Seth L. Pullman

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 (1H 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: 1H 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: 1H 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.

Correlates of functional disability in essential tremor

The decision to treat patients with essential tremor (ET) is based primarily on the functional impact of the tremor. Correlates of functional disability, apart from the severity of the tremor itself, have not been studied. The objective of this work was to study correlates of functional disability in ET, and to present data on the extent of functional disability in community‐dwelling ET cases.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor

Objective: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. Background: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. Methods: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. Results: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. Conclusion: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Clinical utility of surface EMG: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

This report reviews the clinical uses of surface electromyography (SEMG) as a diagnostic tool for neurologic disorders. SEMG is assessed with regard to the evaluation of patients with neuromuscular diseases, low back pain, and disorders of motor control. This broadens the scope of a previous assessment of SEMG in neurologic practice by the American Association of Electrodiagnostic Medicine1 in which its utility was examined with regard to neuromuscular diseases only. Needle electromyographic evaluation (NEMG), in combination with nerve conduction studies, is the gold standard methodology for assessing the neurophysiologic characteristics of neuromuscular diseases. Moreover, fine-wire EMG (FWEMG) often has been used in the evaluation of gait disorders, kinesiologic studies, and research and is also considered a standard. Nevertheless, NEMG and FWEMG are both invasive and painful, and this limits their use when activity from several muscles needs to be monitored simultaneously. SEMG is a technique to measure muscle activity noninvasively using surface electrodes placed on the skin overlying the muscle. SEMG differs from NEMG and FWEMG with respect to technical requirements and electrical properties. Unlike NEMG, SEMG electrodes record from a wide area of muscle territory, have a relatively narrow frequency band (range, 20 to 500 Hz), have low-signal resolution, and are highly susceptible to movement artifact. SEMG electrodes typically are approximately 10 mm in diameter and usually are passive (i.e., they are simple conductive surfaces requiring low skin resistance). They can, however, be active, incorporating preamplifier electronics that lessen the need for low skin resistance and improve the signal-to-noise ratio. SEMG can record both voluntary and involuntary muscle activity in addition to externally stimulated muscle action potentials such as motor evoked potentials after central or peripheral nerve stimulation.2 SEMG has also been used in several non-neurologic settings such as obstetric monitoring and animal research, but these potential …

The sympathetic skin response: normal values, elucidation of afferent components and application limits

The sympathetic skin response (SSR), recorded at the hand and foot, was elicited using different classes of stimuli in 20 normal controls and 10 patients with peripheral neuropathy. We found that SSR latencies changed significantly with different recording sites, but not with different stimulation sites. Additionally, after ischemic conduction block of the arm in 3 normal controls, the previously obtainable SSR recorded at the hand became unobtainable with median nerve stimulation. Also, in one patient with subacute ganglionitis and 3 patients with demyelinating neuropathies, the SSR could not be elicited by electrical stimulation, but it could with deep inspiration. These results suggest that large diameter myelinated fibers may serve as afferents for the SSR. Furthermore, these findings imply that an unobtainable SSR by electrical stimulation may be due not only to dysfunction of the autonomic efferent nerve fibers, but also to abnormalities of the sensory afferents of the reflex. Therefore, investigations of autonomic dysfunction utilizing the SSR must be interpreted with caution in patients with peripheral neuropathies.

Corticospinal System Development Depends on Motor Experience

Early motor experiences have been shown to be important for the development of motor skills in humans and animals. However, little is known about the role of motor experience in motor system development. In this study, we address the question of whether early motor experience is important in shaping the development of the corticospinal (CS) tract. We prevented limb use by the intramuscular injection of botulinum toxin A into selected forelimb muscles to produce muscle paralysis during the period of development of CS connection specificity, which is between postnatal weeks 3 and 7. CS terminations were examined using an anterograde tracer. Preventing normal forelimb use during CS axon development produced defective development of CS terminations at week 8 and in maturity. There were reductions in the topographic distribution of axon terminals, in terminal and preterminal branching, and in varicosity density. This suggests that limb use is needed to refine CS terminals into topographically specific clusters of dense terminal branches and varicosities. To determine correlated effects on motor behavior, cats were tested in a prehension task, to reach and grasp a piece of food from a narrow food well, when the neuromuscular blockade dissipated (by week 10) and in maturity (week 16). Preventing normal limb use also produced a prehension deficit later in development and in maturity, in which there was a loss of the supination component of grasping. This component of prehension in the cat depends on CS projections from the paw representation of rostral motor cortex to the cervical enlargement. Our findings show that motor experiences are necessary for normal development of CS terminations and function.

Repetitive transcranial magnetic stimulation to SMA worsens complex movements in Parkinson's disease

OBJECTIVES To evaluate the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) for Parkinsons disease (PD) by delivering stimulation at higher intensity and frequency over longer time than in previous research. Promising beneficial effects on movement during or after rTMS have been reported. METHODS Ten patients with idiopathic PD were enrolled in a randomized crossover study comparing active versus sham rTMS to the supplementary motor area (SMA). Assessments included reaction and movement times (RT/MT), quantitative spiral analysis, timed motor performance tests, United Parkinsons Disease Rating Scale (UPDRS), patient self-report and guess as to stimulation condition. RESULTS Two of 10 patients could not tolerate the protocol. Thirty to 45 min following stimulation, active rTMS as compared with sham stimulation worsened spiral drawing (P=0.001) and prolonged RT in the most affected limb (P=0.030). No other significant differences were detected. CONCLUSIONS We sought clinically promising improvement in PD but found subclinical worsening of complex and preparatory movement following rTMS to SMA. These results raise safety concerns regarding the persistence of dysfunction induced by rTMS while supporting the value of rTMS as a research tool. Studies aimed at understanding basic mechanisms and timing of rTMS effects are needed.

Operative techniques and morbidity with subthalamic nucleus deep brain stimulation in 100 consecutive patients with advanced Parkinson’s disease

Objective: Subthalamic nucleus (STN) stimulation for patients with medically refractory Parkinson disease (PD) is expanding. Reported experience has provided some indication of techniques, efficacy, and morbidity, but few centres have reported more than 50 patients. To expand this knowledge, we reviewed our experience with a large series of consecutive patients. Methods: From March 1999 to September 2003, 191 subthalamic stimulator devices (19 unilateral) were implanted in 100 patients with PD at New York Presbyterian Hospital/Columbia University Medical Center. Sixteen patients had undergone a prior surgery for PD (pallidotomy, thalamotomy, or fetal transplant). Microelectrode guided implantations were performed using techniques similar to those described previously. Electrode implantation occurred 1–2 weeks before outpatient pulse generator implantation. Results: Reductions of dyskinesias and off severity/duration were similar to prior published reports. Morbidity included: 7 device infections (3.7%), 1 cerebral infarct, 1 intracerebral haematoma, 1 subdural haematoma, 1 air embolism, 2 wound haematomas requiring drainage (1.0%), 2 skin erosions over implanted hardware (1.0%), 3 periprocedural seizures (1.6%), 6 brain electrode revisions (3.1%), postoperative confusion in 13 patients (6.8%), and 16 battery failures (8.4%). Of the 100 patients, there were no surgical deaths or permanent new neurological deficits. The average hospital stay for all 100 patients was 3.1 days. Conclusion: Subthalamic stimulator implantation in a large consecutive series of patients with PD produced significant clinical improvement without mortality or major neurological morbidity. Morbidity primarily involved device infections and hardware/wound revisions.

Subthalamic nucleus stimulation in advanced Parkinson’s disease: blinded assessments at one year follow up

Objective: To measure the effect of deep brain stimulation (DBS) of the subthalamic nucleus in patients with advanced Parkinson’s disease. Design: Open label follow up using blinded ratings of videotaped neurological examinations. Patients: 30 patients with advanced Parkinson’s disease (19 male, 11 female; mean age 58.8 years; mean disease duration 12.8 years), complicated by intractable wearing off motor fluctuations and dopaminergic dyskinesias. Main outcome measures: Unified Parkinson’s disease rating scale (UPDRS), part III (motor), score at one year, from blinded reviews of videotaped neurological examinations. Secondary outcomes included the other UPDRS subscales, Hoehn and Yahr scale, activities of daily living (ADL) scale, mini-mental state examination (MMSE), estimates of motor fluctuations and dyskinesia severity, drug intake, and patient satisfaction questionnaire. Results: Subthalamic nucleus stimulation was associated with a 29.5% reduction in motor scores at one year (p<0.0001). The only important predictors of improvement in UPDRS part III motor scores were the baseline response to dopaminergic drugs (p = 0.015) and the presence of tremor (p = 0.027). Hoehn and Yahr scores and ADL scores in the “on” and “off” states did not change, nor did the mean MMSE score. Weight gain occurred in the year after surgery, from (mean) 75.8 kg to 78.5 kg (p = 0.028). Duration of daily wearing off episodes was reduced by 69%. Dyskinesia severity was reduced by 60%. Drug requirements (in levodopa equivalents) declined by 30%. Conclusions: The 30% improvement in UPDRS motor scores was a more modest result than previously reported. DBS did not improve functional capacity independent of drug use. Its chief benefits were reduction in wearing off duration and dyskinesia severity.

Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

Abstract The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery.