Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial.

The goal of this randomized, blinded, crossover clinical trial was to determine whether Nuedexta (dextromethorphan and quinidine) enhanced speech, swallowing, and salivation in patients with ALS. Sixty patients with amyotrophic lateral sclerosis (ALS) received either Nuedexta or placebo for 28 to 30 days, followed by a 10 to 15-day washout period. Subsequently, patients were switched to the opposite treatment arm for the remaining days of the trial. The primary endpoint was a reduction in the self-report Center for Neurologic Study Bulbar Function Scale (CNS-BFS) score. The rater-administered ALS Functional Rating Scale Revised was the principal secondary endpoint. The CNS-BFS score improved with active treatment, decreasing from a mean of 59.3 in the placebo arm of the trial to 53.5 during the drug-treatment arm (p < 0.001). Each of the individual domains of bulbar function interrogated by the CNS-BFS responded to treatment with Nuedexta as follows: salivation: 15.8 versus 14.3 (p = 0.004); speech: 24.6 versus 22.2 (p = 0.003); swallowing: 18.9 versus 17.1 (p = 0.009). Similarly, the bulbar component of the ALS Functional Rating Scale Revised improved with active treatment (p = 0.003), although the drug did not affect the motor and respiratory components of this scale. This study is unique for several reasons. Firstly, it was driven by patient reports of improved speech and swallowing while taking Nuedexta for control of emotional lability. Secondly, the study was conducted over a short duration (70 days), and thirdly, a self-report scale was selected as the principle outcome measure. Considering the importance of bulbar functions, these results, if confirmed, point to an additional use of Nuedexta as an adjunct to the management of ALS.

End-of-life decision making in 42 patients with amyotrophic lateral sclerosis.

OBJECTIVE: To determine when end-of-life issues were discussed with patients afflicted with amyotrophic lateral sclerosis (ALS). METHODS: This was a retrospective analysis of ALS patients referred to the neuromuscular clinic at Georgetown University Hospital. Patients were seen by a pulmonologist and a neurologist at the initial diagnosis or referral, and every 2-3 months thereafter. End-of-life discussions were addressed at each visit. Other variables recorded included the amount of time afflicted with ALS, serial pulmonary function test results, and the subjective level of bulbar dysfunction. RESULTS: We saw 43 patients (age range 39-94 y) between June 1999 and September 2004. One patient was on a ventilator at the initial visit, and was therefore excluded from the study. Discussion about the patients' end-of-life care preferences were initiated at the first pulmonary visit with 40 patients. With 2 patients, end-of-life decisions were discussed at the second office visit. Twenty-five patients chose do-not-resuscitate and do-not-intubate (DNR/DNI) orders after the initial end-of-life discussion with the pulmonologist. Five other patients chose DNR/DNI orders during subsequent clinic visits. Four patients were still undecided at their last clinic visit. Six patients were lost to follow-up before a decision was made. Two patients requested full ventilatory support. Both the forced vital capacity and the level of bulbar dysfunction were not statistically different between the patients who chose DNR/DNI and the patients who were either undecided or requested full ventilatory support. CONCLUSIONS: Decisions about end-of-life care are often delayed in patients with ALS. These patients' final decisions seem to be independent of their level of respiratory insufficiency or bulbar function, and most related to the physician addressing end-of-life care decisions in a timely manner.

Collateral sprouting of human epidermal nerve fibers following intracutaneous axotomy.

Despite the clinical need, there are no therapeutic compounds available to promote peripheral nerve regeneration. In part, this may be due to a lack of sensitive measures of nerve growth. Here, we describe a novel approach of measuring collateral sprouting of epidermal nerve fibers (ENF) in human subjects and describe the effect of the neuroimmunophilin ligand timcodar dimesylate on collateral nerve sprouting. The objective of this study was to describe a model of intracutaneous axotomy and evaluate the ability of timcodar dimesylate to accelerate human cutaneous nerve regeneration through collateral sprouting. Subjects were randomized to receive placebo, 12.5 or 50 mg/day timcodar dimesylate in a prospective, two-center, double-blind, placebo-controlled trial. A 3-mm distal thigh punch skin biopsy was performed at baseline, and a 4-mm overlapping concentric biopsy was taken after 56 days of treatment. Biopsies were processed to visualize ENF, and the collateral sprouting distance (CSD) was measured. Sixty-two subjects completed the trial, and the CSD was measurable in 52. The CSD (mean +/- SEM) was 474.5 microm +/- 38.3, 473.4 microm +/- 28.4, and 450.8 microm +/- 26.5 for the placebo, low and high dose groups, respectively (p = 0.84). The baseline ENF density was associated with the CSD (p = 0.02). Collateral sprouting was efficiently measured using an intracutaneous axotomy model and suggests a collateral sprouting rate of 8.5 microm/day in healthy subjects. The model was consistent across treatment groups and had a low coefficient of variation. Timcodar dimesylate treatment was safe over an 8-week period but did not improve collateral sprouting among healthy subjects.

The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy.

We sought to develop and validate a standardized cutaneous nerve regeneration model and to define the rate of epidermal nerve fibre (ENF) regeneration first in healthy control subjects and then in neuropathic and neuropathy-free subjects with diabetes. Next, we assessed the effect of different factors on the rate of nerve fibre regeneration and investigated whether such an approach might offer insight into novel trial designs and outcome measures. All subjects had a standardized topical capsaicin dressing applied to the distal lateral thigh. ENF densities derived from skin biopsies were determined at baseline, after capsaicin treatment and at reinnervation time points. For each subject, the best fit line from post-denervation data was determined and the slope was used as the rate of regeneration. In healthy control subjects, regeneration was correlated with psychophysical sensory testing, electron microscopy studies and immunohistochemistry with alternative axonal membrane markers. Topical capsaicin application produced complete or nearly complete denervation of the epidermis in both control subjects and people with diabetes. The rate of regeneration was associated with the baseline ENF density (P < 0.001), but not age (P = 0.75), gender (P = 0.18), epidermal thickness (P = 0.4) or post-capsaicin treatment density (P = 0.7). ENF regeneration, as determined by recovery of ENF density, occurred at a rate of 0.177 +/- 0.075 fibres/mm/day in healthy control subjects and was significantly reduced in subjects with diabetes (0.074 +/- 0.064, P < 0.001) after adjusting for changes in baseline ENF density. Among subjects with diabetes, the presence of neuropathy was associated with a further reduction in regenerative rate (0.10 +/- 0.07 versus 0.04 +/- 0.03, P = 0.03), though diabetes type (P = 0.7), duration of diabetes (P = 0.3) or baseline glycated haemoglobin (P = 0.6) were not significant. These results have several implications. First, topical capsaicin application can produce a uniform epidermal nerve fibre injury that is safe and well tolerated, and offers an efficient strategy to measure and study nerve regeneration in man. Secondly, using our techniques, reduced rates of nerve regeneration were found in people with diabetes without evidence of neuropathy and indicate that abnormalities in peripheral nerve function are present early in diabetes, before signs or symptoms develop. These results suggest that regenerative neuropathy trials could include non-neuropathic subjects and that trial duration can be dramatically shortened.