About MS
MS is a chronic autoimmune inflammatory disease of the central nervous system (CNS) and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. Demyelination in MS occurs when the myelin, the fatty coating of healthy nerves, is broken down by macrophages sent by an errant immune system and replaced by scar tissue. It generally affects multiple sites in the brain and/or spinal cord, causing tissue hardening (sclerosis), impairing the brain’s ability to send and receive messages along the nerves to various parts of the body. Because these messages control all voluntary and involuntary movements, MS can impair bodily functions.
The cause of MS remains unclear, but at the root, there is an incorrect immune response. The immune system is a composite of defense mechanisms that serves to destroy invaders such as harmful bacteria and viruses. In MS, this defense system may begin to attack the cells of the body itself. Contributors have been speculated to be general autoimmune abnormalities, genetic susceptibility 1,2, and external triggers such as viruses, diet, or environmental factors such as pollutants 1,3,4.
Types of MS
There are currently six known types of MS. The following are general summaries, with links to more in-depth descriptions at the National Multiple Sclerosis Society’s and Cedars Sinai Medical Center’s websites.
Clinically Isolated Syndrome (CIS)
CIS refers to an episode of neurologic symptoms lasting 24 hours or more, and which is linked to inflammation and demyelination in the central nervous system. It is considered to be its own syndrome because though the symptoms are similar to those of MS, it may not progress to the full-blown disease.
Additional episodes become likely if symptoms are concurrent with MS-like brain or spinal lesions visible with magnetic resonance imaging (MRI). Without such lesions, the likelihood of a diagnosis of relapsing-remitting MS is much lower.
Individuals with CIS considered to be at high risk for developing MS may undergo disease-modifying therapy (DMT) – a term applied to MS medications – to delay onset of MS.
Tumefactive Multiple Sclerosis (TMS)
TMS is a rare form of MS, generally presenting with one or more large, distinctive “Balo’s concentric” lesions in the CNS 5. Symptoms of TMS often are not similar to those of more common MS types, but rather mimic those of a brain tumor. These include headaches, cognitive abnormalities, mental confusion, difficulty understanding and forming speech (“aphasia”), difficulty with the movement patterns needed to produce speech (“apraxia”), seizures, and weakness 6. Though cases do not necessarily progress to other types of MS, TMS lesions can appear in existing MS, and they can relapse. Outcomes and treatment recommendations do not generally differ from those recommended for more common MS types 7,8.
RRMS is the most common MS course, affecting approximately 85% of people with the disease initially or long-term. It is characterized by multiple episodes of new or increasing neurologic symptoms (called relapses), followed by partial or complete recovery and periods without episodes (remissions). Even if an acquired disability continues, there is no progression during remission. RRMS can be further categorized as either active (with relapses and/or new MS lesions per MRI) or inactive, as well as worsening (increased disability following a relapse) or not worsening. New lesions on MRI often occur as part of a relapse. Of note, new MS lesions may also occur without apparent symptoms.
Secondary Progressive MS (SPMS)
SPMS starts out on a relapsing-remitting course, with some people eventually experiencing gradual increases in disability over time. It affects approximately 5% of MS cases. SPMS can be categorized as either active (with relapses and/or new MS lesions per MRI) or not active, as well as with progression (disability accumulation with or without relapses or new lesions) or without progression. In SPMS, occasional relapses and periods of stability may occur.
PPMS is a rarer form of MS, affecting approximately 10% of people with the disease. From the beginning it is characterized by worsening neurologic function (accumulation of disability) over time, without early relapses or remissions. PPMS can be categorized as either active (with an occasional relapse and/or evidence of new MS lesions per MRI) or not active, as well as with progression (disability accumulation over time, with or without relapse or new lesions) or without progression. PPMS can have brief periods of inactivity, as well as periods when increasing disability occurs with or without new relapses or lesions.
Progressive-Relapsing MS (PRMS)
PRMS is the rarest form of MS. It is characterized by a progressive worsening of the condition due to nerve damage, similarly to PPMS, but with occasional episodes of intensified symptoms due to inflammation, similarly to those experienced in RRMS.
Signs and Symptoms of MS
MS symptoms vary from person to person and from time to time in the same person. They can range from mild to severe, and may include the following:
• Muscle twitching or spasms
• Eye problems (loss of vision, blurred or double vision, etc.)
• Weakness or abnormal fatigue
• Lack of sensation or numbness
• Dragging feet, rocking or unstable walking
• Trembling or involuntary movements
• Poor coordination
• Loss of bladder or bowel control
• Impaired reproductive function
• Impaired memory, concentration, or skills
• Speech problems
• Dysphagia (difficulty swallowing)
• Partial or complete paralysis of any part of the body
MS signs leading to diagnosis may include a physical examination by a healthcare provider, blood tests, and imaging tests such as magnetic resonance imaging (MRI). An MRI looks for evidence of lesions (areas of damage) in the brain or spinal cord characteristic of MS. A spinal tap (lumbar puncture) may also need to be done to identify abnormal proteins and inflammatory indicative of MS in the cerebrospinal fluid. The fluid is taken out for testing through a thin needle inserted in the lower back. If these tests don’t provide a clear answer, a neurologist may recommend an evoked potentials test, which assesses nerve function by measuring electrical activity in the brain and spinal cord.
Who Can Get MS?
Theorized Causes of MS
The pathophysiology of autoimmune diseases such as MS involves a complex interaction between genetic and environmental factors. While susceptibility to MS appears to be influenced by genetics 1,14, environmental factors play an important role in the risk for development and progression of the disease 14-22. These include Epstein-Barr virus (EBV), vitamin D level, smoking, obesity, microbiome disruption 1,14,21, and mercury toxicity 23. When risk factors occur in combination, it can create a perfect storm.
Genetics and Epigenetics
In genetics, several human leukocyte antigen (HLA) alleles (particularly HLA-DRB1*1501) appear to be risk factors for the disease, while others (such as HLA-A*0201) may be protective. Additionally, some gene variants involved in vitamin D metabolism, transport, function, and blood levels have been linked to MS susceptibility 24. Vitamin D deficiency is a proposed contributor to MS risk 21,25.
In epigenetics (“above genetics”), interactions between genetic and environmental risk or protective factors may occur during pregnancy and could continue in the offspring during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life 26,27.
After conception, genetic susceptibility could be influenced, negatively or positively, by such factors as infection with Epstein-Barr virus (EBV), vitamin D status, and/or cigarette smoking. All currently suspected risk factors, including genetic and environmental factors, share influences in the immune system, with possibly critical interventions at certain key periods of system maturation, in particular in utero (during pregnancy) through childhood. Theoretically, the combination of unfavorable genetics, more frequently encountered in siblings of patients with MS, past EBV infection – especially if it occurred late and with high residual anti-EBV antibody levels – chronic vitamin D insufficiency – in particular during the major part of infancy, childhood, and early adulthood – and cigarette smoking – particularly in a case of a high level of tobacco intoxication – could maximize the MS risk, whereas the conjunction of healthy conditions could bring protection. The cumulative effect of all currently known risk factors for MS was calculated to theoretically increase overall risk more than 400-fold 28.
It has been noted that MS risk is significantly increased in the case of the conjunction of HLA-DRB1*1501 and either high anti-EBV antibody levels or clinically symptomatic infectious mononucleosis 29-33; the existence of both HLA-DRB1*1501 and cigarette smoking 34; the addition of these three preceding risk factors 35; with a probable regulation of the expression of HLA-DRB1*1501 by vitamin D 36,37; and with a possible potentiation of the effects of EBV infection and vitamin D insufficiency in MS risk 26,38-41.
Epstein-Barr Virus (EBV)
Epstein-Barr virus (EBV), computer illustration. EBV, also known as human herpes virus 4, is 1 of 8 herpes viruses that infects humans. It is best known as the cause of infectious mononucleosis (glandular fever), but is also associated with some forms of cancer, including Burkitt’s lymphoma. In both infections, the virus infects one type of white blood cell, the B lymphocytes. Infection with EBV is common and usually harmless; additional factors potentiate the development of more serious diseases.[/caption]
It has long been suspected that the immune-modulated demyelination in the brain and spinal cord characteristic of MS may be triggered by a viral infection. Accumulating evidence suggests that the agent in question is the Epstein-Barr virus (EBV). EBV is a human herpesvirus associated with lifelong after-infection that exists in a largely dormant state in immune cells 43 . A causal role of EBV is supported by the increased MS risk after infectious mononucleosis, the clinical manifestation of EBV infection 44, as well as by elevated serum antibody titers against EBV nuclear antigens (EBNAs) 45,46 and the presence of EBV in MS lesions reported in some studies 45,47,48. It is generally held that the negative consequences of EBV infection result from the disruption of the virus-host immune system balance and resultant provoked immune response. This response reprograms the immune system to attack the cells carrying the virus, which include immune cells themselves 45.
Direct evidence of causality – that people who developed MS after EBV infection would not have developed MS if they had not been infected with EBV – remains elusive, as a randomized clinical trial is not feasible. The next best option is likely a long-term investigation of MS incidence in a group of EBV-negative individuals, some of whom will be infected with EBV during the follow-up and some who will not. Such an investigation was conducted over the course of 20 years in a racially diverse population of more than 10 million active-duty United States military personnel, linking EBV with a 32-fold increased risk of developing MS 49.
Vitamin D Deficiency
Vitamin D status of a person’s mother during pregnancy, month of birth, sun exposure during childhood, and sun exposure and vitamin D status in early adulthood may influence MS risk 21. A gene-based analysis controlling for confounding factors found a strong connection between vitamin D status and incidence of MS across two different populations 25.
Vitamin D-deficiency may lead to dysregulation of immune cell function and increase the risk of this inflammatory autoimmune disease 51. The immune-affecting role of vitamin D has been demonstrated in MS in both the experimental autoimmune encephalomyelitis (EAE) animal model and humans, and studies have investigated actions in the CNS 54. Furthermore, some of the genes involved in vitamin D metabolism (including CYP27B1 and that for vitamin D receptors, VDR) appear to play a significant role in genetic predisposition 24,51,53,55. Vitamin D insufficiency is widespread in areas with high MS incidence and in MS patients at the earliest stages of the disease, supporting a key connection. Additionally, some clinical findings suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS 21.
On the neurological side, vitamin D receptors have been found in various brain cells, with the highest concentrations in parts of the brain known to be affected in MS. Vitamin D helps the regulation of brain cell development through the synthesis of growth factors and neuromodulators 54. Additionally, it appears to regulate the remyelination process. First, vitamin D promotes clearance of myelin debris following normal demyelination, thereby activating the remyelination process 56. Second, vitamin D promotes maturation and differentiation of oligodendrocyte precursor cells (OPCs) 57-59, enabling them to reach the site of remyelination, complete it 60, and prevent it from eventually stopping 61-63. Third, because it may impact the balance between local inflammatory and anti-inflammatory mechanisms, vitamin D provides a microenvironment conducive to OPC maturation and differentiation into oligodendrocytes, in turn enabling remyelination. Studies have shown that by activating VDR via vitamin D, there is an increase in the OPC differentiation and consequent remyelination 64. When vitamin D is insufficient, remyelination may not take place, and demyelination can continue unabated 54.
In EAE, calcitriol has been observed to have both preventive and treatment effects 65,66 in the presence of calcium 67 and activated VDRs that enable uptake of vitamin D by cells 68. Benefits have been attributed to an anti-inflammatory effect 69-72, inhibition of macrophages 73 and autoimmune cells 74-77, and stimulation of beneficial Treg activity 78-81. In MS patients, vitamin D blood levels have been linked to Treg numbers and activity 82, and Tregs are increased with vitamin D supplementation 54,83. Interestingly, low VDRs with increases in autoimmune cells appear to enable EAE, suggesting that MS risk could be elevated despite high levels of sunshine 84.
An optimal blood level of vitamin D is considered to be 75-200 nmol/liter (30-80 ng/mL). A level of less than 30 indicates insufficiency, and less than 12 ng/mL deficiency.
It is recommended that MS patients who have vitamin D insufficiency or deficiency supplement with at least moderate doses of the vitamin, likely well above the current amount recommended for the general population 21.
Smoking
Toxic components of tobacco smoke and related dangers to health have been studied extensively for decades. Smoking is also of interest as an environmental influence on MS, as its status as a risk factor is supported by much epidemiological data 85,86.
Cigarette smoking rose globally from 1950-2000 87, in parallel with MS incidence, particularly in females 19,50,88-92. Moreover, smoking rates for men and women are similar in some countries where MS is highly prevalent (e.g., Norway, Sweden, and New Zealand), while they are usually higher in males in the rest of the world 93.
The risk of MS in smokers appears to be dose-dependent, as duration and intensity of smoking are associated with a greater risk of MS 94-100. Dose-response associations suggest causality and strengthen the link between smoking and MS 85.
Smoking has been observed to enhance the proposed causality of other MS risk factors. For example, it can strengthen the association between EBV and increased MS risk 35,101,102. Among individuals with genetic risk factors, smoking was shown to increase MS risk nearly three-fold 103.
Further, cigarette smoking has been observed to worsen the course of established MS, including disease activity (clinical relapses and new lesions), brain atrophy, conversion from a first demyelinating clinical event (i.e., CIS, optic neuritis, or partial myelitis) to confirmed MS or from relapsing-remitting to secondary progressive MS, and neurological deterioration once MS has become progressive 85,86.
Cigarette smoking is an irritant to the lungs, starting a proinflammatory cascade that can lead to autoimmunity. Inflammation may increase the risk of MS through cross-reactivity between lung and myelin antigens. Additionally, free radicals, cyanates, and carbon monoxide in cigarette smoke may be toxic to neurons and the CNS overall (Rosso and Chitnis, 2020). Free radicals and cyanide can damage the mitochondria, which may lead to energy dysfunction and severe myelin damage 104-106. Excessive and prolonged exposure to oxidative stress may induce the release of glutamate 107, which may then destroy neurons through excessive activation (“excitotoxicity”) 108. In parallel, peroxynitrite and superoxide may damage axons directly 109.
Overall, though causality has not yet been established, smoking appears to increase the risk of MS 85,86.
Obesity
Obesity is defined as a body mass index (BMI) of 30 or more. BMI is the result of dividing body weight in kilograms by height in meters squared, or weight in pounds divided by height in inches squared then multiplied by 703. Because BMI can be confounded by significant muscle mass – as muscle is heavier than fat – a complementary measurement for obesity in adults is sometimes used: abdominal (waist) circumference (performed by placing the tailoring meter in the middle of the distance between the lower edge of the last rib and the upper edge of the iliac crest, with the person in standing position and complete expiration), with the criterion being a value of more than 88 cm (35 inches) in women and 102 cm (40 inches) in men 110.
Various health conditions have been linked to obesity as a contributing factor, including metabolic (e.g., insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease) and immune mediated (e.g., some types of cancer, rheumatoid arthritis, MS). Obesity and obesity-related illnesses have significantly increased in prevalence over the past several decades, for both genders and for all age groups, including children and young adults, in both well-developed and many developing countries around the world 111. During the same period of time, autoimmune diseases such as MS have also increased in prevalence 112,113. Additionally, it was observed in several studies that the majority of MS patients tend to be overweight or obese 114.
Autoantibody production, an indicator of autoimmune disorders, has been demonstrated in obese animal models and humans. Obesity results in deficiencies of human self-tolerance mechanisms by promoting pro-inflammatory processes that result in increased autoimmune cell activity 112. Both obesity and autoimmune disorders involve elevated levels of the key hormones leptin, resistin, and visfatin, a condition linked to reductions in serum adiponectin levels and Tregs, with increases in inflammatory factors 115,116.
A link between adolescent obesity and the risk of developing MS was initially observed in women 117, but soon shown to be regardless of gender. Child and adolescent obesity were later shown to double the risk 15, with the critical period appearing to be during adolescence 118. Moreover, a combination effect with genetic predisposition increased the risk 119.
Of note, subjects with obesity tend to have more severe forms of autoimmune disorders such as MS, with a less positive response to medical therapies 112. This indicates a benefit to weight management even following disease onset.
Microbiome Disruption
The gut microbiome – the collective genome or genetics of local microorganisms – plays an important role in immunity and thus autoimmunity. Its proper functioning is dependent upon a healthy balance between species of beneficial or “commensal” microbes (predominantly bacteria), and no less importantly, a greater number of beneficial compared to harmful species. Commensals perform many important tasks, including protection against harmful microbes and production of vitamins and other needed substances, including short-chain fatty acids (SCFA). An imbalance is called “dysbiosis,” and is associated with various inflammatory and neurological conditions, including MS 120.
The “hygiene hypothesis” has been advanced as an explanation for the recent significant increase in allergy and autoimmunity in developed countries 121-123. According to this hypothesis, a lack of evolutionarily normal infectious exposures in early life in areas with high levels of sanitation contributes to abnormal immune regulation in susceptible individuals. In other words, individuals living in environments that are too clean lack crucial exposure to “immune-tolerizing” products and activities of microbes, resulting in poorly regulated immune systems and increased immune-mediated diseases 1,124.
It was demonstrated already in the 1960s that MS tends to be more prevalent in areas with high sanitation125, and with more recent epidemiological surveys confirming this association 126. Several studies have reported alterations in the gut microbiome of MS patients 127-129. Studies in animal models of MS have identified members of the gut commensal microflora that exacerbate neuroinflammation130,131.
Integrating the hygiene hypothesis and the microbiome has contributed to the identification of potential causal mechanisms in MS. It was recently proposed that a defective microbiome in MS may not provide normal levels specifically of TLR2-tolerizing bacterial products for the immune system. This may result in abnormally regulated systemic innate TLR2 responses that play a critical role in both the inflammatory and defective remyelinating mechanisms characteristic of MS124. TLRs, or “toll-like receptors,” enable the body to discriminate between self and non-self, which is a point of failure in autoimmune disorders. TLR2 has been observed to upregulated in inflammatory conditions, including MS, which in turn may activate autoimmunity132.
Mercury Toxicity
Mercury is a heavy metal with a number of industrial applications throughout history. It is one of the most toxic elements, and has been associated with neurological health problems, including MS.
A principal feature of MS is nerve demyelination, and mercury toxicity is known to cause this. Additional neurological similarities include brain atrophy/shrinkage and scarring, dysmetria, Bell’s palsy, and damage to white matter and axons, as well as undesirable changes in the basal ganglia, myelin basic protein, myelin oligodendrocytes, glycoprotein, oligoclonal bands, ciliary neutrophil factor, glial cells, electroencephalography, and brainstem auditory evoked potentials 23. Immunological similarities include changes in T-cells – shifting them toward an autoimmune imbalance – antioxidant defense 133, cytokines, interferon, and gamma globulins. Additionally, both can give rises to hormonal changes. Finally, mercury may increase EBV replication in the body, with EBV being another suspected cause of MS 23.
A connection between mercury from dental amalgams (fillings) and MS was suggested several decades ago. As a result, MS patients were advised by the United States Food and Drug Administration to avoid these 134, and many have had them removed, with reported improvement in MS symptoms 135. “Silver” dental fillings consist of 50% mercury, which is constantly being released from the material in the form of vapor. The inhaled mercury enters the bloodstream, ultimately crossing the blood brain barrier and becoming entrapped within the brain and rest of the CNS for many years 136.
Of note, there are alternatives to mercury amalgams. Also referred to as dental composites or resins, they may comprise a blend of plastics and fillers such as silica and dimethylglyoxime.
A more common source of mercury is the food supply. Because mercury is often present in the water, air, and soil, it can enter into plants and algae. These are then consumed by animals that are in turn consumed by other animals, and so on, thus accumulating to high levels in tissues that are ultimately consumed by people. Though this is true for various animal foods, the most affected are sea creatures that are “top predators,” meaning they accumulated several increasing concentrations of mercury before being caught 137,138. Such species include American lobster, Chilean sea bass, cod, mackerel (especially king and Spanish), marlin, orange roughy, shark, swordfish, tilefish, and tuna (especially bigeye, bluefin, and albacore).
More information about mercury exposure can be found on the United States Environmental Protection Agency (EPA) website.
The safe mercury level for seafood consumption is 1 part per million (ppm) per week. It is possible to stay below this by limiting intake to 4 ounces (about 120 grams) twice per week and choosing seafood low in mercury, such as catfish, crab, eel, oysters, salmon, scallops, and shrimp. Additionally, it has been shown that adequate intake of selenium – an essential antioxidant mineral – may be protective against mercury toxicity139-141. Food sources of selenium include Brazil nuts, seafood, and organ meats, and to a lesser extent, breads, cereals, poultry, red meat, and eggs.
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