Background
Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system. Although the exact pathogenesis remains unknown, the leading theory is that it results from immune ...system dysregulation. Approved disease‐modifying therapy appears to modulate the immune system to improve MS‐related outcomes. There is substantial interest in the ability of dietary interventions to influence MS‐related outcomes. This is an update of the Cochrane Review 'Dietary interventions for multiple sclerosis' (Farinotti 2003; Farinotti 2007; Farinotti 2012).
Objectives
To assess the effects of dietary interventions (including dietary plans with recommendations for specific whole foods, macronutrients, and natural health products) compared to placebo or another intervention on health outcomes (including MS‐related outcomes and serious adverse events) in people with MS.
Search methods
On 30 May 2019, we searched CENTRAL, MEDLINE, Embase, and Web of Science. We also searched ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (ICTRP), and Networked Digital Library of Theses and Dissertations (NDLTD). We checked reference lists in identified trials and requested information from trial authors to identify any additional published or unpublished data.
Selection criteria
We included any randomized controlled trial (RCT) or controlled clinical trial (CCT) examining the effect of a dietary intervention versus placebo or another intervention among participants with MS on MS‐related outcomes, including relapses, disability progression, and magnetic resonance imaging (MRI) measures.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. Planned primary outcomes were number of participants experiencing relapse and change in disability progression, according to a validated disability scale at the last reported follow‐up. Secondary outcomes included MRI activity, safety, and patient‐reported outcomes. We entered and analysed data in Review Manager 5.
Main results
We found 41 full‐text articles examining 30 trials following full‐text review. Participants were adults with MS, defined by established criteria, presenting to MS clinics in Europe, North America, and the Middle East. Study design varied considerably, although all trials had at least one methodological issue leading to unknown or high risk of bias. Trials examined: supplementation to increase polyunsaturated fatty acids (PUFAs) (11 trials); a variety of antioxidant supplements (10 trials); dietary programmes (3 trials); and other dietary supplements (e.g. acetyl L‐carnitine, biotin, creatine, palmitoylethanolamide, probiotic, riboflavin) (6 trials).
In three trials comparing PUFAs with monounsaturated fatty acids (MUFAs), the evidence was very uncertain concerning difference in relapses (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.20; 3 studies, 217 participants; 75% in the PUFA group versus 74% in the MUFA group; very low‐certainty evidence). Among four trials comparing PUFAs with MUFAs, there may be little to no difference in global impression of deterioration (RR 0.85, 95% CI 0.71 to 1.03; 4 studies, 542 participants; 40% in the PUFA group versus 47% in the MUFA group; low‐certainty evidence). In two trials comparing PUFAs with MUFAs (102 participants), there was very low‐certainty evidence for change in disability progression. None of the PUFA versus MUFA trials examined MRI outcomes. In one trial comparing PUFAs with MUFAs (40 participants), there were no serious adverse events; based on low‐certainty evidence.
In two trials comparing different PUFAs (omega‐3 versus omega‐6), there may be little to no difference in relapses (RR 1.02, 95% CI 0.62 to 1.66; 2 studies, 129 participants; 30% in the omega‐3 versus 29% in the omega‐6 group; low‐certainty evidence). Among three trials comparing omega‐3 with omega‐6, there may be little to no difference in change in disability progression, measured as mean change in Expanded Disability Status Scale (EDSS) (mean difference (MD) 0.00, 95% CI ‐0.30 to 0.30; 3 studies, 166 participants; low‐certainty evidence). In one trial comparing omega‐3 with omega‐6, there was likely no difference in global impression of deterioration (RR 0.99, 95% CI 0.51 to 1.91; 1 study, 86 participants; 29% in omega‐3 versus 29% in omega‐6 group; moderate‐certainty evidence). In one trial comparing omega‐3 with omega‐6 (86 participants), there was likely no difference in number of new T1‐ weighted gadolinium‐enhancing lesions, based on moderate‐certainty evidence. In four trials comparing omega‐3 with omega‐6, there may be little to no difference in serious adverse events (RR 1.12, 95% CI 0.38 to 3.31; 4 studies, 230 participants; 6% in omega‐3 versus 5% in omega‐6 group; low‐certainty evidence).
In four trials examining antioxidant supplementation with placebo, there may be little to no difference in relapses (RR 0.98, 95% CI 0.59 to 1.64; 4 studies, 345 participants; 17% in the antioxidant group versus 17% in the placebo group; low‐certainty evidence). In six trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning change in disability progression, measured as mean change of EDSS (MD ‐0.19, 95% CI ‐0.49 to 0.11; 6 studies, 490 participants; very low‐certainty evidence). In two trials examining antioxidant supplementation with placebo, there may be little to no difference in global impression of deterioration (RR 0.99, 95% 0.50 to 1.93; 2 studies, 190 participants; 15% in the antioxidant group versus 15% in the placebo group; low‐certainty evidence). In two trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning difference in gadolinium‐enhancing lesions (RR 0.67, 95% CI 0.09 to 4.88; 2 studies, 131 participants; 11% in the antioxidant group versus 16% in the placebo group; very low‐certainty evidence). In three trials examining antioxidant supplementation versus placebo, there may be little to no difference in serious adverse events (RR. 0.72, 95% CI 0.17 to 3.08; 3 studies, 222 participants; 3% in the antioxidant group versus 4% in the placebo group; low‐certainty evidence).
Authors' conclusions
There are a variety of controlled trials addressing the effects of dietary interventions for MS with substantial variation in active treatment, comparator, and outcomes of interest. PUFA administration may not differ when compared to alternatives with regards to relapse rate, disability worsening, or overall clinical status in people with MS, but evidence is uncertain. Similarly, at present, there is insufficient evidence to determine whether supplementation with antioxidants or other dietary interventions have any impact on MS‐related outcomes.
“No evident disease activity” (NEDA) is a proposed measure of disease activity-free status in multiple sclerosis (MS) that is typically defined as absence of relapses, disability progression, and MRI ...activity over a defined time period. NEDA is increasingly reported in randomized controlled trials of MS disease modifying therapies where it has some perceived advantages over outcomes such as annualized relapse rate. NEDA has also been proposed as a treatment goal in clinical care. At this point, the long-term implications of early NEDA remain largely unknown. We review current NEDA definitions, use in clinical trials, and its prospects for routine use as an actionable treatment target in clinical practice.
•NEDA-3 is defined as no relapses, disability progression, or MRI activity.•NEDA-4 also includes brain atrophy assessment as a marker of neurodegeneration.•NEDA is a potential sensitive outcome measure for therapeutic efficacy in clinical trials.•Early NEDA may not protect against long-term disability progression.•Observational studies will help determine whether NEDA has clinical merit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We describe the neuroradiologic features of a cohort of patients with Erdheim-Chester disease.
We assessed patients at Mayo Clinic Rochester between January 1, 1990, and July 31, 2016, with ...pathologically confirmed Erdheim-Chester disease (n = 53).
Neuroimaging, including head CT (n = 17), brain MRI (n = 39), orbital MRI (n = 15), and spine MRI (n = 16), was available for 42 participants. Median age at diagnosis was 55 years (interquartile range 46-66) with higher male prevalence (33:20). Neurologic symptoms were identified in 47% (25/53); BRAF
mutation in 58% (15/26). Median follow-up was 2 years (range 0-20) with 18 patients deceased. Radiologic disease evidence was seen in dura (6/41), brainstem (9/39), cerebellum (8/39), spinal cord (2/16), spinal epidura (2/16), hypothalamic-pituitary axis (17/39), and orbits (13/42). T2 white matter abnormalities (Fazekas score ≥1) were present in 21/34 patients. Diabetes insipidus was present in 30% (16/53); 8 had abnormal hypothalamic-pituitary axis imaging. Radiographic evidence of CNS involvement (i.e., dural, brain, including Fazekas score >1, or spinal cord) occurred in 55% (22/40) and was unassociated with significantly increased mortality.
Erdheim-Chester disease commonly and variably involves the neuraxis. Patients with suspected Erdheim-Chester disease should undergo MRI brain and spine and screening investigations (serum sodium, serum and urine osmolality) for diabetes insipidus to clarify extent of neurologic disease.
Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human ...butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a "training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final "challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Comorbidity count does not affect disease-modifying therapy (DMT) persistence.•Mental health comorbidity is associated with increased risk of DMT discontinuation.•Comorbidity may increase lack of ...tolerability in combination with lack of efficacy.
Comorbidity decreases the likelihood of initiating disease-modifying therapy (DMT) for multiple sclerosis (MS). Our objective was to characterize the relationship between comorbidity and initial DMT persistence along with reasons for DMT discontinuation.
We identified individuals with relapsing remitting MS or clinically isolated syndrome starting a platform DMT (interferon-β, glatiramer acetate, dimethyl fumarate, teriflunomide) as initial therapy in the Canadian province of Nova Scotia from 2001 to 2016. Cases were identified using a clinic database for the only clinic providing specialty MS care in a province with universal publicly-funded health care. Comorbidity was determined by linkage of MS cases to provincial health administrative data using validated case definitions for mental health disorder, hypertension, hyperlipidemia, diabetes, chronic lung disease, ischemic heart disease, epilepsy, and inflammatory bowel disease. Cox proportional hazards models explored the relationship between comorbidity, as a count or individual comorbidities, and time to discontinuation of initial DMT. Logistic regression models explored reasons for DMT discontinuation.
Among 1464 individuals starting platform therapy as initial DMT, the median duration on first DMT was 4 years (95% CI 4 – 4). Comorbidity count (0, 1, ≥2) was not associated with time to discontinuation of initial DMT. However, the presence of a mental health disorder was associated with an increased hazard of discontinuing DMT (hazard ratio 1.22, 95% CI 1.03-1.44). Comorbidity count was not associated with discontinuation for lack of efficacy or lack of tolerability after adjusting for covariates.
Individuals with mental health comorbidity may have unique challenges that affect persistence on DMT after treatment initiation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection. The pathophysiology of the neuropathy associated with HCV is not definitively known; ...however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV‐mediated vasculitis. The optimal treatment for HCV‐related peripheral neuropathy has not been established.
Objectives
To assess the effects of interventions (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) for cryoglobulinemic or non‐cryoglobulinemic peripheral neuropathy associated with HCV infection.
Search methods
On 26 August 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We also searched two trials registers, the Networked Digital Library of Theses and Dissertations (NDLTD) (October 2014), and three other databases. We checked references in identified trials and requested information from trial authors to identify any additional published or unpublished data.
Selection criteria
We included all randomized controlled trials (RCTs) and quasi‐RCTs involving participants with cryoglobulinemic or non‐cryoglobulinemic peripheral neuropathy associated with HCV infection. We considered any intervention (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) alone or in combination versus placebo or another intervention ('head‐to‐head' comparison study design) evaluated after a minimum interval to follow‐up of at least six months.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration. The planned primary outcome was change in sensory impairment (using any validated sensory neuropathy scale or quantitative sensory testing) at the end of the follow‐up period. Other planned outcomes were: change in impairment (any validated combined sensory and motor neuropathy scale), change in disability (any validated disability scale), electrodiagnostic measures, number of participants with improved symptoms of neuropathy (global impression of change), and severe adverse events.
Main results
Four trials of HCV‐related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV‐related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group.
Authors' conclusions
There is a lack of RCTs and quasi‐RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi‐RCTs to make evidence‐based decisions about treatment.
Natalizumab is an efficacious disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS), often limited by risk of progressive multifocal leukoencephalopathy. We describe the ...clinical course of RRMS patients switched from natalizumab to another DMT. We identified all RRMS patients treated with natalizumab ≥3 months with JC virus antibody positivity who switched to another DMT. Overall, 84 individuals switched DMT with 57 (68%) beginning fingolimod. On fingolimod, survival without a relapse was 74% (55.8-85.6%) at 36 months and survival without disease progression was 78% (62.6-87.6%) at 36 months. In conclusion, fingolimod is an effective therapy post-natalizumab.
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