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The cost of prescription drugs in the United States is rising like never before and has led to an inflection point where clinicians must consider the potential financial damage to the patient and to society related to the more expensive drugs available. Many of the highest-priced drugs are approved as orphan drugs, a legally defined status providing additional benefits to pharmaceutical companies that is intended to incentivize therapeutic development for rare diseases. The Orphan Drug Act has been a great success since it was enacted in 1983, resulting in the development of many innovative, life-changing, and even lifesaving drugs; however, high drug prices place patients at risk for personal bankruptcy, prescription abandonment, and higher rates of hospitalization. These negative consequences have become more widespread and severe because some companies exploit pricing via the market exclusivity granted to them under the provisions of the Orphan Drug Act. As more and more companies develop these drugs, the cost to society increases as does the capacity to tolerate unjustified prices. The societal effects of drug pricing must be considered through the prism of opportunity costs; that is, what benefit is lost by choosing to spend on one thing instead of another. Clinical- and economic-based analyses from independent groups such as the Institute for Clinical and Economic Review can help physicians understand the value of drugs (ie, the benefits relative to cost). When prescribing a high-priced medication, clinicians should discuss the drug's value and the associated opportunity cost with patients and have an open discussion about patients' ability to financially tolerate the treatment.

The evolution of broadcast audio has been rapidly changing over the past 10–15 years with the advent of podcasts in the early 2000s. As with other media, podcast audio has been adapted for use within medical and specifically neurology education in the form of the Neurology Podcast since 2007. As podcasts were an initial step in the field of on-demand media, further technological evolution has resulted in increasing customization of a listener's audio experience. We believe a historical inflection point has been reached with the increasingly mainstream adoption of virtual assistant technology which allows for consumption of brief on-demand self-curated audio productions. As editors of the Neurology Podcast, we have introduced a new audio product to this technological landscape, the Neurology Minute. In doing so, we hope that curated on-demand educational audio will become a part of the daily routine of many practicing neurologists as we move into this new technological age.

Objective: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). Methods: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody–positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. Results: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4–12 prednisone AUDTC when compared to placebo (difference MTX − placebo: −488.0 mg, 95% confidence interval −2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). Conclusions: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. Classification of evidence: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

Editor's Note: Ted Burns is the founding editor of our podcast, an enormously successful venture, bringing Neurology ® and AAN content to listeners worldwide. One of the highlights of the podcast to date was Ted's insightful and moving discussion when he was initially diagnosed with cancer. In presenting this update, we continue a series of pieces that present a patient or caregiver's views; these are important and informative, and we hope that our readership (or listeners) will benefit by seeing these perspectives. —Robert A. Gross, MD, PhD, FAAN

Background: Improved outcome measures are necessary to reduce sample size and increase power in amyotrophic lateral sclerosis (ALS) clinical trials. Motor unit number estimation (MUNE) is a potentially attractive tool. MUNE methods previously employed in multicenter trials exhibited excessive variability and were prone to artifact. Objective: To evaluate a modification of standard incremental MUNE in a multicenter natural history study of subjects with ALS. Methods: Fifty healthy subjects were evaluated twice and 71 subjects with ALS were studied repeatedly for up to 500 days. Side and nerve studied was based on clinical examination findings. Nerves were stimulated at 3 specified locations and 3 increments were obtained at each location. Average single motor unit action potential (SMUP) amplitude was calculated by adding the amplitude of the third increment at each location and dividing by 9; SMUP was divided into maximum CMAP amplitude to determine the MUNE. Results: Test-retest variability was 9% in normal subjects. Average MUNE for normal subjects was 225 (±87), and was 41.9 (±39) among subjects with ALS at baseline. Subjects with ALS showed clear decrements over time, with an overage rate of decline of approximately 9% per month. SMUP amplitude increased with time in a fashion consistent with the known pathophysiology of ALS. Conclusion: Multipoint incremental MUNE has a number of attributes that make it attractive as an outcome measure in ALS and other diseases characterized by motor unit loss. It can be rapidly performed on any EMG machine and has repeatability and rates of decline that favorably compare to other previously described methods.

Polyneuropathy has an estimated prevalence of 2%–3% in the general population and a prevalence as high as 8% in people over the age of 55 years.1 Roughly one-third of polyneuropathies will have a genetic cause, one-third an acquired etiology, and one-third will be idiopathic, despite appropriate diagnostic evaluation.2 There are over 100 known acquired and inherited disorders that may cause polyneuropathy, a fact that presents challenges and can contribute to uncertainty about the scope, direction, and level of aggressiveness of any evaluation.3 This sometimes leads to a one-size-fits-all diagnostic strategy, a strategy that is unfocused, inefficient, and costly, and sometimes places the patient at unnecessary risk of a procedure-related complication (e.g., nerve biopsy). In this article, we present a simple and easy-to-remember algorithm for diagnosing polyneuropathy, based on first answering 4 clinical questions: what, where, when, and what setting (figure 1).3 The 4-step clinical characterization should almost always be followed by electrodiagnostic (EDX) characterization with appropriate nerve conduction and needle EMG. The clinical and EDX characterization can then be combined, as necessary, with a consultation of appropriate tables and lists of differentials or the figure we provide in this article, allowing for the generation of a focused differential diagnosis and appropriate and efficient evaluation. Figure 1 A suggested construct for the approach to neuropathy, using the “what, where, when, and what setting” approach for characterizing polyneuropathy Only the most common etiologies are found in this figure. Red font indicates predominantly demyelinating polyneuropathies and yellow font indicates predominantly axonal polyneuropathies. CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CMT = Charcot-Marie-Tooth; cryo = cryoglobulinemia; GBS = Guillain-Barre syndrome; hDMN = hereditary distal motor neuropathy (uncommon); HNPP = hereditary neuropathy with liability to pressure palsies; HSN = hereditary sensory neuropathy (uncommon); IgM M protein = also known as distal acquired demyelinating symmetric (DADS) neuropathy or frequently anti-MAG neuropathy; MMN = multifocal motor neuropathy; M protein = monoclonal protein; N-NSS = negative …

The assessment of intraepidermal nerve fiber density (IENFD) can be an objective, valid, and useful tool for the diagnosis of small-fiber neuropathy. IENFD testing involves sampling a small area of epidermis; a reduced IENFD relative to published age and sex normal values aids the diagnosis of small-fiber neuropathy. Patients often have borderline values, however, raising concerns of sampling bias, human error, and technical variations. In this issue of Neurology ® , Engelstad et al.1 report on efforts to refine the sampling process and the analytical protocol for IENFD assessment. The investigators obtained 3-mm skin punch biopsies from the distal leg and proximal thigh in healthy participants and patients with diabetes mellitus. Processed specimens were cut into 50-μm sections, taking 10 serial “skip sections” (sections 5, 7, 9, 11–23) for analysis. The epidermal nerve fibers/mm were counted by one technician and audited for accuracy by another. The variability of IENFD among sections was calculated for different numbers of sections counted (e.g., 4 vs 10 sections evaluated). The more sections reviewed, the lower the variability in IENFD (figure 1 of their article). While not surprising, this result is important because it suggests the number of sections to be quantified might need to be tailored for each patient, thus increasing reliability. Most laboratories currently base IENFD on measurement of 4 sections.2 The authors provide results from several patients with 95% confidence intervals (CIs) that straddle the divide between normal and abnormal when 4 sections are counted, but whose 95% CIs narrow dramatically and fall clearly into normal or abnormal when 10 sections are counted (figure 2 of their article). These data suggest that improved accuracy results when using CIs to determine the appropriate number of sections to be analyzed, but in the examples provided, the average of 4 samples would still have yielded the correct diagnosis. It is nevertheless reasonable to assume that narrower CIs have a greater likelihood of identifying the correct diagnosis.

It seems like the report of an important advance in neurology is a weekly occurrence. For many of us, the potential and rapid progress of neurology was one of the major attractions for our choosing this career. But for residents and fellows, already busy with personal lives and the fundamentals of neurology training, it’s challenging to also stay current with exciting advances. This task is particularly daunting when one considers that there are well over 100 neuroscience journals. The challenge of staying up to date does not disappear after residency and fellowship because lives and work remain busy. For the neurologist, any failure to stay current can have negative consequences on patient care. In response to this challenge, there are a few fee-based services that provide reviews, usually in print, of recent neurology literature, but downsides of these services include cost and the difficulty in finding time even to read these publications. With these issues in mind, about a year ago I was struck by the immense potential for podcasting to provide timely, free neurology literature updates. Podcasting1 …