Edward Kasarskis - Academia.edu (original) (raw)

Papers by Edward Kasarskis

Archives of internal medicine, 1992

A patient with sinus bradycardia and atrioventricular block, induced by carbamazepine, prompted a... more A patient with sinus bradycardia and atrioventricular block, induced by carbamazepine, prompted an extensive literature review of all previously reported cases. From the analysis of these cases, two distinct forms of carbamazepine-associated cardiac dysfunction emerged. One patient group developed sinus tachycardias in the setting of a massive carbamazepine overdose. The second group consisted almost exclusively of elderly women who developed potentially life-threatening bradyarrhythmias or atrioventricular conduction delay, associated with either therapeutic or modestly elevated carbamazepine serum levels. Because carbamazepine is widely used in the treatment of many neurologic and psychiatric conditions, the recognition of the latter syndrome has important implications for the use of this drug in elderly patients.

Objective: To examine whether the responses to standard sleep questionnaires used in ALS correlat... more Objective: To examine whether the responses to standard sleep questionnaires used in ALS correlate with measures of pulmonary function. Background: Presently, NIV is initiated in ALS when FVC falls below 50% or the patient is dyspneic. Additionally, sleep disorders have been described in ALS and some investigators utilize sleep studies to titrate NIV. The Pittsburgh Sleep Quality Questionnaire Index (PSQI) and the Epworth Sleepiness Scale (ESS) are validated questionnaires used to detect sleep disorders. We evaluated the correlation of the PSQI and the ESS with pulmonary function in ALS. Design/Methods: 153 patients were enrolled as part of a multicenter pilot study of nutrition and NIPPV in ALS. All participants completed the ESS and PSQI at their baseline visit along with the ALSFRS-R score, ALS Functional Dyspnea Scale (ALSFDS), Supine FVC (sFVC) and upright FVC (uFVC). The relationship between these measurements and the questionnaires was evaluated using Pearson Correlation Coefficients. Results: The mean baseline scores for the scales were: ALSFRS-R 31.2 +/- 9.06, PSQI 7.95 +/-3.99, and ESS 5.38 +/- 3.78. The number of questionnaires collected were: 87 for ALSFRS-R, 73 for ALSFDS, PSQI and ESS. The ALSFRS-R showed the best correlation with the uFVC (R = 0.76, p\u3c0.001) and sFVC (R= 0.61, p\u3c0.001). The PSQI correlation with uFVC (R = -0.22, p = 0.06) and sFVC (R = -0.14, p = 0.26) was not significant. The ESS correlation with uFVC (R = -0.19, p = 0.11) and sFVC (R = -0.18, p = 0.14) was not significant. Conclusions: The ALSFRS-R scale was most significantly correlated to supine & upright FVC when compared with PSQI and ESS. This suggests that sleep symptoms detected by questionnaires are not as sensitive to declining in respiratory function as changes on ALSFRS-R

Amyotrophic lateral sclerosis & frontotemporal degeneration, Jul 30, 2021

Annals of Internal Medicine, Jul 7, 2020

Muscle & Nerve, Jun 5, 2017

Dysphagia is a common symptom in neurological and neuromuscular disorders. Especially if accompan... more Dysphagia is a common symptom in neurological and neuromuscular disorders. Especially if accompanied by the complaint of dysarthria, it demands investigation as to the cause. This frequently begins with direct evaluation of the oropharynx by an otolaryngologist. A functional swallowing assessment is usually performed with a bedside swallowing study, fiberoptic endoscopic evaluation of swallowing (FEES), or a modified barium swallow. If the pathological cause for dysphagia is not identified by these evaluations, then attention is shifted to possible neurological causes. Obviously, the differential diagnosis is broad, including neurodegenerative disorders, stroke, multiple sclerosis, or neuromuscular diseases, and the neurological investigation proceeds accordingly. Most readers are familiar with this process. We need to take a few steps back, however, and put swallowing function in context. To state the obvious, the “goal” of swallowing is fundamental to survival—the ingestion of sufficient energy (calories), protein, vitamins, micronutrients, and fluid to meet our needs for energy expenditure, hydration, and structural integrity of the body to ensure survival and reproduction. But there is a lot more beyond physiology. In his book, Cooked, Michael Pollan observes: “The shared meal is no small thing. It is a foundation of family life, the place where our children learn the art of conversation and acquire the habits of civilization: sharing, listening, taking turns, navigating differences, arguing without offending.” It is obvious that the totality of the meal experience is disrupted, if not shattered, by a person with dysphagia who may be coughing, drooling, and choking. The study by Youssof and colleagues in this issue of the journal evaluates the effect of chronic dysphagia on quality of life (QOL) in patients with oculopharyngeal muscular dystrophy (OPMD) using the SWAL-QOL scale. The SWAL-QOL instrument was developed in 2000 and refined in 2002 by McHorney et al. The scale consists of 44 items, each rated on a 5-point Likert scale by the patient, representing 11 domains surrounding the meal experience that could impact QOL. These domains include questions regarding eating duration, desire for food, food selection, socialization, and fear. The relationship of the SWAL-QOL with abnormalities on the modified barium swallow has been demonstrated in patients with amyotrophic lateral sclerosis (ALS), indicating a reduction across all domains of the SWAL-QOL in aspirators. This confirmed and extended an earlier study in ALS comparing the SWAL-QOL with the extent of dysphagia using dysphagia rating scales. However the SWAL-QOL has not been evaluated in other neuromuscular disorders with a dysphagia component. The Youssof et al. study evaluated the SWAL-QOL instrument in patients with OPMD and identified limitations of the SWAL-QOL in this disorder, including domains with low specificity for OPMD patients with dysphagia. These studies reveal several themes that may actually be common features of the dysphagic state regardless of etiology, and which merit our awareness and attention. Not surprisingly, impaired swallowing function correlates negatively with duration of meal and desire for food. It is possible, if not likely, that individuals with impaired swallowing function are those at greatest risk for inadequate intake of food (energy) and fluid. We spend a lot of time encouraging these patients to embrace alternative routes of nutritional intake, be it from food modification or feeding gastrostomy. However, these studies also reveal a pervasive sense of fear during eating which probably diminishes the pleasurable social aspect of the meal and may contribute to depression, anxiety, and fatigue. Although the SWAL-QOL was administered to patients with dysphagia, clinical observation suggests that the sense of fear during meals extends to family and caregivers who worry that the next bite of food will lead to the need for a Heimlich maneuver or phone call for an ambulance. When the increased duration of feeding is added to the heightened vigilance on the part of both the dysphagic patient and caregiver, and it is not surprising that the pleasant social aspects of the meal may be a distant memory. Acknowledging these dimensions may help us be This work was supported by the Cynthia Shaw Crispen Endowment

Alcoholism: Clinical and Experimental Research, Aug 1, 1989

The long‐term consequences of prenatal ethanol exposure on histochemically detectable hippocampal... more The long‐term consequences of prenatal ethanol exposure on histochemically detectable hippocampal mossy fiber zinc was examined using a recently developed quantitative histofluorescence procedure. Pregnant Sprague‐Dawley rats were maintained throughout gestation on one of three dietary regimens: (a) a liquid diet containing either 3.35% ethanol, (b) an isocalorically matched liquid diet pair‐fed to the 3.35% ethanol group, or (c) lab chow ad libitum. At 45 days of age, offspring from each of the three diet groups were sacrificed for determination of hippocampal mossy fiber zinc and zinc analysis of selected tissues by atomic absorption spectroscopy.Hippocampal mossy fiber zinc was reduced by 36% in dorsal and 20% in ventral hippocampal formation stratum lucidum of rats exposed to the 3.35% ethanol diet compared to the offspring of the pair‐fed control and ad libitum control dams. No significant differences in zinc: TS‐Q histofluorescence were observed between the ad libitum and pair‐fed control groups. No significant differences were observed among groups in tissue wet weight or tissue zinc concentration in any of the brain or other body regions analyzed. These results indicate a long lasting prenatal ethanol exposure‐induced reduction in hippocampal mossy fiber zinc in the absence of changes in any indices of total body zinc nutriture. These results suggest that prenatal exposure to relatively low blood ethanol levels (30–40 mg/dl) has subtle, yet long‐lasting effects in the hippocampal formation, a brain region important in the process of memory consolidation.

Neurology, Dec 1, 1993

We studied a large family with a previously undescribed, autosomal dominant dystonia-parkinsonism... more We studied a large family with a previously undescribed, autosomal dominant dystonia-parkinsonism syndrome. We chose to call the disorder &amp;quot;rapid-onset dystonia-parkinsonism&amp;quot; (RDP) based on the unusually rapid evolution of signs and symptoms. Affected individuals developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in six individuals with the abrupt onset of symptoms over the course of several hours, and subacute in four others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and one obligate gene carrier was asymptomatic at 68 years. CSF levels of homovanillic acid were decreased in the two individuals tested, but dopaminergic therapy provided only slight benefit. The DYT1 gene responsible for early-onset, generalized idiopathic torsion dystonia in Jewish and some non-Jewish families has been mapped to chromosome 9q34. Linkage analysis with three markers near the DYT1 gene showed several obligate recombinations, excluding DYT1 as a candidate gene for RDP. We believe RDP is unique and should be classified separately from other forms of hereditary dystonia-parkinsonism.

Neurology, May 16, 2022

Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease. Neurologi... more Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease. Neurologists generally see patients as requested and as schedules allow. This practice is part of the reason it takes approximately 12 months from onset of new progressive weakness to receive a definitive diagnosis of ALS. It is well recognized that the disease of ALS starts long before symptom onset. In mutant SOD1 transgenic mice, early loss of motor neurons and compensatory morphological changes precede a rapid loss of motor neurons that coincides with symptom onset. In a human autopsy study, anterior roots in the “presymptomatic” stage indicate that ∼20% loss of motor neurons had already occurred. Sera collected from individuals who later developed ALS and sera from presymptomatic members of families with ALS harboring pathogenic gene variants demonstrated high neurofilament (Nf) levels, again suggesting that the neurodegenerative process is already active at a clinically presymptomatic stage. Potential benefits of hastening the diagnosis of ALS include earlier initiation of therapy to slow the fundamental neurodegenerative process. Such effects are observed in treatment with riluzole, edaravone, methylcobalamin, and sodium phenylbutyrate-taurursodiol in patient care and clinical trial settings. Early initiation of multidisciplinary care results in cost savings and prolonged survival. Early diagnosis after symptom onset also seems to reduce psychological distress. Hence, how can we facilitate an earlier diagnosis of ALS? We already have the necessary tools. New and simple ALS diagnostic criteria (Gold Coast Criteria) have been introduced along with genetic testing. At least 2 studies provide Class II evidence that establishes the reliability and sensitivity of CSF and/or serum Nf levels in supporting a diagnosis of ALS. Challenges, however, still exist as to how to facilitate earlier recognition of possible ALS by primary care physicians and other nonneurologist providers and how to foster a sense of urgency among neurologists to accelerate the diagnostic process. In this article, we provide a number of recommendations that we hope will help achieve these ends.

Human Molecular Genetics, Jul 21, 2020

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the preferent... more Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the preferential death of motor neurons. Approximately 10% of ALS cases are familial and 90% are sporadic. Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein implicated in familial ALS and frontotemporal dementia (FTD). The physiological function and pathological mechanism of FUS are not well understood, particularly whether post-translational modifications play a role in regulating FUS function. In this study, we discovered that FUS was acetylated at lysine-315/316 (K315/K316) and lysine-510 (K510) residues in two distinct domains. Located in the nuclear localization sequence, K510 acetylation disrupted the interaction between FUS and Transportin-1, resulting in the mislocalization of FUS in the cytoplasm and formation of stress granule-like inclusions. Located in the RNA recognition motif, K315/K316 acetylation reduced RNA binding to FUS and decreased the formation of cytoplasmic inclusions. Treatment with deacetylase inhibitors also significantly reduced the inclusion formation in cells expressing ALS mutation P525L. More interestingly, familial ALS patient fibroblasts showed higher levels of FUS K510 acetylation as compared with healthy controls. Lastly, CREB-binding protein/p300 acetylated FUS, whereas both sirtuins and histone deacetylases families of lysine deacetylases contributed to FUS deacetylation. These findings demonstrate that FUS acetylation regulates the RNA binding, subcellular localization and inclusion formation of FUS, implicating a potential role of acetylation in the pathophysiological process leading to FUS-mediated ALS/FTD.

Muscle & Nerve, Oct 30, 2020

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO)... more An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

Muscle & Nerve, Jun 3, 2022

Springer eBooks, 1980

Pseudotumor cerebri or benign intracranial hypertension can result from impaired outflow of newly... more Pseudotumor cerebri or benign intracranial hypertension can result from impaired outflow of newly-formed cerebrospinal fluid (CSF) from functionally deranged arachnoid villi. An infant with a fat malabsorption syndrome accompanied by deficiency of circulating retinol developed sustained intracranial hypertension that responded to Vitamin A (Vit A) replacement. Simulation of this condition in the rat revealed the reversible pathophysiological mechanism for decreased CSF outflow.

Journal of Neurology, Neurosurgery, and Psychiatry, May 16, 2022

Neuroepidemiology

Introduction: We investigated the associations between antecedent all-cause CVD diagnoses, cause-... more Introduction: We investigated the associations between antecedent all-cause CVD diagnoses, cause-specific CVD diagnosis, and CVD medication prescriptions with the risk of developing amyotrophic lateral sclerosis (ALS). Materials and Methods: We conducted a population-based case-control study of U.S. Medicare enrollees from 2006 to 2013. The final sample included 3,714 incident ALS cases and 18,570 controls (matched on age, sex, enrollment length, and county). Information was collected from Medicare Parts A, B, and D administrative claims data on hypertension, ischemic heart disease, heart failure, acute myocardial infarction, atrial fibrillation, prescriptions of angiotensin-converting enzyme inhibitors, angiotensin II receptors blockers, calcium channel blockers, beta blockers, and antiarrhythmics. Associations were evaluated using conditional logistic regression adjusting for age, sex, race/ethnicity, geographical location, alcohol and tobacco use, and socioeconomic status. Result...

New England Journal of Medicine, 2020

Electroencephalography and Clinical Neurophysiology, 1989