantly affect the quality of life in patients diagnosed with schizophrenia. Additionally, the primary negative symptom of asociality (i.e., withdrawal from social contact that derives from indifference or lack of desire to have social contact) is a major contributor to poor psychosocial functioning and has been found to play an important role in the course of the disorder. Nonetheless, the pathophysiology underlying these symptoms is unknown and currently available treatment options (e.g., antipsychotics and cognitive-behavioral therapy) fail to reliably produce efficacious benefits. Utilizing rodent paradigms that measure social behaviors (e.g., social withdrawal) to elucidate the neurobiological substrates that underlie social dysfunction and to identify novel therapeutic targets may be highly informative and useful to understand more about the negative symptoms of schizophrenia. Accordingly, the purpose of this review is to provide an overview of the behavioral tasks for assessing social functioning that may be translationally relevant for investigating negative symptoms associated with schizophrenia.

Evidence for transgenerational metabolic programming in Drosophila.

Worldwide epidemiologic studies have repeatedly demonstrated an association between prenatal nutritional environment, birth weight and susceptibility to adult diseases including obesity, cardiovascular disease and type 2 diabetes. Despite advances in mammalian model systems, the molecular mechanisms underlying this phenomenon are unclear, but might involve programming mechanisms such as epigenetics. Here we describe a new system for evaluating metabolic programming mechanisms using a simple, genetically tractable Drosophila model. We examined the effect of maternal caloric excess on offspring and found that a high-sugar maternal diet alters body composition of larval offspring for at least two generations, augments an obese-like phenotype under suboptimal (high-calorie) feeding conditions in adult offspring, and modifies expression of metabolic genes. Our data indicate that nutritional programming mechanisms could be highly conserved and support the use of Drosophila as a model for evaluating the underlying genetic and epigenetic contributions to this phenomenon.

Convergent validity and interrater reliability of estimating the ABCD2 score from medical records.

BACKGROUND AND PURPOSE: The ABCD(2) score is increasingly used for risk stratification of transient ischemic attack patients. We sought to determine the reliability and convergent validity of retrospective ABCD(2) score estimation from medical records. METHODS: We compared ABCD(2) scores that were prospectively determined by a vascular neurology attending to scores determined retrospectively from medical record review. Emergency department records and neurology consult notes for patients with acute transient ischemic attack were abstracted with explicit ABCD(2) scoring redacted. Scores were estimated by 2 independent raters using these records. Estimated ABCD(2) component scores, total scores, and risk category were compared both between retrospective raters and with prospectively obtained scores. Reliability was assessed using unweighted κ statistics. RESULTS: Interrater reliability was substantial with 72% exact agreement in total score between retrospective raters (κ=0.64) and nearly perfect with 82% agreement for ABCD(2) category (κ=0.71). Interrater agreement was best for age and diabetes mellitus and poorest for clinical features and duration. Agreement between the retrospective raters and prospectively obtained score was >90% for age, blood pressure, and diabetes mellitus, but only ≈70% for clinical features and duration. Retrospectively, estimated total ABCD(2) score exactly matched the prospective score in 58% of patients for rater 1 and 44% of patients for rater 2. Retrospectively, estimated ABCD(2) category matched the prospectively scored category in 67% of patients for rater 1 and 71% of patients for rater 2. CONCLUSIONS: The ABCD(2) score can be abstracted from medical records with substantial interrater reliability but limited convergent validity. This may lead to misclassification of risk category in more than one third of patients.

Variable maternal stress in rats alters locomotor activity, social behavior, and recognition memory in the adult offspring.

Rats repeatedly exposed to variable prenatal stress (PNS) exhibit behavioral signs that are similar to those manifested in several neuropsychiatric disorders such as deficits in attention and inhibitory control, and impairments in memory-related task performance. The purpose of the study described here was to conduct a comprehensive battery of tests to further characterize the behavioral phenotype of PNS rats as well as to evaluate the sensitivity of the model to therapeutic interventions (i.e., to compounds previously shown to have therapeutic potential in neuropsychiatric disorders). The results of this study indicated that PNS in rats is associated with: 1) increased locomotor activity and stereotypic behaviors, 2) elevated sensitivity to the psychostimulant amphetamine, 3) increased aggressive behaviors toward both adult and juvenile rats and 4) delay-dependent deficits in recognition memory. There was no evidence that PNS rats exhibited deficits in other areas of motor function/learning, sensorimotor gating, spatial learning and memory, social withdrawal, or anhedonia. In addition, the results revealed that the second generation antipsychotic risperidone attenuated amphetamine-related increases in locomotor activity in PNS rats; however, the effect was not sustained over time. Furthermore, deficits in recognition memory in PNS rats were attenuated by the norepinephrine reuptake inhibitor, atomoxetine, but not by the α7 nicotinic acetylcholine receptor partial agonist, GTS-21. This study supports the supposition that important phenomenological similarities exist between rats exposed to PNS and patients afflicted with neuropsychiatric disorders thus further establishing the face validity of the model for evaluating potential therapeutic interventions.

Exposure to variable prenatal stress in rats: effects on anxiety-related behaviors, innate and contextual fear, and fear extinction.

Rats repeatedly exposed to variable prenatal stress (PNS) exhibit behavioral features often observed in neuropsychiatric disorders including elevated sensitivity to stimulants and impairments of attention, inhibitory control and memory-related task performance. However, to date there have been relatively few studies designed to assess the effects of PNS on anxiety, stress and fear responses, or the function of the hypothalamic-pituitary-adrenal (HPA) axis (a system clearly linked to stress and fear-related responses as well as neuropsychiatric disorders). In the current study, rats exposed to variable PNS were evaluated for anxiety-related behaviors in open field, elevated plus maze, and light/dark preference tasks. Innate fear responses were assessed using a predatory odor task and learned fear and extinction were assessed with a contextual fear conditioning task. As an indicator of HPA axis function, serum corticosterone levels were determined by enzyme immunoassay at various time points. The results indicated that PNS resulted in several behavioral anomalies including decreased innate fear responses to predator odor, impaired fear extinction, increased locomotor activity and stereotypic-like behaviors. Baseline levels of corticosterone in PNS subjects were similar to non-stressed controls; however, when exposed to acute stress, they exhibited an increase in corticosterone that was greater in magnitude. PNS was not associated with increased anxiety-like behaviors or deficits in learning or retention during contextual fear conditioning. Collectivity, these data support the argument that variable PNS in rats is a valid model system for studying some behavioral components of neuropsychiatric disorders as well as the influence of stress hormones.

The acute effects of dimebolin, a potential Alzheimer's disease treatment, on working memory in rhesus monkeys.

BACKGROUND: Dimebolin (latrepirdine), a compound with multiple potential drug targets, is being evaluated in clinical trials for the treatment of Alzheimer's disease (AD) and preliminary results suggest it can slow the disease process. There is also evidence that dimebolin directly improves aspects of cognition. Here we examined the acute effect of dimebolin on components of working memory in non-human primates, young adult (11-17 years old) and aged (20-31 years old) rhesus macaques. EXPERIMENTAL APPROACH: The effects of dimebolin (3.9-118 µg kg(-1)) on working memory, as measured by performance on delayed matching-to-sample (DMTS), were examined in the normal young adult monkeys and aged adult monkeys. All the monkeys studied were proficient in the performance of a computer-assisted DMTS task. In a subsequent experiment in the same subjects, dimebolin was administered 15 min before a cognitively-impairing dose (20 µg kg(-1)) of scopolamine. KEY RESULTS: In both the young adult and aged monkeys, dimebolin significantly increased the DMTS task accuracies. In young adults, the task improvement was associated with long (retention/retrieval) delay trials, and a protracted enhancement was observed for sessions run 24 h post administration of a single dose. Dimebolin did not significantly attenuate the scopolamine-induced impairment. In the aged monkeys, dimebolin significantly improved the reduced task accuracies associated with long delay intervals. CONCLUSIONS AND IMPLICATIONS: Here we demonstrated that dimebolin is able to improve components of working memory in monkeys and to induce a protracted response for at least 24 h after administration of a single dose.

Combined optic neuropathy and myelopathy secondary to copper deficiency.

We report two patients, both with a history of gastric surgery, who presented with progressive optic neuropathy and myelopathy. The patients' symptoms were initially attributed to vitamin B12 deficiency and/or neuromyelitis optica; however, after the neurologic deficits continued to progress with the use of conventional treatments, further evaluation was initiated, and a severe copper deficiency was revealed. Copper deficiency is a rare cause of progressive optic neuropathy and myelopathy and should be considered in the differential diagnosis. It is crucial to elicit a history of gastric surgery or other risk factors for hypocupremia in those patients undergoing an evaluation for subacute or chronically progressive optic neuropathy or myelopathy.