Clifton L. Gooch

Double‐blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy

Objective The objective of this study was to evaluate the efficacy and safety of tramadol in treating the pain of diabetic neuropathy. Background The pain of diabetic neuropathy is a major cause of morbidity among these patients and treatment, as with other small-fiber neuropathies, is often unsatisfactory. Tramadol is a centrally acting analgesic for use in treating moderate to moderately severe pain. Methods This multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group study consisted of a washoutlscreening phase, during which all analgesics were discontinued, and a 42-day double-blind treatment phase. A total of 131 patients with painful diabetic neuropathy were treated with tramadol (n = 65) or placebo (n = 66) tramadol, which were administered as identical capsules in divided doses four times daily. The primary efficacy analysis compared the mean pain intensity scores in the tramadol and placebo groups obtained at day 42 of the study or at the time of discontinuation. Secondary efficacy assessments were the pain relief rating scores and a quality of life evaluation based on daily activities and sleep characteristics. Results Tramadol, at an average dosage of 210 mg/day, was significantly (p < 0.001) more effective than placebo for treating the pain of diabetic neuropathy. Patients in the tramadol group scored significantly better in physical (p = 0.02) and social functioning (p = 0.04) ratings than patients in the placebo group. No statistically significant treatment effects on sleep were identified. The most frequently occurring adverse events with tramadol were nausea, constipation, headache, and somnolence. Conclusions The results of this placebo-controlled trial showed that tramadol was effective and safe in treating the pain of diabetic neuropathy.

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.

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.

Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy

OBJECTIVE The objective of this study was to evaluate the efficacy and safety of tramadol in a 6-month open extension following a 6-week double-blind randomized trial. RESEARCH DESIGN AND METHODS Patients with painful diabetic neuropathy who completed the double-blind study were eligible for enrollment in an open extension of up to 6 months. All patients received tramadol 50-400 mg/day. Self-administered pain intensity scores (scale 0-4; none to extreme pain) and pain relief scores (scale -1-4; worse to complete relief) were recorded the first day of the open extension (last day of the double-blind phase) and at 30, 90, and 180 days. RESULTS A total of 117 patients (56 former tramadol and 61 former placebo) entered the study. On the first day of the study, patients formerly treated with placebo had a significantly higher mean pain intensity score (2. 2+/-1.02 vs. 1.4+/-0.93, P<0.001) and a lower pain relief score (0. 9+/-1.43 vs. 2.2+/-1.27, P<0.001) than former tramadol patients. By Day 90, both groups had mean pain intensity scores of 1.4, which were maintained throughout the study. Mean pain relief scores (2. 4+/-1.09 vs. 2.2+/-1.14) were similar after 30 days in the former placebo and former tramadol groups, respectively and were maintained for the duration of the study. Four patients discontinued therapy due to ineffective pain relief; 13 patients discontinued due to adverse events. The most common adverse events were constipation, nausea, and headache. CONCLUSIONS Tramadol provides long-term relief of the pain of diabetic neuropathy.

RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways

Axotomy of peripheral nerve stimulates events in multiple cell types that initiate a limited inflammatory response to axonal degeneration and simultaneous outgrowth of neurites into the distal segments after injury. We found that pharmacological blockade of RAGE impaired peripheral nerve regeneration in mice subjected to RAGE blockade and acute crush of the sciatic nerve. As our studies revealed that RAGE was expressed in axons and in infiltrating mononuclear phagocytes upon injury, we tested the role of RAGE in these distinct cell types on nerve regeneration. Transgenic mice expressing signal transduction‐deficient RAGE in mononuclear phagocytes or peripheral neurons were generated and subjected to unilateral crush injury to the sciatic nerve. Transgenic mice displayed decreased functional and morphological recovery compared with littermate controls, as assessed by motor and sensory conduction velocities;and myelinated fiber density. In double transgenic mice expressing signal transduction deficient RAGE in both mononuclear phagocytes and peripheral neurons, regeneration was even further impaired, suggesting the critical interplay between RAGE‐modulated inflammation and neurite outgrowth in nerve repair. These findings suggest that RAGE signaling in inflammatory cells and peripheral neurons plays an important role in plasticity of the peripheral nervous system.—Rong, L. L., Yan, S.‐F., Wendt, T., Hans, D., Pachydaki, S., Bucciarelli, L. G., Adebayo, A., Qu, W., Lu, Y., Kostov, K., Lalla, E., Yan, S. D., Gooch, C., Szabolcs, M., Trojaborg, W., Hays, A. P.,Schmidt, A. M. RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways. FASEB J. 18, 1818–1825 (2004)

Observational study of spinal muscular atrophy type I and implications for clinical trials

Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I). Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered. Results: Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1–22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p = 0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n = 10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Childrens Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21–2.33, p = 0.02). Conclusions: Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.

Prospective cohort study of spinal muscular atrophy types 2 and 3

Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers.

The diabetic neuropathies.

Background:Diabetes remains the most common cause of neuropathy in the United States and is a significant source of morbidity and mortality, accounting for substantial suffering and billions of dollars in health care expenditures each year. Review Summary:Our insight into the pathophysiology of the diabetic neuropathies has increased considerably over the last decade, aided by advances in the basic science of diabetes itself. A wide variety of potential mechanisms for nerve injury in diabetes has been identified, including the polyol pathway of glucose metabolism, oxidative nerve injury, the deposition of advanced glycosylation end products within the nerve and the effects of vascular insufficiency, among others. Diabetic neuropathy may take variety of clinical forms beyond the well-know distal symmetric neuropathy, many of which are often misdiagnosed or overlooked entirely, sometimes with serious consequences for the patient. Proper therapy after diagnosis is also critical and may include not only primary management, but also treatment of painful diabetic neuropathy through an expanding repertoire of increasingly effective pharmacologic agents. Though primary treatment trials have not yet provided effective therapies, ongoing and future trials offer continuing promise. Conclusions:The diabetic neuropathies are exceedingly common, but often improperly diagnosed and incompletely treated. A proper understanding of the mechanisms underlying these diseases and the clinical recognition of their various forms is highly important as appropriate primary and symptomatic management can substantially reduce the morbidity and mortality associated with these disorders.

Vascular Endothelial Growth Factor Gene Transfer for Diabetic Polyneuropathy: A Randomized, Double-Blinded Trial

Randomized, blinded trial of intramuscular gene transfer using plasmid vascular endothelial growth factor (VEGF) to treat diabetic polyneuropathy.

Ischemic stroke after use of the synthetic marijuana “spice”

Objectives: To report and associate acute cerebral infarctions in 2 young, previously healthy siblings with use of the street drug known as “spice” (a synthetic marijuana product, also known as “K2”), which they independently smoked before experiencing acute embolic-appearing ischemic strokes. Methods: We present history, physical examination, laboratory data, cerebrovascular imaging, echocardiogram, ECG, and hospital course of these patients. Results: We found that in both siblings spice was obtained from the same source. The drug was found to contain the schedule I synthetic cannabinoid JWH-018. Full stroke workup was unrevealing of a stroke etiology; urine drug screen was positive for marijuana. Conclusions: We found that our 2 patients who smoked the street drug spice had a temporal association with symptoms of acute cerebral infarction. This association may be confounded by contaminants in the product consumed (i.e., marijuana or an unidentified toxin) or by an unknown genetic mechanism. The imaging of both patients suggests an embolic etiology, which is consistent with reports of serious adverse cardiac events with spice use, including tachyarrhythmias and myocardial infarctions.