Minocycline-induced skin and dental pigmentations.
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Aged↗
Biomedical subjects
Paul H Gordon
Publications and source records attributed to Paul H Gordon.
Selecting promising ALS therapies in clinical trials.
Riluzole is the only approved medication that extends survival for patients with amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been evaluated in randomized clinical trials, none has shown unequivocal success and none has been approved by regulatory agencies. Few symptomatic therapies have been tested in ALS. Effectiveness for drugs with modest benefit can be established only through large phase III randomized clinical trials. With numerous potential agents but limited resources, priority should be given to agents that show promise in phase II trials before proceeding to evaluation in phase III trials. In this article, we review drug development in early phase ALS trials and introduce novel designs. First, to maximize the therapeutic potential of the test medication, we need to identify the highest dose that produces a tolerable level of side effects. Second, candidate treatments should be ranked by conducting randomized selection trials between competing new treatments. The selection paradigm adopts a statistical viewpoint different from the hypothesis testing framework in conventional trials. We exemplify this approach by describing a group-sequential selection design developed for a phase II, randomized, multicenter trial of two combination treatments in patients with ALS, and illustrate the sample size reduction from a conventional trial.
Amyotrophic Lateral Sclerosis↗
Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.
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Aged↗
An observational study of cognitive impairment in amyotrophic lateral sclerosis.
BACKGROUND: Cognitive impairment is increasingly recognized in patients with amyotrophic lateral sclerosis (ALS). Clinical and pathologic features overlap in frontotemporal lobar dementia and ALS. Demographics, respiratory status, bulbar site of onset, and disease severity are potential risk factors for cognitive impairment in ALS. OBJECTIVES: To further delineate the frequency, nature, and implications of cognitive impairment in ALS and to assess previously identified risk factors. DESIGN: Case-control and retrospective cohort study. SETTING: Academic referral center. PARTICIPANTS: Forty consecutive patients with ALS underwent baseline neurologic and neuropsychologic examinations. Cognitive test performance was compared in patients with ALS and matched controls. An exploratory analysis of the relationship between cognitive performance and ALS survival was performed. MAIN OUTCOME MEASURES: Neuropsychologic test performance, ALS severity, and survival. RESULTS: Twelve patients (30%) showed evidence of cognitive impairment, including 9 (23%) who met the neuropsychologic criteria for dementia. No statistically significant differences were found between demented and nondemented ALS groups regarding demographics, family history, site of onset, bulbar dysfunction, or ALS severity. Only 1 patient with dementia had bulbar-onset disease. An association was observed between increasing ALS severity and declining verbal fluency performance. Demented patients with ALS showed predominant impairment in free recall, executive function, and naming, with relative preservation of attention, psychomotor speed, and visuospatial function. No association was observed between cognition and survival, controlling for ALS severity. CONCLUSIONS: Nearly a third of the patients with ALS showed evidence of cognitive impairment in a pattern consistent with frontotemporal lobar dementia. Cognitive performance was not related to site of onset or survival.
Amyotrophic Lateral Sclerosis↗
Advances in clinical trials for amyotrophic lateral sclerosis.
Because treatments are not yet powerful enough to reverse the symptoms of amyotrophic lateral sclerosis (ALS), randomized placebo-controlled trials remain the gold standard for testing new therapies. To date, only one drug, riluzole, has been shown to slow the course of ALS, albeit in a very modest way. Since the approval of riluzole almost 10 years ago, there have been a number of negative trials, and we still await the discovery of a medication with a truly meaningful effect. With each study, our sophistication in trial design grows, but hurdles remain, including how to use transgenic animal models optimally, which outcome measures most accurately reflect changes in the disease, and how to reduce the often high dropout rates in trials of ALS. This article is devoted to the recent evolution of clinical trials in ALS and discusses specific trials conducted during the past 5 years.
Amyotrophic Lateral Sclerosis↗
Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: discrete entities or spectrum?
Among the motor neuron diseases, three share the clinical features of prominent upper motor neuron signs--amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and the hereditary spastic paraplegias (HSP). While genetic testing can assist in the identification of several variants of the latter, in the remaining cases, including those in which spasticity may be associated with amyotrophy, clinical differentiation of the three disorders may prove difficult. In this paper we review the evidence that these are distinct disorders and conclude that, for ALS and PLS particularly, there may be justification in considering them as single points along a continuum of multisystem disorders with conspicuous motor neuron involvement. Only through the development and application of exacting clinical diagnostic criteria to epidemiological studies, along with greater numbers of post-mortem examinations, however, will these questions be answered fully.
Amyotrophic Lateral Sclerosis↗
Reaction time and movement time after embryonic cell implantation in Parkinson disease.
BACKGROUND: Embryonic nigral cell implants are a novel treatment for Parkinson disease (PD). Reaction time (RT) and movement time (MT) analysis, validated quantitative measures of premovement neural processing and motor execution, can be used as objective physiological markers of motor performance in PD. OBJECTIVES: To gauge the change in motor performance in patients with PD who received implants, and to determine whether the physiological findings correlate with clinical outcome measures after transplantation. DESIGN: Double-blind, placebo-controlled trial. Patients Forty patients with levodopa-responsive, Hoehn and Yahr stage III or greater PD. INTERVENTIONS: Random assignment to embryonic tissue implants or placebo (sham) operation. MAIN OUTCOME MEASURES: Combined RT + MT scores measured preoperatively and at 4 and 12 months postoperatively in the "off" state. RESULTS: The difference in mean RT + MT scores between the sham and implant groups was statistically significant (P =.005) and was greatest in those 60 years or older (P =.003). Changes correlated with Unified Parkinson's Disease Rating Scale off scores at 4 (r = 0.87, P =.001) and 12 (r = 0.75, P =.01) months in those younger than 60 years. There was a significant deterioration in the sham surgery group at 12 months (P =.03) that was thought to be due to worsening in subjects 60 years and older (P<.001). CONCLUSIONS: The physiological measures detected significant changes in patients undergoing embryonic nigral cell implants and correlated directly with clinical outcome measures. Comprehensive analyses of RT paradigms can document subtle changes in motor performance over time, making them useful outcome measures in therapeutic trials of PD. These findings support further research into nigral cell implantation for PD.
Adult↗
Woman with a 26-year history of parkinsonism, supranuclear ophthalmoplegia, and loss of postural reflexes.
A woman who had her first serious fall at age 48 years subsequently developed neurological symptoms. Her case is described, differential diagnoses are presented, pathology is discussed, and a final diagnosis is reached.
Aged↗
ALSFRS-R.
The ALSFRS-R is an attractive primary outcome measure in clinical trials of ALS because it is validated, easy to administer, minimizes dropout, reduces cost, and correlates with survival. Unlike the other standard outcome measures currently employed, the ALSFRS-R is also a measure of global function.
Activities of Daily Living↗
Amyotrophic lateral sclerosis.
In this case study, we describe the symptoms, neurological examination, and pathology of a woman with amyotrophic lateral sclerosis (ALS). ALS is a rare disorder leading to degeneration of the voluntary motor system and death in, on average, 3 to 4 years. The loss of motor neurons in the brain and spinal cord causes the progressive symptoms of muscular weakness, atrophy, fasciculation (muscle twitching), spasticity, and hyperreflexia. Signs of disease in both upper and lower motor neurons are required for a definitive clinical diagnosis. Pathology shows degeneration of the lateral corticospinal tracts, loss of motor neurons and astrogliosis in the brain and brain stem, and neuronal inclusions. This case was marked by the onset of weakness and muscle atrophy in the hand, which spread to involve contiguous muscle segments. Cognition, the extraocular muscles, and the urinary sphincters were spared. Respiratory muscle weakness was a late manifestation.
Amyotrophic Lateral Sclerosis↗
Extensor digitorum brevis test and resistance to botulinum toxin type A.
We studied 22 patients with dystonia to determine the normal range of values for the extensor digitorum brevis (EDB) test, and to determine its sensitivity and specificity in detecting resistance to botulinum toxin type A (BTX-A). Three compound muscle action potentials (CMAPs) elicited by peroneal nerve stimulation were averaged before and 2 weeks after injection of 20 units of BTX-A into the EDB. Amplitude and area ratios were calculated by dividing the averaged postinjection CMAP by the averaged preinjection CMAP values. The difference in means of this ratio between clinically sensitive and resistant subjects was statistically significant (P < 0.002). A normal range of <0.45 for each ratio was determined by adding two standard deviations to the ratio mean of 14 clinically sensitive subjects. Four of five resistant patients had values outside the normal range. The EDB test is a simple quantitative method of detecting resistance to BTX-A, with a sensitivity of 80% and specificity of 94%.
Action Potentials↗