The Effect of Disease Modifying Therapies on Brain Atrophy in Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis

Background

The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMD) on brain atrophy in patients with relapsing-remitting multiple sclerosis (RRMS) using available randomized-controlled trial (RCT) data.

Methods

We conducted a systematic review and meta-analysis according to PRISMA guidelines of all available RCTs of patients with RRMS that reported data on brain volume measurements during the study period.

Results

We identified 4 eligible studies, including a total of 1819 RRMS patients (71% women, mean age 36.5 years, mean baseline EDSS-score: 2.4). The mean percentage change in brain volume was found to be significantly lower in DMD versus placebo subgroup (standardized mean difference: -0.19; 95%CI: -0.27–-0.11; p<0.001). We detected no evidence of heterogeneity between estimates (I² = 30%, p = 0.19) nor publication bias in the Funnel plots. Sensitivity analyses stratifying studies according to brain atrophy neuroimaging protocol disclosed no evidence of heterogeneity (p = 0.16). In meta-regression analyses, the percentage change in brain volume was found to be inversely related with duration of observation period in both DMD (meta-regression slope = -0.03; 95% CI: -0.04–-0.02; p<0.001) and placebo subgroups (meta-regression slope = -0.05; 95% CI: -0.06–-0.04; p<0.001). However, the rate of percentage brain volume loss over time was greater in placebo than in DMD subgroup (p = 0.017, ANCOVA).

Conclusions

DMD appear to be effective in attenuating brain atrophy in comparison to placebo and their benefit in delaying the rate of brain volume loss increases linearly with longer treatment duration.     

The Effect of Disease Modifying Therapies on Disease Progression in Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis

Importance

A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS

Methods

We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate in each subgroup and the overall estimates.

Results

DMDs for RRMS were found to have a significantly lower risk of disability progression compared to placebo (RR = 0.72, 95%CI: 0.66–0.79; p<0.001), with no evidence of heterogeneity or publication bias. In subsequent subgroup analyses, neither dichotomization of DMDs as “first” and “second” line RRMS therapies [(RR = 0.72, 95% CI = 0.65–0.80) vs. (RR = 0.72, 95% = 0.57–0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64–0.87) vs. RR = 0.74 (95% CI = 0.66–0.83); p = 0.92] had a differential effect on the risk of disability progression. Either considerable (5–20%) or significant (>20%) rates of loss to follow-up were reported in many study protocols, while financial and/or other support from pharmaceutical industries with a clear conflict of interest on the study outcomes was documented in all included studies.

Conclusions

Available DMD are effective in reducing disability progression in patients with RRMS, independently of the route of administration and their classification as “first” or “second” line therapies. Attrition bias needs to be taken into account in the interpretation of these findings.     

Regional Distribution and Evolution of Gray Matter Damage in Different Populations of Multiple Sclerosis Patients

Background

Both gray-matter (GM) atrophy and lesions occur from the earliest stages of Multiple Sclerosis (MS) and are one of the major determinants of long-term clinical outcomes. Nevertheless, the relationship between focal and diffuse GM damage has not been clarified yet. Here we investigate the regional distribution and temporal evolution of cortical thinning and how it is influenced by the local appearance of new GM lesions at different stages of the disease in different populations of MS patients.

Methods

We studied twenty MS patients with clinically isolated syndrome (CIS), 27 with early relapsing-remitting MS (RRMS, disease duration <5 years), 29 with late RRMS (disease duration ≥ 5 years) and 20 with secondary-progressive MS (SPMS). The distribution and evolution of regional cortical thickness and GM lesions were assessed during 5-year follow-up.

Results

The results showed that new lesions appeared more frequently in hippocampus and parahippocampal gyri (9.1%), insula (8.9%), cingulate cortex (8.3%), superior frontal gyrus (8.1%), and cerebellum (6.5%). The aforementioned regions showed the greatest reduction in thickness/volume, although (several) differences were observed across subgroups. The correlation between the appearance of new cortical lesions and cortical thinning was stronger in CIS (r² = 50.0, p<0.001) and in early RRMS (r² = 52.3, p<0.001), compared to late RRMS (r² = 25.5, p<0.001) and SPMS (r² = 6.3, p = 0.133).

Conclusions

We conclude that GM atrophy and lesions appear to be different signatures of cortical disease in MS having in common overlapping spatio-temporal distribution patterns. However, the correlation between focal and diffuse damage is only moderate and more evident in the early phase of the disease.     

A Randomized,Double-Blind,Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes

Context

Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.

Objective

To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.

Hypothesis

Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.

Design, Setting, and Participants

A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage.

Results

Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups.

Conclusions

This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.

Trial Registration

ClinicalTrial.gov NCT01334125     

Coenzyme Q10 Levels Are Decreased in the Cerebellum of Multiple-System Atrophy Patients

Background

The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases.

Methods

Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson''s disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography.

Results

We detected a statistically significant decrease (by 3–5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson''s disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)].

Conclusion

Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated.     

CROP – The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are Patterns of Retinal and MRI Changes Heterogeneous and Thus Not Predictable?

Background

To date, no direct scientific evidence has been found linking tissue changes in multiple sclerosis (MS) patients, such as demyelination, axonal destruction or gliosis, with either steady progression and/or stepwise accumulation of focal CNS lesions. Tissue changes such as reduction of the retinal nerve fiber layer (RNFL) and the total macular volume (TMV), or brain- and spinal cord atrophy indicates an irreversible stage of tissue destruction. Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial. The objective of our study was to determine, whether there was any correlation between the RNFL or TMV of patients with MS, and: (1) the lesion load along the visual pathways, (2) the ratios and absolute concentrations of metabolites in the normal-appearing white matter (NAWM), (3) standard brain atrophy indices, (4) disease activity or (5) disease duration.

Methods

28 MS patients (RRMS, n = 23; secondary progressive MS (SPMS), n = 5) with moderately-high disease activity or long disease course were included in the study. We utilised: (1) magnetic resonance imaging (MRI) and (2) -spectroscopy (MRS), both operating at 3 Tesla, and (3) high-resolution spectral domain-OCT with locked reference images and eye tracking mode) to undertake the study.

Results

There was no consistency in the pattern of CNS metabolites, brain atrophy indices and the RNFL/TMV between individuals, which ranged from normal to markedly-reduced levels. Furthermore, there was no strict correlation between CNS metabolites, lesions along the visual pathways, atrophy indices, RNFL, TMV, disease duration or disability.

Conclusions

Based on the findings of this study, we recommend that the concept of ‘clinico-radiologico paradox’ in multiple sclerosis be extended to CROP–‘clinico-radiologico-ophthalmological paradox’. Furthermore, OCT data of MS patients should be interpreted with caution.     

Epinephrine Improves the Efficacy of Nebulized Hypertonic Saline in Moderate Bronchiolitis: A Randomised Clinical Trial

Background and Aims

There is no evidence that the epinephrine-3% hypertonic saline combination is more effective than 3% hypertonic saline alone for treating infants hospitalized with acute bronchiolitis. We evaluated the efficacy of nebulized epinephrine in 3% hypertonic saline.

Patients and Methods

We performed a randomized, double-blind, placebo-controlled clinical trial in 208 infants hospitalized with acute moderate bronchiolitis. Infants were randomly assigned to receive nebulized 3% hypertonic saline with either 3 mL of epinephrine or 3 mL of placebo, administered every four hours. The primary outcome measure was the length of hospital stay.

Results

A total of 185 infants were analyzed: 94 in the epinephrine plus 3% hypertonic saline group and 91 in the placebo plus 3% hypertonic saline group. Baseline demographic and clinical characteristics were similar in both groups. Length of hospital stay was significantly reduced in the epinephrine group as compared with the placebo group (3.94 ±1.88 days vs. 4.82 ±2.30 days, P = 0.011). Disease severity also decreased significantly earlier in the epinephrine group (P = 0.029 and P = 0.036 on days 3 and 5, respectively).

Conclusions

In our setting, nebulized epinephrine in 3% hypertonic saline significantly shortens hospital stay in hospitalized infants with acute moderate bronchiolitis compared to 3% hypertonic saline alone, and improves the clinical scores of severity from the third day of treatment, but not before.

Trial Registration

EudraCT 2009-016042-57     

Intra-Articular Corticosteroids in Addition to Exercise for Reducing Pain Sensitivity in Knee Osteoarthritis: Exploratory Outcome from a Randomized Controlled Trial

Objective

To assess the effects of one intra-articular corticosteroid injection two weeks prior to an exercise-based intervention program for reducing pain sensitivity in patients with knee osteoarthritis (OA).

Design

Randomized, masked, parallel, placebo-controlled trial involving 100 participants with clinical and radiographic knee OA that were randomized to one intra-articular injection on the knee with either 1 ml of 40 mg/ml methylprednisolone (corticosteroid) dissolved in 4 ml lidocaine (10 mg/ml) or 1 ml isotonic saline (placebo) mixed with 4 ml lidocaine (10 mg/ml). Two weeks after the injections all participants undertook a 12-week supervised exercise program. Main outcomes were changes from baseline in pressure-pain sensitivity (pressure-pain threshold [PPT] and temporal summation [TS]) assessed using cuff pressure algometry on the calf. These were exploratory outcomes from a randomized controlled trial.

Results

A total of 100 patients were randomized to receive either corticosteroid (n = 50) or placebo (n = 50); 45 and 44, respectively, completed the trial. Four participants had missing values for PPT and one for TS at baseline; thus modified intention-to-treat populations were analyzed. The mean group difference in changes from baseline at week 14 was 0.6 kPa (95% CI: -1.7 to 2.8; P = 0.626) for PPT and 384 mm×sec (95% CI: -2980 to 3750; P = 0.821) for TS.

Conclusions

These results suggest that adding intra-articular corticosteroid injection 2 weeks prior to an exercise program does not provide additional benefits compared to placebo in reducing pain sensitivity in patients with knee OA.

Trial Registration

EU clinical trials (EudraCT): 2012-002607-18     

Intrinsic Functional Plasticity of the Sensorimotor Network in Relapsing-Remitting Multiple Sclerosis: Evidence from a Centrality Analysis

Background and Purpose

Advanced MRI studies have revealed regional alterations in the sensorimotor cortex of patients with relapsing-remitting multiple sclerosis (RRMS). However, the organizational features underlying the relapsing phase and the subsequent remitting phase have not been directly shown at the functional network or the connectome level. Therefore, this study aimed to characterize MS-related centrality disturbances of the sensorimotor network (SMN) and to assess network integrity and connectedness.

Methods

Thirty-four patients with clinically definite RRMS and well-matched healthy controls participated in the study. Twenty-three patients in the remitting phase underwent one resting-state functional MRI, and 11 patients in the relapsing-remitting phase underwent two different MRIs. We measured voxel-wise centrality metrics to determine direct (degree centrality, DC) and global (eigenvector centrality, EC) functional relationships across the entire SMN.

Results

In the relapsing phase, DC was significantly decreased in the bilateral primary motor and somatosensory cortex (M1/S1), left dorsal premotor (PMd), and operculum-integrated regions. However, DC was increased in the peripheral SMN areas. The decrease in DC in the bilateral M1/S1 was associated with the expanded disability status scale (EDSS) and total white matter lesion loads (TWMLLs), suggesting that this adaptive response is related to the extent of brain damage in the rapid-onset attack stage. During the remission process, these alterations in centrality were restored in the bilateral M1/S1 and peripheral SMN areas. In the remitting phase, DC was reduced in the premotor, supplementary motor, and operculum-integrated regions, reflecting an adaptive response due to brain atrophy. However, DC was enhanced in the right M1 and left parietal-integrated regions, indicating chronic reorganization. In both the relapsing and remitting phases, the changes in EC and DC were similar.

Conclusions

The alterations in centrality within the SMN indicate rapid plasticity and chronic reorganization with a biased impairment of specific functional areas in RRMS patients.     

Prenatal Docosahexaenoic Acid Supplementation and Offspring Development at 18 Months: Randomized Controlled Trial

Objective

We evaluated the effects of prenatal docosahexaenoic acid (DHA) supplementation on offspring development at 18 months of age.

Design

Randomized placebo double-blind controlled trial.

Settings

Cuernavaca, Mexico.

Participants and Methods

We followed up offspring (n = 730; 75% of the birth cohort) of women in Mexico who participated in a trial of DHA supplementation during the latter half of pregnancy. We assessed the effect of the intervention on child development and the potential modifying effects of gravidity, gender, SES, and quality of the home environment.

Interventions or Main Exposures

400 mg/day of algal DHA.

Outcome Measures

Child development at 18 months of age measured using the Spanish version of the Bayley Scales of Infant Development-II. We calculated standardized psychomotor and mental development indices, and behavior rating scale scores.

Results

Intent-to-treat differences (DHA-control) were: Psychomotor Developmental Index -0.90 (95% CI: -2.35, 0.56), Mental Developmental Index -0.26 (95% CI: -1.63, 1.10) and Behavior Rating Scale -0.01 (95% CI: -0.95, 0.94). Prenatal DHA intake attenuated the positive association between home environment and psychomotor development index observed in the control group (p for interaction = 0.03) suggesting potential benefits for children living in home environments characterized by reduced caregiver interactions and opportunities for early childhood stimulation.

Conclusions

Prenatal DHA supplementation in a population with low intakes of DHA had no effects on offspring development at 18 months of age although there may be some benefit for infants from poor quality home environments.

Trial Registration

Clinicaltrials.gov NCT00646360     

Resveratrol Does Not Influence Metabolic Risk Markers Related to Cardiovascular Health in Overweight and Slightly Obese Subjects: A Randomized,Placebo-Controlled Crossover Trial

Background

In vitro and animal studies have shown positive effects of resveratrol on lipid and lipoprotein metabolism, but human studies specifically designed to examine these effects are lacking.

Objective

The primary outcome parameter of this study in overweight and slightly obese subjects was the effect of resveratrol on apoA-I concentrations. Secondary outcome parameters were effects on other markers of lipid and lipoprotein metabolism, glucose metabolism, and markers for inflammation and endothelial function.

Design

This randomized, placebo-controlled crossover study was conducted in 45 overweight and slightly obese men (n = 25) and women (n = 20) with a mean age of 61 ± 7 years. Subjects received in random order resveratrol (150 mg per day) or placebo capsules for 4 weeks, separated by a 4-week wash-out period. Fasting blood samples were collected at baseline and at the end of each intervention period.

Results

Compliance was excellent as indicated by capsule count and changes in resveratrol and dihydroresveratrol concentrations. No difference between resveratrol and placebo was found in any of the fasting serum or plasma metabolic risk markers (mean ± SD for differences between day 28 values of resveratrol vs. placebo: apoA-I; 0.00 ± 0.12 g/L (P = 0.791), apoB100; -0.01 ± 0.11 g/L (P = 0.545), HDL cholesterol; 0.00 ± 0.09 mmol/L (P = 0.721), LDL cholesterol -0.03 ± 0.57 mmol/L (P = 0.718), triacylglycerol; 0.10 ± 0.54 mmol/L (P = 0.687), glucose; -0.08 ± 0.28 mmol/L (P = 0.064), insulin; -0.3 ± 2.5 mU/L (P = 0.516)). Also, no effects on plasma markers for inflammation and endothelial function were observed. No adverse events related to resveratrol intake were observed.

Conclusion

150 mg of daily resveratrol intake for 4 weeks does not change metabolic risk markers related to cardiovascular health in overweight and slightly obese men and women. Effects on glucose metabolism warrant further study.

Trial Registration

ClinicalTrials.gov NCT01364961     

Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective

Acetyl-L-carnitine (ALC), a constructive molecule in fatty acid metabolism, is an agent potentially effective for treating peripheral neuropathic pain (PNP). Its effect, however, remains uncertain. We aimed to access the efficacy and safety of ALC for the treatment of patients with PNP.

Methods

We searched MEDLINE (1996–2014), EMBase (1974–2014), and CENTRAL (May 2014) up to June 27, 2014 for randomized controlled trials (RCTs) comparing ALC with placebo or other active medications in diabetic and non-diabetic PNP patients that reported the change of pain using visual analogue scale (VAS). Mean difference (MD) and 95% confidence interval (CI) were used for pooling continuous data.

Results

Four RCTs comparing ALC with placebo and reporting in three articles (n = 523) were included. Compared with placebo, ALC significantly reduced VAS scores of PNP patients (MD of VAS, 1.20; 95% CI, 0.68-1.72, P <0.00001). In the subgroup analysis, the effect of ALC on VAS was similar in different administration routes (intramuscular-oral sequential subgroup: MD, 1.19; 95% CI, 0.34-2.04, P = 0.006; oral only subgroup: pooled MD, 1.15; 95%CI, 0.33-1.96, P = 0.006), and ALC appeared more effective in diabetic PNP patients than non-diabetic PNP patients (diabetic subgroup: MD, 1.47; 95%CI, 1.06-1.87, P <0.00001; non-diabetic subgroup: MD, 0.71; 95% CI, -0.01-1.43, P = 0.05). No severe adverse events were reported related to ALC. The common adverse events were pain, headache, paraesthesia, hyperesthesia, retching, biliary colic, and gastrointestinal disorders. The rates of total adverse events were similar in ALC and control group.

Conclusion

The current evidence suggests that ALC has a moderate effect in reducing pain measured on VAS in PNP patients with acceptable safety. Larger trials with longer follow-up, however, are warranted to establish the effects.     

Risk Knowledge in Relapsing Multiple Sclerosis (RIKNO 1.0) - Development of an Outcome Instrument for Educational Interventions

Background

Adequate risk knowledge of patients is a prerequisite for shared decision making but few attempts have been made to develop assessment tools. Multiple Sclerosis (MS) is a chronic inflammatory disease of young adults with an increasing number of partially effective immunotherapies and therefore a paradigmatic disease to study patient involvement.

Objective/methods

Based on an item bank of MS risk knowledge items and patient feedback including perceived relevance we developed a risk knowledge questionnaire for relapsing remitting (RR) MS (RIKNO 1.0) which was a primary outcome measure in a patient education trial (192 early RRMS patients).

Results

Fourteen of the RIKNO 1.0 multiple-choice items were selected based on patient perceived relevance and item difficulty indices, and five on expert opinion. Mean item difficulty was 0.58, ranging from 0.14 to 0.79. Mean RIKNO 1.0 score increased after the educational intervention from 10.6 to 12.4 (p = 0.0003). Selected items were particularly difficult (e.g. those on absolute risk reductions of having a second relapse) and were answered correctly in only 30% of the patients, even after the intervention.

Conclusion

Despite its high difficulty, RIKNO 1.0 is a responsive instrument to assess risk knowledge in RRMS patients participating in educational interventions.     

Abdominal Obesity and Brain Atrophy in Type 2 Diabetes Mellitus

Aim

Type 2 diabetes mellitus (T2D) is associated with gray matter atrophy. Adiposity and physical inactivity are risk factors for T2D and brain atrophy. We studied whether the associations of T2D with total gray matter volume (GMV) and hippocampal volume (HV) are dependent on obesity and physical activity.

Materials and Methods

In this cross-sectional study, we measured waist-hip ratio (WHR), body mass index (BMI), mean steps/day and brain volumes in a community dwelling cohort of people with and without T2D. Using multivariable linear regression, we examined whether WHR, BMI and physical activity mediated or modified the association between T2D, GMV and HV.

Results

There were 258 participants with (mean age 67±7 years) and 302 without (mean age 72±7 years) T2D. Adjusting for age, sex and intracranial volume, T2D was independently associated with lower total GMV (p = 0.001) and HV (p<0.001), greater WHR (p<0.001) and BMI (p<0.001), and lower mean steps/day (p = 0.002). After adjusting for covariates, the inclusion of BMI and mean steps/day did not significantly affect the T2D-GMV association, but WHR attenuated it by 32% while remaining independently associated with lower GMV (p<0.01). The T2D-HV association was minimally changed by the addition of BMI, steps/day or WHR in the model. No statistical interactions were observed between T2D and measures of obesity and physical activity in explaining brain volumes.

Conclusions

Abdominal obesity or its downstream effects may partially mediate the adverse effect of T2D on brain atrophy. This requires confirmation in longitudinal studies.     

Morphological Brain Changes after Climbing to Extreme Altitudes—A Prospective Cohort Study

Background

Findings of cerebral cortical atrophy, white matter lesions and microhemorrhages have been reported in high-altitude climbers. The aim of this study was to evaluate structural cerebral changes in a large cohort of climbers after an ascent to extreme altitudes and to correlate these findings with the severity of hypoxia and neurological signs during the climb.

Methods

Magnetic resonance imaging (MRI) studies were performed in 38 mountaineers before and after participating in a high altitude (7126m) climbing expedition. The imaging studies were assessed for occurrence of new WM hyperintensities and microhemorrhages. Changes of partial volume estimates of cerebrospinal fluid, grey matter, and white matter were evaluated by voxel-based morphometry. Arterial oxygen saturation and acute mountain sickness scores were recorded daily during the climb.

Results

On post-expedition imaging no new white matter hyperintensities were observed. Compared to baseline testing, we observed a significant cerebrospinal fluid fraction increase (0.34% [95% CI 0.10–0.58], p = 0.006) and a white matter fraction reduction (-0.18% [95% CI -0.32–-0.04], p = 0.012), whereas the grey matter fraction remained stable (0.16% [95% CI -0.46–0.13], p = 0.278). Post-expedition imaging revealed new microhemorrhages in 3 of 15 climbers reaching an altitude of over 7000m. Affected climbers had significantly lower oxygen saturation values but not higher acute mountain sickness scores than climbers without microhemorrhages.

Conclusions

A single sojourn to extreme altitudes is not associated with development of focal white matter hyperintensities and grey matter atrophy but leads to a decrease in brain white matter fraction. Microhemorrhages indicative of substantial blood-brain barrier disruption occur in a significant number of climbers attaining extreme altitudes.     

Effect of DA-9701 on Gastric Motor Function Assessed by Magnetic Resonance Imaging in Healthy Volunteers: A Randomized,Double-Blind,Placebo-Controlled Trial

Background

Improving gastric accommodation and gastric emptying is an attractive physiological treatment target in patients with functional dyspepsia (FD). We evaluated the effect of DA-9701, a new drug for FD, on gastric motor function after a meal in healthy volunteers using magnetic resonance imaging (MRI).

Methods

Forty healthy volunteers were randomly allocated to receive either DA-9701 or placebo. After 5 days of treatment, subjects underwent gastric MRI (60 min before and 15, 30, 45, 60, 90, and 120 min after a liquid test meal). Gastric volume was measured through 3-dimensional reconstruction from MRI data. We analyzed 4 outcome variables including changes in total gastric volume (TGV), proximal TGV, and proximal to distal TGV ratio after a meal and gastric emptying rates after adjusting values at the pre-test meal.

Results

Changes in TGV and proximal TGV after a meal did not differ between the DA-9701 and placebo groups (difference between groups -25.9 mL, 95% confidence interval [CI] -54.0 to 2.3 mL, P = 0.070 and -2.9 mL, 95% CI -30.3 to 24.5 mL, P = 0.832, respectively). However, pre-treatment with DA-9701 increased postprandial proximal to distal TGV ratio more than placebo (difference between groups 0.93, 95% CI 0.08 to 1.79, P = 0.034). In addition, pre-treatment with DA-9701 significantly increased gastric emptying as compared with placebo (mean difference between groups 3.41%, 95% CI 0.54% to 6.29%, P = 0.021, by mixed model for repeated measures).

Conclusion

Our results suggested that DA-9701 enhances gastric emptying and does not significantly affect gastric accommodation in healthy volunteers. Further studies to confirm whether DA-9701 enhances these gastric motor functions in patients with FD are warranted.

Trial Registration

ClinicalTrials.gov NCT02091635     

The Effect of Paracetamol on Core Body Temperature in Acute Traumatic Brain Injury: A Randomised,Controlled Clinical Trial

Background

Strategies to prevent pyrexia in patients with acute neurological injury may reduce secondary neuronal damage. The aim of this study was to determine the safety and efficacy of the routine administration of 6 grams/day of intravenous paracetamol in reducing body temperature following severe traumatic brain injury, compared to placebo.

Methods

A multicentre, randomised, blind, placebo-controlled clinical trial in adult patients with traumatic brain injury (TBI). Patients were randomised to receive an intravenous infusion of either 1g of paracetamol or 0.9% sodium chloride (saline) every 4 hours for 72 hours. The primary outcome was the mean difference in core temperature during the study intervention period.

Results

Forty-one patients were included in this study: 21 were allocated to paracetamol and 20 to saline. The median (interquartile range) number of doses of study drug was 18 (17–18) in the paracetamol group and 18 (16–18) in the saline group (P = 0.85). From randomisation until 4 hours after the last dose of study treatment, there were 2798 temperature measurements (median 73 [67–76] per patient). The mean ± standard deviation temperature was 37.4±0.5°C in the paracetamol group and 37.7±0.4°C in the saline group (absolute difference -0.3°C; 95% confidence interval -0.6 to 0.0; P = 0.09). There were no significant differences in the use of physical cooling, or episodes of hypotension or hepatic abnormalities, between the two groups.

Conclusion

The routine administration of 6g/day of intravenous paracetamol did not significantly reduce core body temperature in patients with TBI.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12609000444280     

Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

Background

An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins.

Objective

To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159).

Methods and Findings

Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B₆ and B₁₂ in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B₁₂ (0.5 mg/d) and vitamin B₆ (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.

Results

A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.

Conclusions and Significance

The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer''s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer''s disease, trials are needed to see if the same treatment will delay the development of Alzheimer''s disease.

Trial Registration

Controlled-Trials.com ISRCTN94410159     

Adolescent Pregnancy and Attained Height among Black South African Girls: Matched-Pair Prospective Study

Importance

The impact of adolescent pregnancy on offspring birth outcomes has been widely studied, but less is known about its impact on the growth of the young mother herself.

Objective

To determine the association between adolescent pregnancy and attained height.

Design

Prospective birth cohort study.

Setting

Cohort members followed from birth to age 20 y in Soweto, South Africa.

Participant

From among 840 Black females with sufficient data, we identified 54 matched pairs, in which a girl who became pregnant before the age of 17 years was matched with a girl who did not have a pregnancy by age 20 y. Pairs were matched on age at menarche and height-for-age z scores in the year before the case became pregnant (mean 15.0 y).

Main Outcome Measures

The two groups were compared with respect to attained height, measured at mean age 18.5 y.

Results

Mean age at conception was 15.9 years (range: 13.7 to 16.9 y). Mean height at matching was 159.4 cm in the adolescent pregnancy group and 159.3 cm in the comparison group (p = 0.3). Mean attained height was 160.4 cm in the adolescent pregnancy group and 160.3 cm in the comparison group (p = 0.7).

Conclusions

Among Black females in Soweto, South Africa, adolescent pregnancy was not associated with attained height.     

Fingolimod Prevents Blood-Brain Barrier Disruption Induced by the Sera from Patients with Multiple Sclerosis

Objective

Effect of fingolimod in multiple sclerosis (MS) is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB). However, brain microvascular endothelial cells (BMECs) represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera.

Methods

Changes in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER) in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR) MS, stable phase of RRMS and secondary progressive MS (SPMS), on the function of BBB in the presence of fingolimod-phosphate were assessed.

Results

Incubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera.

Conclusions

Pretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients.