MS / Multiple sclerose
Multiple sclerose (MS) is een chronische aandoening van het centrale zenuwstelsel. Anders dan vaak gedacht wordt, is multiple sclerose dus geen spierziekte. Bij MS gaat het isolerende laagje rondom de zenuwbanen (de myelineschede) langzaam stuk. Daardoor kunnen de zenuwprikkels niet meer goed geleid worden door de zenuwbanen. De gevolgen van MS zijn zeer ernstig. Zo resulteert het in verlammingsverschijnselen. De oorzaak van MS is nog onduidelijk, maar een auto-immuunziekte lijkt het meest waarschijnlijk.
MS openbaart zich bij volwassenen meestal tussen het 20e en 40e levensjaar. In gebieden met een gematigd klimaat (zoals Nederland) behoort multiple sclerose tot de meest voorkomende chronische zenuwziekten.
Cannabis sativum, beter bekend als marihuana of wiet, werd al langer experimenteel ingezet door multiple-sclerosepatiënten. Nu is het als geregistreerd geneesmiddel, uitsluitend op recept, verkrijgbaar.
Het geneesmiddel Sativex is een spray en hoeft dus niet geïnhaleerd te worden. Het verlicht de symptomen van spasticiteit die optreden bij MS-patiënten en is bedoeld om snel effect te hebben. Hier vindt u de bijsluiter van Sativex.
LET OP: Sativex is momenteel nog niet verkrijgbaar in Nederland aangezien het vergoedingentraject nog niet doorlopen is. Patiënten kunnen Sativex op recept verkrijgen bij Duitse apotheken. Omdat verzekeraars nog niet vergoeden dient het middel ter plaatse afgerekend te worden.
Het Bureau Medicinale Cannabis (BMC) verstrekt ook mediwiet voor gebruik bij MS en andere aandoeningen zoals glaucoom, kanker of aids, of klachten van misselijkheid, pijn en spasmen. Of Sativex voordeel biedt boven de (goedkopere) cannabis van het BMC moet nog blijken.
Bron: Nederlands Tijdschrift voor Fytotherapie 2013, nr. 1
Dietary supplements in MS
Omega-3 FAs are a family of polyunsaturated FAs (PUFAs) that contain a common carbon–carbon double bond at the third carbon from the terminal methyl end of the molecule. The parent omega-3 FA is linolenic acid. It is an ‘essential fatty acid’ and cannot be synthesized in humans and therefore must be supplied in the diet. Sources high in linolenic acid are plant-based and include flaxseeds and flaxseed oil, soy and soybean oil, and canola oil. Eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) are two omega-3 FAs that are synthesized from linolenic acid through a series of enzymatic steps . While EPA and DHA can be synthesized from linolenic acid in humans, a rate-limiting enzymatic conversation from linolenic acid to EPA and DHA results in a very low conversion rate to EPA and DHA .
Unlike plant oils, which contain no EPA and DHA, fish and fish oils contain high levels of EPA and DHA, particularly coldwater fish (e.g., salmon and mackerel). DHA can cross the blood–brain barrier and, along with arachidonic acid, is a major component of neuronal cell membranes [44,45]. EPA can be converted to prostaglandin I3 and E3, thrombaxane A3 and leukotriene B5, and therefore has immunomodulatory capacity, acting as an anti-inflammatory agent [42,46].
Although there are numerous studies reporting the immunomodulatory effects of omega-3 FAs, there are few studies evaluating omega-3 FAs in MS. Gallai et al. reported a significant decrease from baseline in the levels of the proinflammatory cytokines secreted from peripheral blood mononuclear cells (PBMCs) of MS subjects and healthy controls supplemented with fish oil . Overall, 20 subjects with MS and 15 age-matched healthy controls were supplemented with 6 g per day of fish oil containing 3.0 g EPA and 1.8 g DHA for 3 months; the study also included a 2-month wash-out period. The significant decrease in PBMC-secreted cytokines was observed after 3 months of supplementation. All MS subjects had a stable course of MS for at least 3 months prior to enrollment, had not modified their diet as a consequence of developing MS and were not on any MS disease-modifying therapies. No differences were demonstrated in baseline ex vivo cytokine levels between MS subjects and controls. Cytokine levels were reported to have returned to baseline values in both groups after a 3-month wash-out period.
Matrix metalloproteinase-9 appears to be important for T-cell migration into the CNS in MS and animal models of MS, and in vitro studies suggest that omega-3 FA supplementation can decrease MMP-9 production [48,49]. In an open-label pilot study, our group reported a significant decrease in MMP-9 levels secreted from unstimulated PBMCs . Ten RRMS patients received fish oil concentrate at 8 g per day (containing 2.9 g EPA and 1.9 g DHA) for 3 months. All subjects showed a decrease in MMP-9 levels, whether or not they were on MS disease-modifying medication .
It is still not known exactly how omega-3 FAs decrease levels of MMP-9 and inflammatory cytokines. Omega-3 FAs have been reported to decrease NF-κB and activator protein-1 binding activity, both of which may alter gene transcription of MMP-9 and some proinflammatory cytokines [49–51]. Therefore, modulating gene expression may be a mechanism by which omega-3 FAs might induce immunomodulation in MS. Future studies warrant evaluating the effects of EPA and DHA on MMP-9 mRNA levels.
There has been only one study evaluating the effects of omega-3 FA on MS disease activity . This was a double-blind placebo-controlled trial in which MS patients (n = 312) were randomized to receive either 20 capsules per day of either omega-3 FA (from fish oil) or an olive oil placebo for 2 years. The olive oil placebo contained 72% oleic acid and the fish oil contained a dose of EPA 1.71 g per day and DHA 1.41 g per day. This study reported a trend in improvement in the omega-3-treated subjects compared with controls in disease severity (measured by Expanded Disability Status Score [EDSS]) over 2 years (p = 0.07). While the results did not achieve statistical significance favoring omega-3 FA supplementation, the study was not optimally designed. Both groups in the study were advised to follow a diet low in animal fat and high in omega-6 FAs. Importantly, both groups developed changes in serum FA content over the 2 years of the study, which may indicate a diet effect in the placebo group.
Omega-3 FAs appear to be safe. The Bates study did not report adverse effects of omega-3 or placebo oil supplementation over 2 years . The published pilot studies conducted by our group support the safety of omega-3 FAs combined with MS disease-modifying therapies at a daily dose range of 2–8 g for 3–6 months [48,53]. No serious adverse effects were reported in either of these studies; any adverse events were mild. The Physician’s Desk Reference for Nutritional Supplements reports no serious adverse events in those taking fish oil supplements up to 15 g/day . The most common side effects are mild and include ‘fishy burps’ and mild gastrointestinal effects (e.g., stomach upset, loose stools/diarrhea and stomach bloating).
Lipoic acid (LA) is an antioxidant and dietary supplement that has a variety of biologic effects. LA is available in both oral and intravenous forms and is prescribed as a treatment for diabetic neuropathy in Germany. While some LA is derived from the diet, LA synthase can catalyze the generation of LA in mammals. Under normal circumstances, essentially no free LA is detectable within the blood. However, following oral or parenteral administration, free LA appears within the blood and a variety of tissues, including the CNS [55–57].
Lipoic acid and its reduced form, dihydrolipoic acid (DHLA), form a redox couple that functions as a cofactor for several mitochondrial dehydrogenases (Figure 1) . In vitro, a number of anti-oxidant activities have been associated with LA/DHLA, including free radical scavenging, metallic ion chelation, regeneration of intracellular glutathione and repair of oxidative damage to macromolecules . Extracellular LA enters the cell via the sodium-dependent multivitamin transport system and by diffusion across cell membranes. Intracellularly, LA is reduced to DHLA within mitochondria by dihydrolipoyl dehydrogenase and in the cytoplasm by glutathione reductase and thioredoxin [58,60,61].
Lipoic acid and its reduced form, dihydrolipoic acid.
Several laboratories have shown that LA is an effective therapy in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE has provided important insights into the immunopathogenesis of MS and has led to the development of new therapeutic approaches for the treatment of MS [62,63]. LA has been shown to be an effective therapy for EAE [64–66]. LA suppresses EAE by interfering with trafficking of encephalitogenic T cells into the spinal cord. Immunomodulatory effects of LA involve several related mechanisms of action, including inhibition of MMP-9 production by T cells at the mRNA level and inhibition of the expression of the adhesion molecules ICAM-1 and VCAM-1 by CNS endothelial cells [64,65,67]. Importantly, LA is able to stimulate production of cAMP via the prostaglandin receptors EP2 and EP4 [68,69]. cAMP is an important second messenger that activates protein kinase A, initiating a cascade of effects that result in immunomodulation. This effect may be central to the therapeutic effect of LA in EAE.
We conducted a double-blind, placebo-controlled, dose-finding trial of orally administered LA in MS, which is the first reported trial of LA in MS and the first trial in humans to relate serum LA concentrations to changes in serum markers of inflammation . This was a 2-week study with 37 subjects that, despite its short duration and small sample size, found that a dose of 1200 mg was significantly better than 600 mg in producing measurable serum LA concentrations and was generally well tolerated. We also found that there was considerable inter-subject variability in peak serum LA concentrations determined by high-performance liquid chromatography (range 0–17 μg/ml with a 1200 mg oral dose). In this study, we also explored the effect of oral LA administration on serum soluble ICAM-1 (sICAM-1) and MMP-9. A significant dose–response effect on serum sICAM-1 level also was observed with increasing doses of LA associated with decreasing levels of serum sICAM-1. We also found a statistically significant negative correlation between peak LA concentrations and changes in serum MMP-9 levels in this study, which considering the small sample size of the trial and the inter-subject variability in absorption of LA, supports the role of LA as potential anti-inflammatory agent. These observations provide the rationale for studying LA as a potential treatment for MS.
Lipoic acid appears to be safe and has been shown in randomized controlled trials to be effective for treating symptoms of diabetic polyneuropathy [71–77]. In these trials, the most common adverse reactions to LA included gastrointestinal intolerance, nausea and headache.
Ginkgo biloba (GB) is one of the traditional Chinese medicine treatments that has been used for centuries in China but has only recently gained popularity in the Western world. Standardized extracts of GB leaves are available as supplement over the counter in the USA. GB extracts have a number of pharmacologic properties that suggest they may alter neural function and enhance cognitive performance. Flavonoids, which are primarily flavon-o-glycosides, and terpenoids are the two major classes of compounds considered to be pharmacologically important in GB extracts. Standardized GB extracts typically contain approximately 24% flavonoids, 4–6% terpenoids and multiple other compounds in smaller quantities. The terpenoids are unique compounds only found in the Ginkgo tree and include bilobalide and the ginkgolides A, B, C, M and J. The flavon-o-glycosides are glycoside derivatives of quercetin, kaempferol and isorhamnetin .
Cognitive impairment can be a significant cause of morbidity and disability and can affect 40–50% of people with MS [79,80]. Currently, there are no effective symptomatic therapies for cognitive dysfunction in MS. GB has been suggested to improve cognitive performance in Alzheimer’s disease, as seen in clinical trials and several other studies [81–86]. However, more recently, there have been negative trials on the effect of GB in dementia [87–90], which makes the issues of clinical efficacy of GB on cognition improvement somewhat more controversial. More recent systematic reviews that included results of these negative trials suggest that GB is safe but that the improvement on cognitive improvement appears to be inconsistent [91,92], which contrasts with earlier systematic reviews .
Our group conducted a randomized placebo-controlled pilot study evaluating the effects of treatment with a standardized GB extract on cognitive performance in 43 subjects with MS . Subjects received GB 120 mg or placebo twice daily for 12 weeks. The outcomes of the study included several neuropsychological tests, including the Stroop test, which is a measure of attention and executive function. Subjects receiving GB showed improved performance on the Stroop test as well as improvement in subjective reports of cognitive deficits. This pilot study also showed that GB was safe and well tolerated. Based on these results, a double-blind placebo-controlled trial involving 100 subjects is underway to further assess the effects of GB on cognitive function in people with MS.
Fatigue is reported in 75–95% of people with MS, and 50–60% of people with MS report that fatigue is their worst problem [95,96]. Treatment options for MS fatigue include the off-label use of CNS stimulants and amantadine. These medications are of limited efficacy, are often poorly tolerated and can be expensive. Ginseng may represent a novel approach to treating MS-related fatigue.
Ginseng is a herbal product that has been used in China for more than 2000 years. This compound is one of the most extensively studied herbal products in the scientific literature [97,98]. The known active constituents in American ginseng are the ginsenosides [99–102], which are reported to have a wide range of biological effects, including antioxidant activity with increased oxygen radical scavenging and decreased lipid peroxidation, stimulation of the hypothalamic–pituitary–adrenal system with a corticosteroidal effect, increased antitumor activity, improved cardiovascular function through vasodilation and reduced platelet aggregation, and hypoglycemic activity [103–110].
Despite uncertainty about its mechanism of action, a limited number of placebo-controlled trials have suggested that ginseng is capable of decreasing fatigue. Of particular interest, one placebo-controlled trial of 501 healthy adults with complaints of stress and fatigue demonstrated an overall improved quality of life after a 12-week treatment trial with an Asian ginseng extract . Another large placebo-controlled trial of ginseng in 384 postmenopausal women with complaints of stress and fatigue demonstrated improved general wellbeing after 16 weeks of treatment .
Because ginseng appeared to be useful for fatigue in other populations, Kim et al. conducted a double-blind placebo-controlled crossover pilot trial of American ginseng extract using an escalating daily dose of 100 mg, 200 mg and 400 mg for the first 3 weeks of a 6-week intervention period in subjects with MS to determine its effects on fatigue . However, this study failed to show any benefit of American ginseng extract on fatigue in these subjects with MS [Kim E, Pers. Comm.]. Some subjects experienced insomnia while on American ginseng, suggesting that higher doses might not be tolerated. Thus, American ginseng does not appear to be a promising treatment for fatigue in MS.
Ginseng extracts appear to be safe, although large doses can cause side effects. Ginseng extracts have been used at doses of up to 2 g per day without adverse effects [108,109]. Excessive intake of ginseng (with dosing at 3–15 g per day) has been associated with hypertension, nervousness, irritability, insomnia, rash and diarrhea . Five different animal models using conventional toxicological methods reported no acute or chronic toxicity of the extract [97,113]
Green tea polyphenols (epigallocatechin-3-gallate)
Epigallocatechin-3-gallate (EGCG) is one of the active constituents in green tea that has been reported to have immunomodulatory and neuroprotective effects in limited rodent models. In mouse models, EGCG has been reported to decrease TNF-α  and have neuroprotective effects in models of amyotrophic lateral sclerosis , Parkinson’s disease  and transient ischemic artery occlusion .
One report evaluating EGCG in EAE found that to prevent disease, an oral dose of 300 μg twice daily per mouse significantly reduced disease severity (p < 0.05), while to treat disease, an effective dose was achieved at 60 μg twice daily per mouse (p < 0.05) .
Although there are no reports evaluating EGCG in MS patients, anti-inflammatory and neuroprotective effects in animal models of a variety of neurologic disorders warrant evaluation of EGCG for neuroprotection in MS. A clinical trial evaluating the safety and neuroprotective effects of EGCG in MS patients is currently underway at Louisiana State University (LA, USA) [Lovera J, Pers. Comm.]. EGCG will be given at a dose of 400 mg twice daily for 2 years. The primary goal is to assess dose safety and to assess neuroprotection via MRI measures.
While EGCG is generally safe, there are reports of rare serious side effects. Daily doses between 400 and 2000 mg have been evaluated in cancer studies [119,120] and in obesity studies [121,122]; in these studies, EGCG has been reported to be well tolerated. Rare cases of liver failure have been reported with green tea extracts [123–125]. This side effect occurred within the first 50 days of starting the product and was reversible in most cases. The most commonly reported side effects are mild and include nausea, abdominal pain, headache and fatigue.
There have been a number of studies evaluating the use cannabinoids in people with MS. As the majority of controlled studies have evaluated cannabinoids for spasticity in MS, we will focus on these studies.
The major psychoactive constituent in cannabis is δ-9-tetrahydrocannabinol (THC). THC binds to cannabinoid receptors (CBs) in the CNS and acts as a partial agonist to both CB1 and CB2 receptors. In MS, the mechanism of action of THC is unknown, although there is limited evidence that it has anti-inflammatory and neuroprotective properties .
Cannabidol (CBD) is a non-psychoactive constituent in cannabis and is the major constituent in the plant. It is thought to decrease the clearance of THC by affecting liver metabolism. It binds to both CB1 and CB2 receptors in the CNS, with a higher affinity to the CB2 receptor.
In a review of six controlled studies evaluating a combination of THC and CBD for spasticity in MS, it was found that THC–CBD was well tolerated and improved patient self-reports of spasticity [149–155]. Objective measures did not show significant improvement compared with placebo . Three of the six studies were placebo-controlled; the sample size range was 12–295 MS patients; the dose range was less than 10 mg/day to 120 mg/day; and the intervention range was 2–15 weeks [152,153,155]. Only one study reported a significant improvement in Ashworth score  and none of the studies reported a significant improvement in timed walk. The authors noted that side effects were mild and reported in both treatment and placebo groups. The authors concluded that there was significant improvement in patient-reported spasticity combined and that the combination of THC and CBD was well tolerated in MS. They noted that objective measures of spasticity showed no significant improvement.
Unlike the dietary supplements discussed, THC is a controlled substance (requiring a prescription in the USA) and is sold under the trade name of Marinol® (Solvay Pharmaceuticals, IL, USA).
Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol). In vertebrates, vitamin D3 is produced in the skin from exposure to UV radiation . Vitamin D3 is converted into 25-hydroxy-vitamin D3 in the liver and 1,25-dihydroxyvitamin D3 in the kidney . 1,25-dihydroxy-vitamin D3, which is the bioactive form of vitamin D, is important for regulating the calcium and phosphorus levels in the blood by promoting their absorption from food and helping normal bone mineralization, growth and remodeling [128–130]. Vitamin D also regulates immune function (reviewed in [131,132]). There are emerging data that support the notion that vitamin D may have a potential immunomodulatory role in MS [133,134].
Epidemiologic studies have found that low vitamin D intake and low serum vitamin D levels may increase the risk of MS [135,136]. Earlier studies looking at serum vitamin D levels in MS and in healthy controls showed mixed results; however, more recent data support a high prevalence of vitamin D deficiency in people with MS. Barnes et al. reported no difference between MS matched controls in either serum vitamin D2 or D3 levels . Van der Mei et al. found no mean difference in serum vitamin D2 levels between MS patients and matched controls, but did find a significant correlation between increasing MS disability and low vitamin D2 levels . Soilu-Hanninen et al. found no mean difference in serum vitamin D2 levels between MS subjects and controls during the winter months but found that MS subjects had significantly lower serum vitamin D2 levels than controls during the summer months . This study also found that MS subjects had lower serum vitamin D2 levels during relapses compared with remission states. A recent study looked at the serum vitamin D levels in people with MS (n = 199) and found 84% of them to be vitamin D-deficient . These authors also examined the change in serum vitamin D levels in 40 MS patients who took either low-dose vitamin D2 (≤800 IU/day) or high-dose vitamin D3 (50,000 IU/day for 7–10 days, followed by 50,000 IU weekly or biweekly) and found that subjects in the high-dose vitamin D3 group had significantly elevated serum vitamin D levels compared with the low-dose vitamin D2 group. In an open-label study, oral calcitrol at a target dose of 2.5 μm/dl was found to be safe and tolerable in 16 MS patient for up to 1 year of supplementation . Another recent study examined the seasonal variation in the serum vitamin D levels in people with MS (n = 103) and healthy controls (n = 110) and found these levels to be significantly higher in summer than in winter in both people with MS and the healthy controls . This study also suggested that women with higher circulating levels of vitamin D had a lower incidence of MS and MS-related disability.
One interesting study that examined whether vitamin D has any effect on genetic susceptibility in MS found that the expression of the MS-associated MHC class II allele HLA-DRB1*1501 appears to be regulated by vitamin D . This discovery may be an important clue towards the relationship between vitamin D and MS.
Studies of vitamin D in EAE, the animal model of MS, have shown that vitamin D inhibits inflammation. A low-calcium diet in conjunction with injection of 1,25-dihydroxy-vitamin D3 prolonged the survival of mice with severe EAE . Cantorna et al. showed that 1,25-dihydroxy-vitamin D3 completely eliminated signs of EAE in mice . Subsequent studies indicated that 1,25-dihydroxy-vitamin D3 treatment resulted in a diminished presence of inflammatory macrophages in the inflamed CNS, suggesting that vitamin D may influence inflammatory cell trafficking or apoptosis .
Clinical trials looking at effects of vitamin D supplementation in people with MS are being conducted. One recent small study that included 29 people with RRMS correlated the levels of serum vitamin D with cytokines, IFN-γ (considered proinflammatory) and IL-4 (considered anti-inflammatory) . This study found that people with high serum vitamin D levels had an improved anti-inflammatory profile, thus suggesting a potential role of vitamin D in regulatory T-cell function in people with MS.
There are emerging data from both animal and small clinical trials that vitamin D may have potential beneficial effects in MS. The more specific role of vitamin D in MS management needs to be clarified in larger clinical trials.
Conservative estimates are that at least a third of multiple sclerosis (MS) patients use complementary and alternative medicine (CAM) therapies.
While the majority of MS patients who use CAM report benefit from diet, omega-3 fatty acids (FAs) and antioxidant supplements, these treatments have not been investigated with the rigor required to determine whether or not they are effective.
There is evidence to support investigating the effectiveness of omega-3 FAs as an anti-inflammatory and neuroprotective therapy for MS.
Lipoic acid (LA) is an antioxidant that has been shown to be effective in treating the animal model of MS, experimental autoimmune encephalomyelitis. Early clinical trials of LA in MS suggest that it can modulate some immunologic markers associated with disease activity, however, LA is erratically absorbed when taken orally. Further studies in MS are warranted.
Ginkgo biloba may improve cognitive performance in MS but a larger clinical trial, which is currently underway, needs to be completed to prove its efficacy.
American ginseng extract is ineffective in treating fatigue in MS.
Vitamin D deficiency appears to increase the risk of developing MS. Results from large clinical trials are needed to determine whether vitamin D supplementation is a potential treatment for MS.
Cannabis may improve spasticity in MS, although most trials show improvements in patient self-report and not in objective measures of spasticity (Ashworth).
A low-fat diet deserves investigation as an adjunctive therapy for the control of relapsing MS.
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Nutr Neurosci. 2014 Sep;17(5):214-21. doi: 10.1179/1476830513Y.0000000083. Epub 2013 Nov 26.
Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum. Naziroglu M, Kutluhan S, Ovey IS, Aykur M, Yurekli VA.
Hypericum perfortarum (HP, St John's wort) is a modulator of Ca(2+) entry in neutrophils and it may modulate intracellular free Ca(2+) ([Ca(2+)]i) entry in leukocytes of patients with multiple sclerosis (MS). We investigated effects of HP on oxidative stress, apoptosis, and [Ca(2+)]i concentrations in serum and leukocytes of patients with MS.
Neutrophils of nine newly diagnosed MS patients and nine healthy subjects within four subgroups were used in the study. The first group was a control; the second group was patients with MS. The neutrophils from patient group were incubated non-specific TRPM2 channel blocker (2-APB), voltage-gated calcium channel blockers, verapamil and diltiazem (V + D) with HP before N-formyl-L-methionyl-L-leucyl-L-phenylalanine stimulation, respectively.
Neutrophil and serum lipid peroxidation, neutrophil apoptosis and [Ca(2+)]i levels in patients with MS were higher than in control although their levels were decreased by HP, 2-APB, and V + D incubations. The modulator role of V + D in MS and MS + HP groups was higher than in the 2-APB group. Neutrophilic glutathione peroxidase (GSH-Px) and serum vitamin A and E concentrations were lower in the MS group than in control. However, the neutrophil GSH-Px activity was increased by HP incubation. The neutrophil reduced glutathione, serum vitamin C and β-carotene concentrations did not change in control and patients.
We observed that HP-induced protective effects on oxidative stress and [Ca(2+)]i concentrations by modulating transient receptor potential and voltage gated calcium channel in the patients with MS. Thus, it may provide useful treatment of neutrophil activity in the patients.