Yadollah Harati

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.

Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy

Objective: To determine the efficacy of IV immunoglobulin (IVIg) given patients with untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: A randomized, double-blind, multicenter, investigator-initiated study compared IVIg (Aventis Behring LLC, King of Prussia, PA) with placebo (5% albumin). On days 1, 2, and 21, IVIg (1 g/kg) or placebo was given. The primary outcome measure was the change in muscle strength from baseline to day 42, using the average muscle score (AMS). Secondary outcome measures included change from baseline AMS at days 10 and 21, the Hughes’ functional disability scale, forced vital capacity (FVC), and nerve conduction studies (NCS) of four motor nerves (median, ulnar, peroneal, and tibial). Results: The patients (n = 33) were randomized. Of these, 30 (14 women, 16 men, aged 54 ± 20 years, range 13 to 82) received IVIg and 23 were given placebo (12 women, 11 men, aged 50 ± 18 years, range 23 to 73). Baseline AMS values of the groups were similar (IVIg 7.06 ± 1.31 versus placebo 7.28 ± 1.18, p = 0.53). There were two dropouts in placebo group and one in the IVIg group. Mean AMS improved at day 42 comparing IVIg with placebo (0.63 versus −0.1, p = 0.006). Improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIg, 11 subjects improved by the functional disability scale; none worsened. This differed (p = 0.019) from those in the placebo-treated group (two improved, two got worse, remainder unchanged). Forced vital capacity did not improve with IVIg treatment. IVIg improved ulnar motor distal latency (p = 0.005), tibial distal compound muscle amplitude (p = 0.003), and peroneal nerve conduction velocity (p = 0.03). Conclusions: IVIg improves strength in patients with untreated CIDP by day 10 with continued benefit through day 42; more than one third improve by at least a functional grade on a disability scale. This study provides data supporting IVIg as the initial treatment for CIDP.

The Amyotrophic Lateral Sclerosis 8 Protein VAPB Is Cleaved, Secreted, and Acts as a Ligand for Eph Receptors

VAP proteins (human VAPB/ALS8, Drosophila VAP33, and C. elegans VPR-1) are homologous proteins with an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to the Eph receptor and induces oocyte maturation. A point mutation (P56S) in the MSP domain of human VAPB is associated with Amyotrophic lateral sclerosis (ALS), but the mechanisms underlying the pathogenesis are poorly understood. Here we show that the MSP domains of VAP proteins are cleaved and secreted ligands for Eph receptors. The P58S mutation in VAP33 leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. We propose that VAP MSP domains are secreted and act as diffusible hormones for Eph receptors. This work provides insight into mechanisms that may impact the pathogenesis of ALS.

A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis

We found Cop 1 to be effective and relatively safe in a previous (exacerbating-remitting) clinical trial. This current trial involves 106 chronic-progressive patients. The major end point, confirmed progression of 1.0 or 1.5 units (depending on baseline disability) on the Kurtzke Expanded Disability Status Scale, was observed in nine (17.6%) treated and 14 (25.5%) control patients. The differences between the overall survival curves were not significant. Progression rates at 12 and 24 months were higher for the placebo group (p = 0.088) with 2-year probabilities of progressing of 20.4% for Cop 1 and 29.5% for placebo. We found a significant difference at 24 months between placebo and Cop 1 at one but not the other center. Two-year progression rates for two secondary end points, unconfirmed progression, and progression of 0.5 EDSS units, (p = 0.03) are significant.

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.

Current management of ALS: Comparison of the ALS CARE Database and the AAN Practice Parameter

Background: The American Academy of Neurology (AAN) ALS Practice Parameter was published in April 1999. The ALS CARE Database has been collecting data on the management of patients with ALS in North America since 1996. Objective: To compare the management of patients with ALS in North America as recorded in the ALS CARE Database with the recommendations of the AAN ALS Practice Parameter. Methods: Data were analyzed from 2018 patients at enrollment and from 373 of these patients who died between enrollment and May 1999. Results: Eighty-two percent of the enrolled patients reported that they had been given enough information about ALS. Only 54% of patients with drooling were receiving medication for this problem. Only 41% of those who reported being depressed most of the time were receiving antidepressant medications. Only 28% of those with dyspnea and only 9.2% of those with a forced vital capacity <40% predicted were receiving noninvasive positive pressure ventilator support. Only 30% of those with moderate to severe dysphagia had a gastrostomy tube. Half of the patients who died did so at home, but only 47% of them received residential hospice services. Although 89% of patients who died were recorded as having done so peacefully, 17% were reported to have had breathing difficulties (i.e., respiratory distress), 8% anxiety, 3.3% pain, and 2.5% choking. Advance directives were in place for 90% of the patients who died, and in 97% of cases these directives were followed. Conclusions: These findings indicate that in the 3-year period prior to the publication of the AAN Practice Parameter, many but not all patients received the care that is recommended in that parameter; there were deficiencies, particularly in the key areas of gastrostomy and noninvasive positive pressure ventilation.

Mapping local blood flow of human brain by CT scanning during stable xenon inhalation.

Non-invasive methods are described for estimating local cerebral blood flows (LCBF) and partition coefficients (Lλ) during inhalation of 35% stable xenon gas (Xea) in oxygen during CT scanning. After denitrogenatioD by 100% oxygen breathing, 35% Xe5 is breathed for 7-8 minutes to minimize subanestbetic effects. Mean changes in brain Hounsfleld units extrapolated to 15 minutes were 7.7 units for white matter and S3 units for gray matter. They were measured from volumes 80 cubic mm (10 mm2 area X 8 mm), or larger with an EMI 1010 scanner at 1 minute intervals. These data were used for computing LCBFs and Lλs. Irradiation measured at the center of brain slices was 1 rad per minute. To calculate Lλs about 6 exposures are necessary, thereafter, each 1 minute scan provides LCBF measurements for 2 adjacent 8 mm slices. ReproducibUity for LCBF was r = 0.85 (P < 0.001). Mean Lλs were 0.86 ± 0.08 for gray and 134 ± 0.10 for white matter. Normative mean flows (mls/100 g brain/min) were: basal ganglia = 79.6 ± 93, cortex = 82.3 ± 8.5, white matter = 29.2 ± 5.9, mldbrain tegmentum = 943 ± 14.8, cerebellar cortex = 80.1 ± 10.9, dorsal poos = 89.3 ± 4.7, brachium ponds = 35.0 ± 4.2. Subject finger exercises produced increases of LCBF in contralateral pre-central and post-central gyri. Eye closure decreased flow values limited to the visual system. Gray matter flow values diffusely decreased in non-REM sleep but increased above normal in REM sleep. Cerebral infarction and hemorrhage resulted hi zones of zero flow with borders having reduced Xs and low flows attributed to edema. Stroke, Vol 12, No 4, 1981

Diabetic Peripheral Neuropathies

Abstract Diabetic peripheral neuropathies are a group of heterogeneous syndromes with considerable morbidity. At least 50% of diabetic patients develop one or several of these neuropathies within 2...

Diabetic autonomic neuropathy

The incidence of autonomic dysfunction as a complication of diabetes mellitus is reported to be as high as 20% to 40%. Symptoms of diabetic autonomic neuropathy (DAN) are often vague, and signs difficult to detect on routine physical examination. The early diagnosis of DAN is possible by utilizing several simple noninvasive tests, which may also be helpful in localizing the lesion(s) to specific autonomic pathways. DAN may affect multiple organ systems, to include cardiovascular, gastrointestinal, genitourinary and/or neuroendocrine, and may, in fact, be life-threatening. The same metabolic disturbances of somatic peripheral nerve may also be responsible for DAN. Like somatosensory neuropathy, definitive therapy for DAN is not yet satisfactory, although multiple chemotherapeutic agents have been tried and warrant further investigation.

A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS

Abstract Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.