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J M Shefner

Publications and source records attributed to J M Shefner.

At least 19 recordsLinked to original sources
PubMed2007

Revised statistical motor unit number estimation in the Celecoxib/ALS trial.

Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. As amyotrophic lateral sclerosis (ALS) is characterized by progressive motor unit loss, this disease offers an ideal setting for the use of MUNE. Statistical MUNE was employed in a recent multicenter trial of creatine in ALS, and was shown to be reliable, reproducible, and to decline with disease progression. However, motor unit amplitude stayed constant over 7 months, a finding believed to reflect an artifact of the method. The statistical method was revised to reflect more accurately the presence of larger motor units and employed in a 12-month study of Celecoxib in ALS. MUNE declined by 49% in 12 months; however, motor unit amplitude again stayed constant over the same period. Statistical MUNE estimates motor unit number based on the variability of response to a repeated stimulus of constant strength, with an underlying assumption that this variability is due solely to the number of motor units responding in an intermittent manner. Based on studies showing that single motor units in ALS display excessive amplitude variability when stimulated repeatedly, we show that response variability in ALS patients is in large part due to single unit changes. Thus, we conclude that the statistical method is not an appropriate measure of motor unit number in any disease associated with motor unit instability.

Action Potentials↗
PubMed2005

Lead exposure as a risk factor for amyotrophic lateral sclerosis.

BACKGROUND: The etiology of amyotrophic lateral sclerosis (ALS) likely involves an environmental component. We qualitatively assessed literature on ALS and lead exposure. Problems of study design make case reports and studies of lead in blood or tissues difficult to interpret. Most previous case-control studies found an association of ALS with self-reported occupational exposure to lead, with increased risks of 2- to >4-fold. However, these results may have been affected by recall bias. OBJECTIVE: To address inconsistencies among published reports, we used both lead biomarkers and interview data to assess lead exposure, and we evaluated the role of genetic susceptibility to lead. METHODS: We conducted a case-control study in New England in 1993-1996 with 109 ALS cases and 256 population-based controls. We measured blood and bone lead levels, the latter using X-ray fluorescence, and interviewed participants regarding sources of lead exposure. RESULTS: In our study, ALS was associated with self-reported occupational lead exposure, with a dose response for cumulative days of exposure. ALS was also associated with blood and bone lead levels, with a 1.9-fold increase in risk for each mug/dl increment in blood lead and a 2.3- to 3.6-fold increase for each doubling of bone lead. A polymorphism in the delta-aminolevulinic acid dehydratase gene was associated with a 1.9-fold increase in ALS risk. CONCLUSION: These results, together with previous studies, suggest that lead exposure plays a role in the etiology of ALS. An increase in mobilization of lead from bone into blood may play a role in the acute onset of disease.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Functional outcome measures as clinical trial endpoints in ALS.

The topiramate study was a 12-month randomized placebo-controlled trial in patients with ALS. Follow-up evaluation of the placebo group (n = 97) constituted a well-described cohort of patients with ALS, in whom multiple outcome measures were assessed at 3-month intervals. During the 12-month study period, the decline of forced vital capacity (FVC%) and ALS functional rating scale (ALSFRS) was linear, whereas the decline of maximum voluntary isometric contraction-arm (MVIC-arm) and MVIC-grip Z scores was curvilinear. Rates of FVC% and ALFRS decline, but not of MVIC-arm or MVIC-grip, were independent predictors of survival.

Adult↗
PubMed2004

A clinical trial of creatine in ALS.

BACKGROUND: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. METHODS: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. RESULTS: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. CONCLUSION: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Adolescent↗
PubMed2004

The use of statistical MUNE in a multicenter clinical trial.

Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. In diseases characterized by progressive motor unit loss, such as amyotrophic lateral sclerosis (ALS), MUNE may be useful to monitor disease progression or beneficial response to treatment. As part of a multicenter, placebo-controlled, randomized, double-blind clinical trial testing the efficacy of creatine in patients with ALS, statistical MUNE was measured in 104 patients tested monthly for 6 months. The objective was to determine whether MUNE was a reliable and sensitive outcome measure in the context of a multicenter trial. Formal training and reliability testing was required for all MUNE evaluators. Testing of normal controls showed a high degree of test-retest reliability. All patient data were combined as the experimental treatment showed no efficacy. There was a 23% decline in MUNE over 6 months. The technique as employed in this trial overemphasized the presence of small motor units; this problem was partially addressed by poststudy data monitoring and censuring. Thus, MUNE can be used reliably as an outcome measure in multicenter clinical trials; specific remedies are suggested for the difficulties encountered in this study.

Action Potentials↗
PubMed2004

ALS surrogate markers. MUNE.

Over the last decade, motor unit number estimation (MUNE) methods have been applied with increasing frequency to the study of amyotrophic lateral sclerosis. MUNE is the ideal tool for the assessment of diseases in which the primary defect is motor unit loss, as it enables quantitation and tracking of motor unit numbers while simultaneously gauging countervailing collateral reinervation. These properties make it particularly useful for assessing the effects of both neuroprotective therapies and therapies designed to enhance collateral reinervation, not only in animal models but also in the living patient. Previous studies have supplied important natural history information, confirming an average 50% loss of motor units for every six months of disease progression, and newer pathophysiological investigations are providing unique insight into motor unit behavior in the face of progressive anterior horn cell death. More recent efforts have incorporated MUNE into ongoing, multi-center clinical trials as a putative early biomarker, with encouraging results. As MUNE methods continue to be refined and disseminated, they are proving to be useful and unique tools for the study of motor neuron disease.

Amyotrophic Lateral Sclerosis↗
PubMed2003

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.

OBJECTIVE: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. METHODS: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. RESULTS: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). CONCLUSIONS: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Adult↗
PubMed2003

Percutaneous endoscopic gastrostomy (PEG) in patients with ALS and bulbar dysfunction.

OBJECTIVE: To compare characteristics of ALS patients with and without percutaneous endoscopic gastrostomy (PEG). METHODS: Using the ALS Patient Care Database, data from patients with and without PEG with ALS Functional Rating Scale-bulbar subscale (ALSFRSb) scores < or = 5 were analyzed; follow-up data were also collected. RESULTS: PEG use was markedly increased with declining ALSFRSb scores. Demographics did not differ, but ALSFRS composite scores and bulbar and arm subscale scores were lower (P<0.0001). PEG patients used significantly more assistive devices, multidisciplinary care, home care nurses and aides, had more frequent physician and emergency department visits and hospital admissions (P<0.0001), and had lower health status based on the mini-SIP scale (P=0.0047). PEG use varied greatly between ALS centers. In the follow-up study, positive impact of PEG was noted in 79 % of PEG patients but in only 37.5% of patients who received PEG later, based on a small number of patients. PEG use showed no survival benefit. CONCLUSION: Patients did not receive PEG until bulbar function was severely reduced and overall ALS had markedly progressed. PEG may have been performed too late to demonstrate survival benefits. Aggressive proactive nutritional management appears essential in patients with ALS. To determine whether PEG provides benefits, it must be performed at earlier stages of the disease and prospectively studied.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Effect of neurophilin ligands on motor units in mice with SOD1 ALS mutations.

BACKGROUND: Mice with trangenes that express mutations in the gene for cytosolic copper/zinc superoxide dismutase (SOD1) develop motor neuron degeneration resembling human ALS. Neurophilin ligands are small molecules that promote neurite outgrowth. OBJECTIVE: To test the hypothesis that treatment with two neurophilin ligands increases survival in these ALS mice by slowing the loss of motor neurons and increasing the sizes of motor units. METHODS: Transgenic mice hemizygous for the G93A mutation were untreated or treated from 30 days of age with one of two doses of two neurophilin ligands (V-13,670; V-10,367, Vertex Pharmaceuticals, Boston, MA). Onset of behavioral abnormalities and survival were recorded. Motor unit number estimation (MUNE) was performed every 21 days starting at age 60 days. RESULTS: In control animals, disease onset occurred at 77.0 days of age and death occurred at 137 days of age. Neither neurophilin ligand affected the disease course. In control animals, MUNE declined with time beginning before behavioral abnormalities were noted, and motor unit size increased concomitantly. There was no effect of drug on motor unit loss as assessed by MUNE; however, motor unit size increased more rapidly and to a greater degree in animals treated with V-13,670. CONCLUSION: As in human ALS, the transgenic ALS mice show physiologic changes in the motor unit prior to the development of clinical signs: MUNE declines as motor unit size increases. Although neither neurophilin ligand significantly affected survival, one produced an increase in motor unit size. The fact that survival was not altered by the increase in motor unit size may reflect the rapid disease course in this animal model.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Reproducibility of motor unit number estimation in individual subjects.

Although the reproducibility of motor unit number estimation (MUNE) for groups of subjects has been studied, there is little such data for individuals. Prediction intervals represent a tool to study individual MUNE reproducibility and represent the range of values expected for a future MUNE if the true number of motor units remains unchanged. MUNE was performed using the statistical method on 48 normal individuals. The prediction interval was found to be a function of the intrasubject coefficient of variation. Using a commercial manufacturer's recommended technique and software, prediction intervals were found to be so broad as to be of uncertain value. We found that by averaging two MUNE observations for each determination, and using the method of weighted averages for calculating the size of an average single motor unit potential, the intrasubject coefficient of variation was reduced from 16.48% to 8.77%, and the 90% prediction interval became sufficiently narrow to be clinically useful. False-negative rates were also lowered substantially using these techniques. Thus, simple modifications of an existing MUNE program improved the clinical utility of this program for the longitudinal study of patients in whom changes in motor unit number over time are of importance, such as those with motor neuron diseases.

Adolescent↗
PubMed2001

Motor unit number estimation in human neurological diseases and animal models.

Motor unit number estimation (MUNE) was introduced in 1971 as a way of providing an objective and meaningful estimate of axon loss in diseases affecting the motor system. Over the last 30 years, different methods of MUNE have been proposed, with each having specific strengths and limitations. The goal of this paper is to review the available methods, and to present data generated using MUNE in a variety of disease entities. The incremental, multiple point stimulation, spike-triggered averaging, F-wave, and statistical methods of MUNE are reviewed, along with data obtained using these methods in patients with neuropathy, motor neuron disorders, and muscle disease. All methods reviewed have theoretical concerns associated with them. However, with the exception of the spike-triggered averaging method, all give results in normal subjects that are quite similar. MUNE has been of great value in assessing progression of motor neuron disease, and has also shown promise in the assessment of generalized neuropathy. Despite the lack of a perfect method for performing MUNE, it has great clinical value in the assessment of progressive motor axon loss. Further refinements in the method will likely increase its utility in the future.

Action Potentials↗
PubMed2001

The use of non-invasive positive pressure ventilation (NIPPV) in ALS patients. A need for improved determination of intervention timing.

We present our experience with 27 patients with symptoms of alveolar hypoventilation, a precursor to respiratory failure, to demonstrate variability in symptoms, physiologic status and outcome of intervention. They represent 27 consecutive patients who tolerated NIPPV for more that 4 hours per 24-h period for more than 2 weeks. All patients received neurological consultation, electromyography and met criteria for ALS according to El Escorial diagnostic criteria. To assess respiratory status, spirometry was measured in sitting and when possible, in the supine positions. Resting arterial blood gases were available in 22 patients. Orthopnea was the most common symptom at the time of institution of NIPPV. No correlation existed between age at institution of NIPPV, duration of effective use of this technology or vital capacity and duration of effective use of NIPPV. The lack of correlation between vital capacity at the institution of NIPPV and duration of its effectiveness suggest that more sensitive indicators for the onset of alveolar hypoventilation must be defined, particularly since the principal benefit from its use is relief of symptoms of alveolar hypoventilation.

Adult↗
PubMed1999

Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy.

OBJECTIVE: To characterize the motor neuron dysfunction in two models by performing physiologic and morphometric studies. BACKGROUND: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of familial ALS (FALS). Transgenes with these mutations produce a pattern of lower motor neuron degeneration similar to that seen in patients with FALS. In contrast, mice lacking SOD1 develop subtle motor symptoms by approximately 6 months of age. METHODS: Physiologic measurements, including motor conduction and motor unit estimation, were analyzed in normal mice, mice bearing the human transgene for FALS (mFALS mice), and knockout mice deficient in SOD1 (SOD1-KO). In addition, morphometric analysis was performed on the spinal cords of SOD1-KO and normal mice. RESULTS: In mFALS mice, the motor unit number in the distal hind limb declined before behavioral abnormalities appeared, and motor unit size increased. Compound motor action potential amplitude and distal motor latency remained normal until later in the disease. In SOD1-KO mice, motor unit numbers were reduced early but declined slowly with age. In contrast with the mFALS mice, SOD1-KO mice demonstrated only a modest increase in motor unit size. Morphometric analysis of the spinal cords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons. CONCLUSIONS: The physiologic abnormalities in mFALS mice resemble those in human ALS. SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functionally impaired in the absence of SOD1.

Action Potentials↗
PubMed1999

The cutaneous silent period is mediated by spinal inhibitory reflex.

High-intensity cutaneous stimuli inhibit tonically firing motor neurons resulting in a silent period (CSP) in EMG activity. To determine the central nervous system (CNS) circuitry of this inhibitory reflex, soleus H reflexes evoked by tibial nerve stimuli were conditioned by high-intensity sural stimuli in 5 normal men and 5 men with complete, traumatic cervical myelopathy. The sural-tibial interstimulus interval (ISI) was varied between 0 and 200 ms. In normals, the CSP in the tonically contracted soleus muscle began 90-100 ms after sural stimuli and had a duration of 60-80 ms. In the relaxed soleus, the conditioned soleus H-reflex amplitude was correspondingly reduced at ISIs of 60-120 ms. In patients, conditioned H-reflex amplitude was also reduced over the same ISI range, but the degree of inhibition was significantly less than in normals. These data support the hypothesis that the CSP is mediated by a spinal inhibitory reflex that is subject to supraspinal descending control.

Adult↗
PubMed1999

Amplitude-dependent slowing of conduction in amyotrophic lateral sclerosis and polyneuropathy.

The mechanism of motor nerve conduction slowing in amyotrophic lateral sclerosis (ALS) is thought primarily to be loss of large, fast-conducting motor fibers; this is less certain in axonal polyneuropathy. We compared motor conduction studies in 64 patients with axonal polyneuropathy with 72 patients with ALS. Compound motor action potential amplitude, distal motor latency, and conduction velocity were converted to a percentage of the upper or lower limit of normal and then represented as a square root (SQRT) transformation, plotted with SQRT amplitude as the independent variable and SQRT latency or SQRT conduction velocity as the dependent variables. Regression analysis of the lower extremity nerve data showed that prolongation of latency and slowing of velocity were amplitude-dependent and were virtually identical in ALS and polyneuropathy. In the upper extremity, amplitude-dependent prolongation of latency was similar in both groups, but amplitude-dependent slowing of velocity was seen in ALS and not in axonal polyneuropathy. Our data support the hypothesis that the major mechanism of slowing is similar in both polyneuropathy and ALS and is the loss of large, fast-conducting fibers. However, the presence of distal but not proximal slowing in the upper extremity of axonal polyneuropathy suggests that additional mechanisms may be contributory.

Action Potentials↗
PubMed1999

Reducing intersubject variability in motor unit number estimation.

Motor unit number estimation (MUNE) attempts to directly assess the number of functioning motor units present in a muscle. It is an important addition to the electrodiagnostic evaluation; however, both intrasubject and intersubject reliability must be minimized for this technique to be clinically useful. A number of MUNE techniques have been developed. We propose a change in the way of calculating the MUNE, using the statistical technique described by Daube, and show that this modification reduces intersubject variability and improves test-retest reliability in normal subjects.

Adult↗
PubMed1999

Ulnar neuropathy at the elbow.

Among the entrapment neuropathies, ulnar neuropathy at the elbow is second only to carpal tunnel syndrome in frequency; however, diagnosis and management are considerably more difficult in ulnar lesions than in carpal tunnel syndrome. Electrodiagnosis is the most important means of identifying and localizing ulnar neuropathies at the elbow, but even sophisticated techniques may sometimes fail to confirm diagnosis and localization preoperatively. Mild lesions are best managed conservatively. More severe lesions require surgical intervention. Simple decompression is now preferred over transposition in the majority of cases, but careful correlation of electrodiagnostic abnormalities and findings at surgery are necessary to ensure optimal outcome.

Decompression, Surgical↗