Sharon G. Lynch

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

Factors that influence adherence with disease-modifying therapy in MS

BackgroundThe complexity and cost of injection treatment can represent a formidable challenge for patients affected by a chronic illness, particularly those whose treatment is primarily preventative and only modestly effective on the more conspicuous symptomatic aspects of the disease process. The aim of this investigation was to identify which factors most influenced nonadherent behavior with the available diseasemodifying injection therapies for multiple sclerosis (MS).MethodsA multicenter, observational (threewave) study using surveys was developed and administered to patients with MS through the World Wide Web. Healthcare providers at 17 neurology clinics recruited patients for the study.ResultsA total of 798 patients responded to the baseline wave of the study (708 responded to all three waves). The nonadherence rates for all patients (missing one or more injections) across these waves remained relatively stable at 39 %, 37 %, and 36 %, respectively. The most common reason participants listed for missing injections was that they simply forgot to administer the medication (58 %). Other factors including injection-site reactions, quality of life, patients’ perceptions on the injectable medications, hope, depression, and support were also assessed in relation to adherence.ConclusionsThis 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.

Cognitive impairment in relapsing and primary progressive multiple sclerosis: Mostly a matter of speed

Based on the assumption that cognitive impairment in MS is consistent with subcortical dementia, a battery of neuropsychological tests was assembled that included measures of executive function (Tower of London and Wisconsin Card Sorting Test), verbal learning and memory (a paired associates learning test), and speeded information processing (Stroop Color Word Interference Test). The battery was administered to patients with relapsing and primary progressive MS and to healthy controls. Differences between patients and controls occurred on several of the measures. However, when differences with respect to fatigue and depression were statistically controlled, the only differences that remained significant involved measures relating to the speed of information processing. Patients performed more slowly than controls, with the disparity being greater for relapsing patients than for those with primary progressive disease. The slowing was evident on measures of automatic as well as controlled processing and regardless of whether speed was an explicit feature of successful performance or recorded unobstrusively while the patient concentrated on planning a correct solution to a problem. Parallels were noted between cognitive slowing associated with MS and that of normal aging.

The cognitive performance of patients with multiple sclerosis during periods of high and low fatigue

The objective of this study was to examine whether multiple sclerosis (MS)-related fatigue affects patients’ cognitive performance. Thirty patients who had substantial fatigue in conjunction with MS and who reported marked diurnal variability in the severity of their fatigue were tested on two occasions: during a period of high fatigue and during a period of relatively low fatigue. The order of these sessions was counterbalanced across patients. During both sessions, patients completed a questionnaire concerning their present state of fatigue and a battery of neuropsychological tests of planning, selective attention, and paired associate learning. A lthough patients confirmed greater fatigue during the period of high fatigue and felt they had performed more poorly during this period, there were no differences in cognitive performance that could be attributed to fatigue. Instead, all subjects showed improvement from the first to the second session regardless of whether the latter entailed a period of high or low fatigue. In contrast to studies reporting fatigue-related declines in MS patients’ cognitive performance, no differences in performance were found when MS patients were tested during periods of high versus low fatigue. These contrasting results, stemming from differences in experimental design, are discussed in terms of their implications for assessing cognitive function in patients with MS.

Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients

The concentrations of ferritin, transferrin and iron were measured in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) and control patients. Ferritin levels were significantly elevated in the CSF of chronic progressive active MS patients (4.71+/-0.54 ng/ml) compared to levels in normal individuals (3.07+/-0.17 ng/ml). MS patients with active or stable relapsing-remitting disease had ferritin levels that were comparable to those found in normal individuals. There were no significant differences in transferrin or iron levels in the CSF between MS and normal individuals. Both ferritin and transferrin levels were elevated in patients that had high CSF IgG values but not in patients with a high IgG index. Since ferritin binds iron, the increase of CSF ferritin levels in chronic progressive MS patients could be a defense mechanism to protect against iron induced oxidative injury. Ferritin levels could be a laboratory measure that helps to distinguish between chronic progressive and relapsing-remitting MS.

The association between cognitive impairment and physical disability in multiple sclerosis.

Background: The association between cognitive impairment and physical disability was examined in a larger, more representative sample of patients with multiple sclerosis (MS) than in previous studies. Method: Two hundred and fifty-three patients attending an MS clinic were assessed with respect to physical disability using the Expanded Disability Status Scale and cognitive impairment using a battery of neuropsychological tests. Results: Physical disability correlated with duration of disease; cognitive impairment did not. Virtually all measures derived from the cognitive battery were significantly correlated with physical disability. Three measures of speeded information processing and one involving delayed recall of verbal material were unique predictors of disability status. The relationship between cognitive impairment and physical disability was equivalent for patients with shorter (<3 years) versus longer (>10 years) disease duration. Cognitive impairment correlated with the rate of disability progression as reflected by the progression index. Conclusion: Cognitive impairment is more closely associated with physical disability than most previous studies indicate. This relationship appears to be stable throughout the duration of MS, although this conclusion is qualified by the cross-sectional design of the study. Further attention should be paid to cognitive impairment as a possible predictor of the rate of patients’ physical decline.

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

BACKGROUND Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. METHODS We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. FINDINGS We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. INTERPRETATION Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. FUNDING National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T

Background: Disability levels for patients with secondary progressive multiple sclerosis (SPMS) often worsen despite a stable MRI T2 lesion burden. The presence of oxidative stress in the absence of measurable inflammation could help explain this phenomenon. In this study, the assessment of an in vivo marker of oxidative stress, cerebral glutathione (GSH), using magnetic resonance chemical shift imaging (CSI) is described, and GSH levels were compared in patients with SPMS and healthy controls. Objective: To assess whether GSH, a key antioxidant in the brain, is lower in the SPMS patients compared to matched controls. Methods: Seventeen patients with SPMS (Expanded Disability Status Scale = 4.0–7.0; length of MS diagnosis = 19.4 ± 7 years) and 17 age- and gender-matched healthy controls were studied. GSH levels were measured in the fronto-parietal regions of the brain using a specially designed magnetic resonance spectroscopy technique, CSI of GSH, at 3T. Results: The levels of GSH were lower for SPMS patients than for controls, the largest reduction (18.5%) being in the frontal region (p = 0.001). Conclusion: The lower GSH levels in these patients indicate the presence of oxidative stress in SPMS. This process could be at least partially responsible for ongoing functional decline in SPMS.

Objective adherence monitoring in multiple sclerosis: initial validation and association with self-report

Poor adherence to medication is commonplace and contributes to poor health outcomes among numerous patient populations. Studies that have examined treatment adherence in multiple sclerosis focus exclusively on retrospective self-reports and/or imprecise measures of treatment discontinuation. To help address these methodological limitations, the present longitudinal study compared adherence outcomes for patients with multiple sclerosis using retrospective self-reports, adherence diaries, and a novel electronic monitoring device. Sixty-seven patients with relapsing—remitting multiple sclerosis were followed for a period of eight weeks during which they used a medication diary and a sharps container that captured electronically the time and date of each needle disposal. The patients also reported at the outset and conclusion of the study how frequently they missed doses. All measures of adherence were highly correlated. Patients reported better adherence than was indicated by medication diaries and electronic monitoring of needle disposals. Nearly one-fifth of the sample exhibited poor adherence, missing more than 20% of their prescribed medication. The results support the validity of electronic monitoring of needle disposal as an effective means of measuring adherence to disease modifying therapies in multiple sclerosis. In contrast, studies employing only self-report may underestimate poor adherence. Larger scale studies that employ prospective objective methods are necessary to gain a better understanding of adherence patterns in multiple sclerosis.

The PROMiSe trial: baseline data review and progress report

The PRO MiSe trial is a multinational, multicentre, double-blind, placebo -controlled trial evaluating the effects of glatiramer acetate treatment over 3 years in patients with primary progressive multiple sclerosis (PPMS). A total of 943 patients were enrolled, and all those remaining on-study had completed at least 24 months as of O ctober 2002. Baseline clinical and MRI character istics and select correlations are reported here. A total of 3.9% of patients exhibited confirmed relapse over 1904 patient-years of exposure, indicating success of efforts to exclude relapsing MS types. O f the 26.3% of patients who have prematurely withdrawn from the study, only 36% discontinued after meeting the study primary endpoint of disease progression. The progression rate in patients in the low Expanded Disability Status Scale (EDSS) stratum (3.0-5.0) observed thus far is markedly lower than the 50% annual progression rate estimate used for determining size and statistical power of the trial; progression was observed in 16.1% of patients with 12 months of study exposure. These early findings raise some concern about the ability of the trial to demonstrate a significant treatment effect, and suggest that the short-term natural history of PPMS may not be as aggressive as previously assumed.