Person: Rutkove, Seward
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Rutkove
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Seward
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Rutkove, Seward
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Publication Electrical impedance myography in the diagnosis of radiculopathy(Wiley, 2013) Spieker, Andrew J.; Narayanaswami, Pushpa; Fleming, Laura; Keel, John C.; Muzin, Stefan; Rutkove, SewardWe sought to determine whether elec- trical impedance myography (EIM) could serve as a diagnostic procedure for evaluation of radiculopathy. Methods: Twenty- seven patients with clinically and radiologically diagnosed cervi- cal or lumbosacral radiculopathy who met a “gold standard” defi- nition underwent EIM and standard needle electromyography (EMG) of multiple upper or lower extremity muscles. Results: EIM reactance values revealed consistent reductions in the radic- ulopathy-affected myotomal muscles as compared with those on the unaffected side; the degree of asymmetry was associated strongly with the degree of EMG abnormality (P<0.001). EIM had a sensitivity of 64.5% and a specificity of 77.0%; in compari- son, EMG had a sensitivity of 79.7% but a specificity of 69.7%. Conclusions: These findings support the potential for EIM to serve as a new non-invasive tool to assist in diagnosis of radicu- lopathy; however, further refinement of the technique is needed for this specific application.Publication Clinical utility of electrodiagnostic studies in the inpatient setting(Wiley, 2009) Perry, Daryl I.; Tarulli, Andrew W.; Nardin, Rachel; Rutkove, Seward; Gautam, Shiva; Narayanaswami, PushpaNerve conduction studies and electromyograms (EMGs) are most often performed in the outpatient setting in patients with suspected neuromuscular diseases, where they help the physician confirm the clinical diagnosis, assess the localization and severity of the disease, and plan further evaluation and treat- ment. Not infrequently, EMGs are requested on a relatively urgent basis for patients who are admitted to the hospital. Inpatient electrodiagnostic studies are usually requested in two situations: (1) as part of the diagnostic evaluation of patients who present with symptoms of a neuromuscular disorder; or (2) in patients who are admitted to the hospital with non-neuromuscular illnesses but develop symptoms suggestive of a neuromuscular disorder during the course of their illness. The second scenario com- monly occurs in patients who are in the intensive care unit and are unable to be weaned from the ven- tilator. This raises the possibility of a neuromuscular disorder as a cause of respiratory muscle weakness and ventilator dependence. The role of EMG in the evaluation of neuro- muscular disorders in the inpatient setting has not been studied previously. In this study, we evaluated the contribution of EMG to the diagnosis and man- agement of hospital inpatients. We hypothesized that inpatient EMGs (IP-EMGs) would frequently find clinically meaningful diagnoses that would affect the subsequent management of patients. The aims of this study were to compare the results of IP-EMGs with the referring physicians’ clinical diag- noses and to assess how often results of IP-EMGs changed the clinical diagnosis and altered further diagnostic evaluation and treatment.Publication Electrophysiologic Biomarkers for Assessing Disease Progression and the Effect of Riluzole in SOD1 G93A ALS Mice(Public Library of Science, 2013) Li, Jia; Sung, Minhee; Rutkove, SewardObjective: To compare electrical impedance myography (EIM) 50 kHz phase to weight, motor score, paw grip endurance (PGE), CMAP amplitude, and MUNE for the identification of disease progression and the effect of riluzole in the SOD1 G93A mouse. Methods: Twenty-three animals received 8 mg/kg/day riluzole in the drinking water starting at 6 weeks of age; 22 animals served as controls. Weight, motor score, PGE, CMAP, MUNE, and EIM were performed weekly to evaluate disease progression. Results: No difference in clinical disease onset or survival was found between treated and untreated groups. In addition, all methods failed to identify any beneficial effect of riluzole. Thus, data from all animals were combined for additional analyses. Of the 4 parameters, EIM phase showed the earliest change from baseline and the most linear decline throughout the entire measurement period. In addition, EIM phase correlated with PGE, CMAP amplitude, and MUNE (Spearman r = 0.92, 0.90, and 0.72, respectively, p<0.01 for all). The rate of EIM phase decline also correlated with individual animal survival (Spearman r = −0.31, p<0.05). Conclusions: At this dose, riluzole is ineffective in slowing progression of ALS. However, EIM phase shows early linear declines, supporting its potential as a useful new biomarker for preclinical drug testing.Publication A Comparison of Three Electrophysiological Methods for the Assessment of Disease Status in a Mild Spinal Muscular Atrophy Mouse Model(Public Library of Science, 2014) Li, Jia; Geisbush, Tom R.; Arnold, William D.; Rosen, Glenn; Zaworski, Phillip G.; Rutkove, SewardObjectives: There is a need for better, noninvasive quantitative biomarkers for assessing the rate of progression and possible response to therapy in spinal muscular atrophy (SMA). In this study, we compared three electrophysiological measures: compound muscle action potential (CMAP) amplitude, motor unit number estimate (MUNE), and electrical impedance myography (EIM) 50 kHz phase values in a mild mouse model of spinal muscular atrophy, the Smn1c/c mouse. Methods: Smn1c/c mice (N = 11) and wild type (WT) animals (−/−, N = 13) were measured on average triweekly until approximately 1 year of age. Measurements included CMAP, EIM, and MUNE of the gastrocnemius muscle as well as weight and front paw grip strength. At the time of sacrifice at one year, additional analyses were performed on the animals including serum survival motor neuron (SMN) protein levels and muscle fiber size. Results: Both EIM 50 kHz phase and CMAP showed strong differences between WT and SMA animals (repeated measures 2-way ANOVA, P<0.0001 for both) whereas MUNE did not. Both body weight and EIM showed differences in the trajectory over time (p<0.001 and p = 0.005, respectively). At the time of sacrifice at one year, EIM values correlated to motor neuron counts in the spinal cord and SMN levels across both groups of animals (r = 0.41, p = 0.047 and r = 0.57, p = 0.003, respectively), while CMAP did not. Motor neuron number in Smn1c/c mice was not significantly reduced compared to WT animals. Conclusions: EIM appears sensitive to muscle status in this mild animal model of SMA. The lack of a reduction in MUNE or motor neuron number but reduced EIM and CMAP values support that much of the pathology in these animals is distal to the cell body, likely at the neuromuscular junction or the muscle itself.Publication Intraspinal Neural Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: Phase 1 Trial Outcomes(BlackWell Publishing Ltd, 2014) Feldman, Eva L; Boulis, Nicholas M; Hur, Junguk; Johe, Karl; Rutkove, Seward; Federici, Thais; Polak, Meraida; Bordeau, Jane; Sakowski, Stacey A; Glass, Jonathan DObjective: The US Food and Drug Administration–approved trial, “A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1,” is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects. Methods: Preliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures. Results: The cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials. Interpretation This is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy.Publication Critically Re-Evaluating a Common Technique: Accuracy, Reliability, and Confirmation Bias of EMG(Ovid Technologies (Wolters Kluwer Health), 2015) Narayanaswami, Pushpa; Geisbush, Thomas; Jones, Lyell; Weiss, Michael; Mozaffar, Tahseen; Gronseth, Gary; Rutkove, SewardObjectives: (1) To assess the diagnostic accuracy of EMG in radiculopathy. (2) To evaluate the intrarater reliability and interrater reliability of EMG in radiculopathy. (3) To assess the presence of confirmation bias in EMG. Methods: Three experienced academic electromyographers interpreted 3 compact discs with 20 EMG videos (10 normal, 10 radiculopathy) in a blinded, standardized fashion without information regarding the nature of the study. The EMGs were interpreted 3 times (discs A, B, C) 1 month apart. Clinical information was provided only with disc C. Intrarater reliability was calculated by comparing interpretations in discs A and B, interrater reliability by comparing interpretation between reviewers. Confirmation bias was estimated by the difference in correct interpretations when clinical information was provided. Results: Sensitivity was similar to previous reports (77%, confidence interval [CI] 63%–90%); specificity was 71%, CI 56%–85%. Intrarater reliability was good (κ 0.61, 95% CI 0.41–0.81); interrater reliability was lower (κ 0.53, CI 0.35–0.71). There was no substantial confirmation bias when clinical information was provided (absolute difference in correct responses 2.2%, CI −13.3% to 17.7%); the study lacked precision to exclude moderate confirmation bias. Conclusions: This study supports that (1) serial EMG studies should be performed by the same electromyographer since intrarater reliability is better than interrater reliability; (2) knowledge of clinical information does not bias EMG interpretation substantially; (3) EMG has moderate diagnostic accuracy for radiculopathy with modest specificity and electromyographers should exercise caution interpreting mild abnormalities. Classification of evidence: This study provides Class III evidence that EMG has moderate diagnostic accuracy and specificity for radiculopathy.Publication Electrical impedance myography as a biomarker to assess ALS progression(Informa UK Limited, 2012) Rutkove, Seward; Caress, James B.; Cartwright, Michael S.; Burns, Ted M.; Warder, Judy; David, William; Goyal, Namita; Maragakis, Nicholas J.; Clawson, Lora; Benatar, Michael; Usher, Sharon; Sharma, Khema R.; Gautam, Shiva; Narayanaswami, Pushpa; Raynor, Elizabeth; Watson, Mary Lou; Shefner, Jeremy M.Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.Publication The effect of subacute denervation on the electrical anisotropy of skeletal muscle: Implications for clinical diagnostic testing(Elsevier BV, 2010) Ahad, Mohammad A.; Narayanaswami, Pushpa; Kasselman, Lora J.; Rutkove, SewardObjective Applied electrical current flows preferentially along rather than across muscle fibers, a characteristic called anisotropy. In this study, we investigate the alteration in muscle anisotropy after denervation. Methods Eight adult male rats underwent sciatic nerve crush and the gastrocnemius was harvested from 1 to 2.5 weeks later. Muscle from 12 additional healthy rats was also obtained. Multifrequency electrical impedance measurements were made on the tissue and its conductivity and relative permittivity (i.e., its polarizability) calculated. Anisotropy of the tissue was determined by calculating conductivity and permittivity differences, subtracting transverse from longitudinal values. Muscle fiber and blood vessel quantification were also performed. Results The mean conductivity difference for sciatic crush animals was higher (p <0.05) than for the healthy animals across the frequency spectrum, due to a greater increase in longitudinal conductivity than in transverse conductivity. For example, at 10 kHz, the conductivity difference was 0.15 S/m for healthy animals and 0.29 S/m for post-crush animals. Relative permittivity difference values, however, were similar between groups. There was a strong correlation of conductivity anisotropy to muscle fiber size but not to blood vessel area. Conclusions Anisotropy of muscle conductivity increases markedly after subacute denervation injury. Significance This alteration in anisotropy has direct relevance to the clinical application of electrical impedance myography. We also speculate that it may impact other forms of diagnostic testing, including needle electromyography and magnetic resonance imaging.Publication The effect of subcutaneous fat on electrical impedance myography when using a handheld electrode array: The case for measuring reactance(Elsevier BV, 2013) Sung, Minhee; Spieker, Andrew J.; Narayanaswami, Pushpa; Rutkove, SewardObjective Recent developments in electrical impedance myography (EIM) have led to the use of handheld electrode arrays (HEA) for data acquisition. Although preferable for several reasons, this approach tends to be more affected by subcutaneous fat (SF) than the original approach in which the impedance-measuring electrodes are widely spaced. In this study, we seek to identify the EIM parameter least impacted by subcutaneous fat (SF) when using an HEA. Methods 18 normal subjects underwent 50 kHz EIM and ultrasound of the medial gastrocnemius muscles on the dominant side. Coefficients of determination (R2 values) were calculated for each of the three major EIM variables (reactance, resistance, and phase) and SF thickness. Results For both resistance and phase, a strong relationship to SF thickness was observed (R2 = 0.64 and R2 = 0.70, respectively, p < 0.001 for both). In contrast, for reactance, the relationship was non-significant, with R2 = 0.07, p = 0.30. Conclusions Unlike resistance and phase, both of which are highly impacted by SF thickness, the reactance shows no significant relationship. Significance Future clinical studies employing HEA’s to perform EIM should evaluate alterations in reactance over those in resistance and phase.Publication Application of futility analysis to refine jitter recordings in myasthenia gravis(Wiley-Blackwell, 2012) Narayanaswami, Pushpa; Pantoja-Galicia, Norberto; Betensky, Rebecca; Rutkove, SewardIntroduction The current practice of single fiber electromyography (SFEMG) requires that 20 fiber pairs with normal jitter be collected to exclude myasthenia gravis (MG). We applied principles of futility analysis from clinical trials in an attempt to reduce that requirement. Methods We utilized conditional power futility analysis to assess the probability of an abnormal 20-pair SFEMG based on ongoing analysis of jitter as each pair is collected. Rules for early test termination in the presence of 0, 1 or 2 abnormal pairs were identified. These rules were then applied to previously collected SFEMG data. Results SFEMG could be stopped at just 12 pairs if all are normal and at 17 pairs if 1 is abnormal. The rules successfully determined when SFEMG could be stopped in 104/106 (98%) studies originally reported to be normal. Discussion If the first 12 SFEMG pairs have normal jitter, the study can be terminated and interpreted as normal.