Kim R. Gottshall

Transthoracic Echocardiography in Models of Cardiac Disease in the Mouse

BACKGROUND Transthoracic echocardiography (M-mode and Doppler) offers a noninvasive approach for in vivo evaluation of the mouse heart. The present study examines its usefulness for assessing the morphological/functional phenotype of the left ventricle (LV) in several transgenic and surgical murine models of cardiac disease. METHODS AND RESULTS Observations were made in 83 intact, anesthetized mice. In mice with a surgical arteriovenous fistula, volume overload and LV dilation were detected. In normal mice, echocardiographic indexes of increased contractility (dobutamine) were confirmed by LV dP/dtmax. In transgenic mice with overexpression of the beta 2-adrenergic receptor, heart rate and mean velocity of circumferential fiber shortening were increased, indicating enhanced contractility. In colony screening of transgenic mice overexpressing the H-ras gene, 45% had increased LV wall thickness (> 0.9 mm), and those showing a striking increase were selected for breeding. In mice with LV hypertrophy (aortic constriction) and normal mice, the actual LV mass determined by echocardiography correlated well (r = .93), and 95% confidence limits were determined. The maximum intraobserver and interobserver coefficients of variation for M-mode data were 0.03 +/- 0.29 mm (+/- 2 SD), < 10% for LV internal dimensions but 27% to 30% for wall thickness. CONCLUSIONS These studies provide the first application of transthoracic echocardiography for morphological/functional characterization of the cardiac phenotype in transgenic and surgical murine models, including (1) high reliability for detecting LV chamber dilation and function; (2) reliability (and its limits) for determining abnormal LV wall thickness and LV mass; (3) identification of marked, sometimes asymmetrical, hypertrophy in a transgenic model of hypertrophic cardiomyopathy; and (4) usefulness for transgenic colony screening to identify markedly abnormal phenotypes.

Characterizing and treating dizziness after mild head trauma.

Objective: The objectives of this study were to characterize patterns of dizziness seen after mild head trauma and to examine the diagnosis and treatment of this disorder. Study Design: Prospective patient registry. Setting: Tertiary referral center. Patients: Fifty-eight cases of active duty and retired military personnel who sustained mild head trauma and had resultant dizziness. Interventions: Vestibular evaluation, characterization by group, and treatment. Main Outcome Measures: Outcome measures include characterization of diagnosis types, patient distribution by diagnosis type, and patient outcome. Results: Individuals suffering from dizziness after mild head injury were divided into three diagnostic groups. Forty-one percent of the individuals suffered from posttraumatic vestibular migraines, 28% of the individuals had posttraumatic positional vertigo, and 19% of the individuals were classified as posttraumatic spatial disorientation. The remaining 12% of the patients could not be characterized. The positional group had objective physical examination findings, which cleared with treatment in all cases. The migraine group of patients and the disorientation group of patients had distinct abnormalities of the vestibulo-ocular reflex (VOR) and the vestibulo-spinal reflex (VSR). Eighty-four percent of the migraine group demonstrated an improvement of these test results as compared with 27% of the disorientation group. Mean time to return to work was less than 1 week for the positional group, 3.8 weeks for the migraine group, and greater than 3 months for the disorientation group. Conclusions: Using our patient registry of individuals suffering from dizziness after mild head trauma, we were able to characterize the majority of these cases into one of three more specific diagnostic groups. We present diagnostic criteria, suggested treatment guidelines, and our prognostic data.

Blast exposure: vestibular consequences and associated characteristics.

Objective: To characterize vestibular and related symptoms seen after blast exposure. Study Design: Prospective single-subject design. Settings: Tertiary care facility and military field hospital. Patients: Active-duty US Military personnel exposed to blast(s) in Iraq and/or Afghanistan. Interventions: Vestibular function tests, auditory tests, and a structured history and physical examination. Results: Blast exposure induced vestibular disorders, and related symptoms are significantly different than those seen in blunt head trauma. The vestibular characteristics and objective tests of vestibular function significantly worsen in blast-exposed patients as a function of time between injury and presentation. Conclusion: Blast exposure produces a unique set of vestibular disorders and associated symptoms that progress over time. Understanding the characteristics of these symptoms as they vary over time may be critical in designing treatment strategies that modify long-term outcome.

Transtympanic versus sustained-release administration of gentamicin: kinetics, morphology, and function.

Objectives/Hypothesis Transtympanic gentamicin therapy has become a popular treatment modality for Menieres disease, but questions regarding the ideal dose of medicine, the best administration paradigm, and the safest treatment end‐point remain unanswered. The goal of this study is to examine the inner ear kinetics of transtympanic gentamicin and compare this with the kinetics of sustained‐release delivery in a basic science model. In addition, we plan to examine the relationship of these kinetics curves to the effect of the two treatment modalities on inner ear function and morphology. It is hoped that this analysis will help clinicians to better apply local medical therapy to the ear.

Objective Vestibular Tests as Outcome Measures in Head Injury Patients

Hypothesis: Dynamic visual acuity testing (DVAT) and the Dizziness Handicap Index (DHI) can be used as reliable outcome measures in patients after head injury. Background: Balance disorders are a significant disability after mild traumatic brain injury (TBI). Assessing when individuals can perform activities of daily living, return to work, and begin to play sports can be difficult to determine. Objective outcome measures that correlate with successful life skills can be useful in managing these patients. Methods: Fifty‐three active duty individuals who suffered mild TBI underwent weekly DVAT testing and were administered a weekly DHI. Results in this group were compared with 46 control subjects who had not experienced TBI. In addition, weekly scores were compared with the patients functional level, time to return to work, and time to perform all job related activities. Results: Individuals with TBI showed an overall increase of 42% in DVAT function over the first 4 weeks of testing, whereas controls showed an 8% increase. Concurrently, individuals with TBI averaged a 18‐point improvement in DHI function, whereas control subjects showed no significant change in this score. Improvement in DVAT and DHI function correlated closely at the 1‐week time point. Improvement in the patients cognitive function, ability to return to activities of daily living, and ability to return to work gradually improved continuously. Conclusion: DVAT and the DHI can be used as reliable outcome measures in evaluating the progress of patients with balance disorders associated with TBI. These measures allow providers to make more reliable recommendations regarding such activities as returning to work.

Tracking recovery of vestibular function in individuals with blast-induced head trauma using vestibular-visual-cognitive interaction tests

Background and Purpose: Traumatic brain injury secondary to blast exposure is a significant international concern and a growing rehabilitation issue. Our objective was to determine whether a novel battery of vestibular-visual-cognitive interaction tests provides objective data to document functioning, and the changes in functioning associated with vestibular physical therapy (VPT) treatment, in individuals with blast-induced balance disorder. Methods: Eighty-two individuals with blast-induced mild traumatic brain injury were evaluated at baseline using a set of vestibular-visual-cognitive tests. Testing was repeated at 4-week intervals after beginning VPT. The tests included static visual acuity, perception time, target acquisition, target following (TF), dynamic visual acuity (DVA), and gaze stabilization tests. The VPT program consisted of exercise procedures that targeted the vestibulo-ocular reflex, cervico-ocular reflex, and depth perception. Somatosensory balance exercises, dynamic gait, and aerobic function exercises were also included. Participants attended VPT twice weekly for 1-hour appointments and were instructed to perform the exercises at home on other days. Mean test values were determined and compared with normative values previously collected in our laboratory from individuals without vestibular dysfunction. Results: Mean participant pre-VPT measures for perception time and target acquisition were similar to normative values, and there was no significant change in these measures. Initially, TF and DVA scores were below normative levels but returned to normative levels after 8 weeks of VPT. Gaze stabilization scores were below normative levels pre-VPT but improved by the time of the week 8 evaluation. Conclusions: This battery of vestibular-visual-cognitive tests seems to be reasonable to establish initial status and to evaluate participant progress associated with participation in VPT. Our data suggest meaningful improvement in TF and DVA after 8 weeks of treatment. A treatment period of 12 weeks or longer may be required for gaze stabilization scores to return to normative values.

Use of the round window microcatheter in the treatment of Meniere's disease.

Objectives/Hypothesis Transtympanic gentamicin is an increasingly popular treatment for Menieres disease. The present report examines the 2‐year follow‐up of our first 27 patients with Menieres disease treated with the use of microdose gentamicin through the Round Window Microcatheter. We applied the 1995 American Academy of Otolaryngology—Head and Neck Surgery criteria to this patient group to analyze the results of treatment.

Strategies for studying cardiovascular phenotypes in genetically manipulated mice.

Unraveling the pathogenesis of complex cardiovascular diseases, such as hypertension, requires the development of in vivo animal model systems. Although large-animal models have long served as the gold standard, recent advances in transgenic and gene-targeting approaches, mouse genetics, and microsurgical technology are initiating a revolution that has led to the unexpected coupling of in vivo molecular physiology with genetically engineered mice. This article discusses the design of strategies to study complex cardiovascular phenotypes in genetically modified mice, including both transgenic and gene-targeted animals. At this time, a number of strategies are used to address specific molecular or physiological questions, and examples are briefly highlighted. In addition, a number of potential problems in the generation and use of transgenic mice in the study of cardiovascular biology are presented.

The Role of Vestibular Rehabilitation in the Treatment of Meniere’s Disease

OBJECTIVE: To study the role of vestibular rehabilitation is treating patients with Menieres disease. METHODS: We examined all Menieres patients presenting to our tertiary care specialized vestibular clinic during a 1-year period. All patients underwent a standardized history and physical examination, a complete auditory-vestibular test battery, and a set of physical therapy tools to measure balance function. RESULTS: A subset of patients suffered from disequilibrium or unsteadiness between attacks. Once the acute fluctuating symptoms of Menieres were controlled in this group of individuals, all of them underwent vestibular physical therapy and demonstrated significant improvement in balance function on both objective and self-report tests. CONCLUSIONS: Due to the fluctuating nature of the disorder, vestibular physical therapy has had a limited role in the treatment of Menieres disease. In general, rehabilitation has been used only as a postoperative treatment for the acute vertigo seen after vestibular neurectomy or labyrinthectomy. This is the first report advocating the role of vestibular physical therapy in a group of patients receiving medical therapy of intraear medicines (other that gentamicin).

Transtympanic management of tinnitus

Transtympanic therapy is becoming and important treatment modality for many inner ear disorders. The current therapies aimed at Menieres disease, sudden sensorineural hearing loss, noise-induced hearing loss, and the tinnitus associated with these disorders and idiopathic tinnitus, however, represents simply an evolutionary step in this treatment modality and must be validated by further scientific study. A number of promising developments including newer more targeted neuroactive medicines, a better understanding of medicine delivery, and the knowledge of the site, origin, and pathophysiology of the symptoms complex will make this therapy more effective. In the future it is possible that many inner ear disorders will be amenable to inner ear medical therapy. Ideally in the future with knowledge of the disease and its etiology the physician will simply pick the established medicine, the established dose, and the established route of administration and achieve a relatively predictable result.