In this 'double-blind', randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing-remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

This study characterizes factors that are associated with failure to fully adhere with disease modifying injection therapy for MS and underscores the principles associated with optimizing adherence and its implications for effective treatment of the disease process in MS.

Background Cumulative adversity and stress are associated with risk of psychiatric disorders. While basic science studies show repeated and chronic stress effects on prefrontal and limbic neurons, human studies examining cumulative stress and effects on brain morphology are rare. Thus, we assessed whether cumulative adversity is associated with differences in gray matter volume, particularly in regions regulating emotion, self-control, and top-down processing in a community sample. Methods One hundred three healthy community participants, aged 18 to 48 and 68% male, completed interview assessment of cumulative adversity and a structural magnetic resonance imaging protocol. Whole-brain voxel-based-morphometry analysis was performed adjusting for age, gender, and total intracranial volume. Results Cumulative adversity was associated with smaller volume in medial prefrontal cortex (PFC), insular cortex, and subgenual anterior cingulate regions (familywise error corrected, p <.001). Recent stressful life events were associated with smaller volume in two clusters: the medial PFC and the right insula. Life trauma was associated with smaller volume in the medial PFC, anterior cingulate, and subgenual regions. The interaction of greater subjective chronic stress and greater cumulative life events was associated with smaller volume in the orbitofrontal cortex, insula, and anterior and subgenual cingulate regions. Conclusions Current results demonstrate that increasing cumulative exposure to adverse life events is associated with smaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion and reward regulation, and impulse control. These differences found in community participants may serve to mediate vulnerability to depression, addiction, and other stress-related psychopathology.

Objective Alcoholism is associated with gray matter volume deficits in frontal and other brain regions. Whether persistent brain volume deficits in abstinence are predictive of subsequent time to alcohol relapse has not been established. The authors measured gray matter volumes in healthy volunteers and in a sample of treatment-engaged, alcohol-dependent patients after 1 month of abstinence and assessed whether smaller frontal gray matter volume was predictive of subsequent alcohol relapse outcomes. Method Forty-five abstinent alcohol-dependent patients in treatment and 50 healthy comparison subjects were scanned once using high-resolution (T1-weighted) structural MRI, and voxel-based morphometry was used to assess regional brain volume differences between the groups. A prospective study design was used to assess alcohol relapse in the alcohol-dependent group for 90 days after discharge from 6 weeks of inpatient treatment. Results Significantly smaller gray matter volume in alcohol-dependent patients relative to comparison subjects was seen in three regions: the medial frontal cortex, the right lateral prefrontal cortex, and a posterior region surrounding the parietal-occipital sulcus. Smaller medial frontal and parietal-occipital gray matter volumes were each predictive of shorter time to any alcohol use and to heavy drinking relapse. Conclusions These findings are the first to demonstrate that gray matter volume deficits in specific medial frontal and posterior parietal-occipital brain regions are predictive of an earlier return to alcohol use and relapse risk, suggesting a significant role for gray matter atrophy in poor clinical outcomes in alcoholism. Extent of gray matter volume deficits in these regions could serve as useful neural markers of relapse risk and alcoholism treatment outcome.

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266