Multipoint incremental motor unit number estimation as an outcome measure in ALS.

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.

Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS.

An open-label dose-escalation trial was performed to assess the safety and tolerability of high doses of coenzyme Q10 (CoQ10) in ALS. CoQ10, a cofactor in mitochondrial electron transfer, may improve the mitochondrial dysfunction in ALS. In this study, CoQ10 was safe and well tolerated in 31 subjects treated with doses as high as 3,000 mg/day for 8 months.

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.

A novel method of inducing muscle cramps using repetitive magnetic stimulation.

The lack of a practical model has hampered attempts to study the pathophysiology of muscle cramps. We investigated the feasibility, efficacy, and reproducibility of repetitive magnetic stimulation in producing experimental cramps. In 14 healthy subjects, the tibial nerve at the ankle was stimulated with a magnetic stimulator at rates beginning at 4 Hz to a maximum of 20 Hz. The frequency was gradually increased until a cramp was produced. Ten of 14 subjects demonstrated a muscle cramp. All subjects rated the discomfort of the procedure to be mild or moderate. Repeat testing yielded values that were highly reproducible. This technique holds promise for clinical studies and therapeutic trials.

In vitro measurement of muscle volume with 3-dimensional ultrasound.

The aim was to test the accuracy of muscle volume measurements with a new 3-dimensional (3-D) ultrasound system, which allows a freehand scanning of the transducer with an improved quality of the ultrasound images and therefore the outlines of the muscles. Five resected cadaveric hand muscles were insonated and the muscle volumes calculated by 3-D reconstructions of the acquired 2-D ultrasound sections. Intra-reader, inter-reader and follow-up variability were calculated, as well as the volume of the muscle tissue measured by water displacement. In the results, 3-D ultrasound and water displacement measurements showed an average deviation of 10.1%; Data of 3-D ultrasound measurements were: intra-reader variability 2.8%; inter-reader variability 2.4% and follow-up variability 2.3%. 3-D measurements of muscle volume are valid and reliable. Serial sonographic measurements of muscle may be able to quantitate changes in muscle volume that occur in disease and recovery.

A case of Hodgkin's lymphoma producing neuromyotonia.

The syndrome of neuromyotonia produces muscle stiffness, cramps, and frequently, excessive sweating. Most cases are idiopathic, but some are associated with neoplasms, especially immune cell cancers. Voltage-gated potassium channels may be the target of an autoantibody attack in idiopathic generalized neuromyotonia (Isaacs' syndrome). The cases associated with neoplasms may also have an autoimmune etiology. We report the first case of neuromyotonia as the presenting feature of Hodgkin's lymphoma and propose a paraneoplastic mechanism that would link the purported autoimmune etiology in Isaacs' syndrome with the cancer-associated cases.

Hereditary neuralgic amyotrophy: evidence for genetic homogeneity and mapping to chromosome 17q25.

Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder on chromosome 17q, associated with recurrent, episodic, painful brachial plexus neuropathy. Dysmorphic features, including hypotelorism, long nasal bridge and facial asymmetry, are frequently associated with HNA. To assess genetic homogeneity, determine the cytogenetic location, and identify flanking markers for the HNA locus, six pedigrees were studied with multiple DNA markers from distal chromosome 17q. The results in all pedigrees supported linkage of the HNA locus to chromosome 17. A maximum combined lod score (Z = 10.94, theta = 0.05) was obtained with marker D17S939 and the maximum multipoint lod score was 22.768 in the interval defined by D17S802-D17S939. An analysis of crossovers placed the HNA locus within an approximate 4.0-cM interval flanked by D17S1603 and D17S802. Analysis of DNA from a human/mouse somatic cell hybrid with linked markers suggests that band 17q25 harbors the HNA locus. These results support genetic homogeneity within HNA and define a specific interval and a precise cytogenetic location in chromosome 17q25 for this disorder.

Urinary dysfunction in Duchenne muscular dystrophy.

In Duchenne muscular dystrophy (DMD), sphincter muscles tend to be clinically spared. However, urinary incontinence is occasionally reported, usually late in the course of the disease. We wished to determine the etiology of urinary dysfunction in patients with DMD. Seven boys with DMD and urinary dysfunction were examined by a neurologist and a urologist followed by urodynamic and electrophysiological assessment. Based on the results of these evaluations, patients were defined as having an upper motor neuron (UMN), lower motor neuron (LMN), or myopathic lesion. Five of the patients had UMN abnormalities consisting of either uninhibited contractions or bladder/sphincter dyssynergy. One patient had a LMN lesion with prolonged duration and high-amplitude motor units. No patient demonstrated myopathic motor units. Five boys had undergone spinal fusion for scoliosis. We conclude that urinary incontinence in DMD is most often due to UMN dysfunction and not due to a severe myopathy of the detrusor or external sphincter. The most likely causes of the UMN abnormalities are severe scoliosis or a complication of spinal fusion surgery.

Paraspinal muscle hematoma after electromyography.

There have been few reports of complications related to electromyography. Needle examination of certain muscles is sometimes avoided in patients taking anticoagulant agents, although no clear guidelines have been established. We describe a patient who was not receiving an anticoagulant and developed a large paraspinal muscle hematoma after routine electromyography. Subsequently, all patients who underwent paraspinal muscle electromyography and were diagnosed with radiculopathy at our institution over a 14-month period were reviewed. From this group, 17 patients were identified who had also underwent MRI of the appropriate spinal levels within 1 week after the needle examination. These images were reviewed for evidence of paraspinal muscle hematomas. Four small hematomas were identified in four different patients. None of these were radiologically significant compared with the large hematoma described in the case report. Radiologically apparent paraspinal hematomas after electromyography are an unusual complication of needle examination and do not appear to have any clinical significance. Nevertheless, the presence of these lesions justifies caution when considering electromyography of paraspinal and other deeper muscles in anticoagulated patients.

Torticollis acquired in late infancy due to a cerebellar gangliocytoma.

Torticollis in infancy is a common disorder and is typically benign and self-limiting. However, in some instances it is the presentation of serious disease. A critical distinction is whether the condition is congenital or acquired. We present a case of acquired late infantile torticollis caused by a cerebellar gangliocytoma that underscores the importance of making this determination prior to initiating a treatment plan. A gangliocytoma presenting with torticollis has not been previously described.

Pure motor hemiplegia including the face induced by an infarct of the medullary pyramid.

Four autopsy cases of pure motor hemiparesis due to medullary pyramid infarcts have been previously reported. The deficits that were described included overt limb weakness and "slight facial weakness". According to current neurological teaching, the lesion responsible for an upper motor neuron facial palsy affects the corticobulbar tract at the level of the midpons or more rostrally.

Comparison of digital sensory studies in patients with carpal tunnel syndrome.

Electrodiagnosis of carpal tunnel syndrome (CTS) often depends on the demonstration of focal slowing of median sensory fibers across the wrist. We compared the relative sensitivity of the four median innervated digits in demonstrating focal slowing in patients with CTS. Antidromic sensory studies of digits 1, 2, 3, and 4 were performed on 30 control subjects to develop normative data. Fifty-nine consecutive patients with CTS were then studied to determine the sensitivity of focal slowing of each median innervated digit. In the 26 CTS patients with a normal distal motor latency (DML) to abductor pollicis brevis, digit 1 was abnormal in 81%, digit 2 in 42%, digit 3 in 54%, and digit 4 in 38%. In the 33 CTS patients with a prolonged DML, digit 1 was abnormal in 94%, digit 2 in 88%, digit 3 in 91%, and digit 4 in 88%. We conclude that in milder cases of CTS with a normal DML, digit 1 is the most sensitive in identifying focal slowing of sensory conduction across the wrist. However, in patients with a prolonged DML, the sensitivity of sensory conduction is not significantly different among the four digits.