Quantitative objective markers for upper and lower motor neuron dysfunction in ALS.

OBJECTIVE: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS. METHODS: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging ((1)H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects. RESULTS: (1)H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001). MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls. All objective markers correlated well with the ALS Functional Rating Scale-Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline. CONCLUSIONS: (1)H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.

Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial.

OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. METHODS: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety. RESULTS: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. CONCLUSION: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.

Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study.

AIMS: The appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel. MATERIALS AND METHODS: In this non-randomised study, we assessed neurologic signs and symptoms, and changes in nerve-conduction studies in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks (median 32 days) after treatment. RESULTS: Patients who received glutamine developed significantly less weakness (P = 0.02), less loss of vibratory sensation (P = 0.04) and less toe numbness (P = 0.004) than controls. The per cent change in the compound motor action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes after paclitaxel treatment was lower in the glutamine group, but this finding was not statistically significant in these small groups. CONCLUSIONS: In this study, serial neurologic assessment of patient symptoms and signs seemed to be a better indicator of a possible glutamine effect than sensory- or motor-nerve-conduction studies. Prospective randomised trials are needed to clarify the effect of glutamine on paclitaxel and other types of chemotherapy-induced neuropathy.

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.

Stimulated single fiber electromyography in the mouse: techniques and normative data.

As the number of new transgenic mouse models of human neuromuscular disease continues to increase, the development of sophisticated electrophysiologic techniques for assessing the peripheral nervous system in these models has become important. Neuromuscular junction (NMJ) dysfunction, in particular, is often not detectable by morphologic or other techniques. To enable sensitive testing of murine NMJ function, we developed and tested a method for stimulated single fiber electromyography (S-SFEMG) in the gastrocnemius muscles of anesthetized mice. Jitter was assessed by measuring the mean consecutive latency difference (MCD) of single fiber responses to sciatic nerve stimulation at 2 HZ. Mean MCD values in normothermic mice were in the range of 6-8 micros for different strains, with no MCD values exceeding 25 micros. Reduced core temperature (to 29 degrees--30 degrees C) resulted in increased jitter, whereas intubation and mechanical ventilation of mice did not alter these values. Intraperitoneal and intravenous injection of vecuronium, however, resulted in progressively increased jitter followed by blocking in continuously monitored fibers. These observations validate the utility of S-SFEMG in mice as an index of NMJ function under a variety of physiologic conditions, and suggest that a high safety factor for neuromuscular transmission exists at mouse NMJs.

Motor unit number estimation, ALS and clinical trials.

Motor unit number estimation (MUNE) techniques have evolved substantially over the past decade and have been applied, with increasing frequency, to the study of amyotrophic lateral sclerosis (ALS). As major clinical therapeutic trials in motor neuron disease continue to appear, the need for a clear quantitative method of following motor unit physiology in the living subject grows ever more pressing. In this article, we review the major modern techniques of MUNE and the data supporting their reproducibility and utility in patients with ALS, with particular attention to their role in evaluating the efficacy of new therapeutic interventions.

Repetitive axonal stimulation of the same single motor unit: a longitudinal tracking study.

We elicited three single motor unit action potentials (S-MUAPs) via multiple point stimulation and subjected them to repetitive stimulation (RS) in 3 healthy subjects. We tracked each S-MUAP and its RS trains over two separate sessions as well as the compound motor action potential (CMAP) RS trains obtained from the same muscle following whole nerve stimulation. Repetitive axonal stimulation yields consistent results when carefully performed with minimal variation in each S-MUAP RS train from session to session, providing previously unobtainable data regarding neuromuscular junction function in the same single motor unit over time. In this small, normative sample, no significant correlation between S-MUAP and CMAP RS responses was observed.