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Thread: Multiple Sclerosis: Causes, Symptoms, Diagnosis, and Risk Factors

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    Distinguished Community Member Sherman Peabody's Avatar
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    Default Multiple Sclerosis: Causes, Symptoms, Diagnosis, and Risk Factors

    Multiple sclerosis (MS) is the most common autoimmune disease of the brain and previously thought of as incurable. However, the idea that MS can be hacked and put into remission has recently emerged.

    In this post, we summarize everything that has been published on MS, including causes, mechanisms, and both conventional and alternative treatments.

    Multiple sclerosis (MS) is a chronic autoimmune debilitating disease in which nerve damage (demyelination of neurons) in the brain and spinal cord disrupts its communication to the body.

    MS is a leading cause of disability in young adults and is the most common inflammatory disorder of the brain.

    Diagnosis and Symptoms of MS

    Demyelination and damage to neuronal axons can lead to many observable negative health effects and symptoms associated with multiple sclerosis. Clinical diagnosis can be made through medical imaging (MRI) and laboratory testing (CSF testing).

    While MS symptoms vary greatly from patient to patient, these commonly include:

    - Painful eye movement and blurred vision (damage to the optic nerve)
    - Tremors and loss of coordination/balance (damage to the cerebellum)
    - Limb and muscle weakness, spasms, and numbness lead to mobility problems (damage to the spinal cord)
    - Blurred or double vision (damage to the brainstem)
    - Constipation, incontinence, bladder problems, or erectile dysfunction (loss of upper neural motor neuron control)
    - Speech impairment and trouble swallowing; however, only a small percent of MS patients are affected by these symptoms (impairment of motor speech processes in the brainstem)
    - Memory and cognitive problems
    - Fatigue, which may potentially coexist with depression
    - Depression: MS is strongly correlated with depression – 41.8% of MS patients had clinically depressive symptoms

    Given that MS patients display different symptoms unique to themselves, the management should be tailored to the patient and each symptom mitigated individually. Patients facing fatigue and muscle weakness can undergo physical therapy to be able to undertake daily activities.

    Based solely on these symptoms, MS is difficult to diagnose non-invasively because the disease shares many symptoms with other neurological disorders such as acute disseminated encephalomyelitis and neuromyelitis optica. As a result, clinical symptoms combined with medical imaging/laboratory testing are sufficient for the diagnosis (McDonald diagnostic criteria).

    Progression of Multiple Sclerosis

    ~85% of MS cases start off as relapse-remitting before developing into secondary progressive. When MS first develops, typically in younger patients (teenage – 30 years old) it typically presents as relapse-remitting MS – the disease flares up and then disappears. After 1 – 2 decades, it can progress into secondary progressive MS, when the symptoms don’t go into remission and may progressively get worse.

    The remaining 15% of MS cases are primary progressive MS, which starts as progressive. In some cases, the disease can be initially progressive and then go into remission.

    Early Warning Signs of MS

    Damage to the axons of neurons is an early event and continues over time. However, surprisingly the severity and degree of the damage decrease over time.

    Due to the damage to neuronal axons, the signs and symptoms of the early stages of MS are very similar to those of the later stages, which include:

    - Vision loss or pain in the eyes (optic neuritis)
    - Blurred vision (brainstem syndromes)
    - Numbness or tingling in limbs (brainstem and spinal cord syndromes)
    - Mobility problems (dysfunction of long tracts)

    MS Causes and Mechanism of Action

    The hallmark of MS is the formation of:

    - Lesions in the nervous system
    - Sclerotic plaques
    - Inflammation
    - Demyelination of neurons in the brain

    The myelin sheath is a white, fatty, and electrically insulating substance surrounding the axons of neurons. It allows for faster conduction of electrical impulses.

    Proteins on the myelin, such as myelin basic protein and proteolipid protein, can be attacked by myelin-reactive T cells, which are typically present in the blood of healthy people, but not activated.

    When they are activated and there is a leaky blood brain barrier, T cells can cross the blood-brain barrier and attack the myelin sheaths in the brain.

    How Myelin-Reactive T Cells Are Activated

    Myelin proteins, including myelin basic protein and proteolipid protein, have some amino acid similarities to many viruses, bacteria, and proteins in foods.

    When the immune system is activated by the following pathogens or foods, it can trigger MS. However, other factors, such as overall inflammation levels, blood-brain barrier permeability, and imbalanced immune system are also at play.

    Pathogens:

    - Epstein-Barr Virus
    - Herpes Virus
    - Papilloma Virus
    - Various bacteria including Pseudomonas

    The gut bacteria Bacteroides thetaiotaomicron and Bacillus fragilis typically don’t cause diseases, but they have proteins that are similar to the myelin proteins. These gut bacteria could potentially trigger multiple sclerosis.

    Milk or dairy products contain the protein butyrophilin, which has some similarities with the proteins on myelin sheaths.

    Imbalanced Immune System (Th1, Th2, and Th17)

    White blood cells of MS patients have abnormal inflammatory responses in all three Th systems (also called Helper T cells or CD4+ T cells), including:

    - Increased Th1 cytokines (IFN-gamma)
    - Increased Th2 cytokines (IL-4 and IL-5)
    - Increased Th17 cytokines, including IL-17
    - Increased TNF-alpha
    - Decreased anti-inflammatory cytokines (IL-10)
    - Decreased Regulatory T cells (the cell that prevents inflammatory Th1, Th2, and Th17 from autoimmune or allergic responses)

    In addition, levels of IL-17 and IL-5 correlated with the number of active plagues on MRI images.

    CD4+ T cells are T helper cells that release cytokines that help suppress or regulate immune responses and are present in acute MS lesions.

    These activated myelin-reactive cells are present in both the blood and cerebrospinal fluid of MS patients.

    Intestinal Permeability or Leaky Gut

    Leaky gut is a major precipitating factor in autoimmune diseases.

    In a small pilot study, more patients with relapsing-remitting MS had intestinal permeability (73%) compared to healthy controls (25%).

    On the other hand, inflammation of the (central) nervous system can also increase gut permeability and affect the structure of the small intestine mucosa.

    Gastrointestinal Microbiota

    Microbial imbalance and maladaptation in the gut (gut dysbiosis) play an important role in the development of autoimmune diseases.

    An altered physiology of gut mucosa and microbiota can affect intestinal permeability, allowing the passage of different macromolecules (from foods), toxins, and bacteria, which can trigger MS.

    The gut bacteria can also influence the blood-brain barrier integrity.

    The gut microbiota plays an important role in educating the immune system. T cells (regulatory and helper) become more knowledgeable of the composition of cells and chemicals in the gut.

    On the other hand, the disease can also lead to dysbiosis.

    MS patients have a reduced number of gut bacteria species and an imbalance of certain bacterial families compared to healthy people.

    However, despite that the gut microbiome plays a role in autoimmunity, further studies are needed to identify the specific microbes that can potentially induce an autoimmune reaction by the T cells.

    A Leaky Blood Brain Barrier

    The function of the blood-brain barrier is to protect the brain preventing foreign and unnecessary materials to reach the brain, like errant T cells.

    Autoimmunity and inflammation can damage this barrier leading to a leaky blood brain barrier.

    In normal circumstances, errant cells undergo induced cell death (apoptosis) by external body signals. The rogue T cells in MS are unresponsive to these signals, so they accumulate in the brain and spinal cord forming plaques and causing inflammation.

    In MS, the inflammation is caused by myelin-reactive T cells, which destroy the myelin sheath. Demyelination can lead to irreversible damages of the axons and MS progression.

    Moreover, recent studies have demonstrated that B cells from MS patients are also capable of directing immune responses against neurons (neural antigens).

    Oxidative Stress

    Plaque formation and lesions may be caused by oxidative stress and mitochondrial injury.

    Oxidative stress plays an important role in the progression of MS. Reactive oxygen species (ROS) contribute (act as mediators) to the demyelination and axonal damage in the brain.

    Due to the low concentration of antioxidants in the brain, reactive oxygen species are effective at causing oxidative damage to the cells in the brain and the whole nervous system.

    Oxidative stress can lead to inflammation, while inflammation can also cause oxidative stress. Through a self-perpetuating process, these two adverse effects lead to the progression of MS.

    Risk Factors and Potential Exacerbating Causes of MS

    The causes of MS are still not fully understood. It is a complex disease with many varying and interconnecting factors affecting its development and onset. Both environmental and genetic factors together cause MS.

    1) Gender and Sex Hormones

    Women are twice as likely to develop MS than men.

    In women, the onset of MS is generally earlier. However, men tend to progress faster and have a more severe disease course.

    This disparity is potentially caused by differences in sex hormones and the immune environments between men and women.
    Hormones and MS

    Immune cells have receptors for hormones, and these hormones affect immune function.

    Estrogen may enhance autoimmunity at low levels. However, at higher concentrations, it has the opposite effect – it protects against MS by shifting from inflammatory Th1 to Th2.

    This might explain why MS and several other Th1-dominant autoimmune diseases improve during pregnancy, since estrogen level increases during pregnancy.

    On the other hand, prolactin and growth hormones, which are also higher in women, enhance autoimmunity.

    2) Viral Infections May Cause or Precipitate MS

    There are two general hypotheses for the infectious causes of MS, both involving a widespread microbe rather than a rare pathogen.

    The first hypothesis is called the poliomyelitis hypothesis or hygiene hypothesis, which involves viruses that increase the risk of developing MS if acquired in late childhood or during adulthood. Acquiring the virus before, would produce protective immunity in the individual.

    One of the main predicted is the Epstein-Barr virus, which causes mononucleosis, and similar latent viruses might be also the causal agents of MS.

    Despite finding a positive correlation, observational studies have not identified a single infectious pathogen as the causative factor for MS.

    The second hypothesis is the prevalence hypothesis, which states that MS is caused by a pathogen that is predisposed to areas with a high MS prevalence. This hypothesis is based on the premise that the widespread pathogen is initially inactive (asymptomatic) until, many years after the primary infection, it causes MS symptoms.

    3) Vitamin D Deficiency and Lack of Sun Exposure

    This hypothesis is supported by the environmental risk factor for vitamin D deficiency. Increasing exposure to sunlight or ingesting vitamin D is correlated with decreased MS risks. This correlation is supported by epidemiological evidence that MS frequencies are more prevalent in high latitudes, where sunlight is of lower intensity.

    4) Stress May Precipitate or Worsen MS

    For stress and MS, the most compelling factors include:

    - Stressor duration: Long-term stressors have contributed to MS relapses
    - Severity of the stressor: Intermediate to strong intensity stressors are more strongly associated with MS relapses
    - Frequency of the stressor: Accumulation of stress increases the risk of MS relapses
    - Cardiovascular reactivity and heart rate: Higher heart rate and cardiovascular responses to stressors will increase the risk of relapses
    - Social support: A stronger social support and network can reduce relapses associated with MS

    5) Dietary Factors that May Increase the Risk of MS

    The results of dietary studies and risks of MS need to be interpreted with caution as most of them are observational. Such studies are prone to confounding factors or bias and typically do not imply causation without additional evidence. Other than observational studies, there is one case-controlled study.

    Saturated Fat, Polyunsaturated Fats, and Multiple Sclerosis

    There is one cohort study (observing participants over a long period) on the effects of dietary fat and risks of developing MS. In this study, neither animal nor saturated fats were associated with an increased risk for MS.

    Higher omega-3 fatty acid (alpha linolenic, but not EPA or DHA) intake may reduce the risk of MS.

    Dietary Antioxidants

    Lower vitamin C and juice intake, but not intake of vitamin E, beta-carotene, or fruits and vegetables increased the risk of MS. However, other studies did not find any significant association between vitamins C, E, or fruits and vegetable intake, and the risks of MS [R, R, R]. However, the benefits of these nutrients and antioxidant intakes cannot be excluded.

    Low consumption of plant-based foods and high consumption of animal products increase the risks of MS.

    Obesity May Increase the Risk of MS

    Higher body mass index is associated with an increased risk of developing MS, although, interestingly, taller women are more likely to develop MS than shorter ones.

    Dairy Product Consumption May Increase the Risks of MS

    Consumption of milk, rather than cheese, seems to increase the risk of MS.

    A milk protein called butyrophilin has some similarities (molecular mimicry) to a myelin protein called myelin oligodendrocyte glycoprotein [R]. If the body develops an antibody against this protein, this can lead to MS. In a rat model of MS (Experimental Autoimmune Encephalitis), butyrophilin can trigger MS-like symptoms.

    Toxicity-Related Risk Factors of MS

    Some chemicals and toxic substances can cause the immune system to malfunction, which can lead to MS.

    6) Cigarette Smoking

    Cigarette smoke:

    - Increases oxidative stress
    - Contain neurotoxic substances
    - May alter immune function and cause brain inflammation

    Therefore, smoking not only increases the risks of MS but also accelerate the progression from relapsing-remitting to secondary progressive MS.

    In addition, cigarette smoking can increase the risk for other immune diseases.

    7) Vaccine Adjuvants

    Vaccine adjuvants are immune-stimulating agents that are typically contained in vaccines to increase the immune response to the antigen in the vaccine. They can be microbial products such as LPS-like substances, mineral salts, metals like aluminum and thimerosal, emulsions, microparticles, and liposomes.

    How adjuvants make vaccines work better are not completely understood. Generally, the adjuvants stimulate the immune system, including inflammatory immune responses. Vaccines that are made to raise an immune response against bacteria and viruses typically trigger cellular (Th1) immunity.

    In some cases, vaccine adjuvants can trigger autoimmune responses, but these are rare and only case reports are available. So far, case-control and large-cohort studies have not been able to demonstrate that vaccines cause MS.

    In MS patients, it is recommended that vaccines without adjuvants be used instead.

    8) Toxic Chemical Exposures and MS

    Most studies that look at occupational toxic exposures and MS risk focused on organic solvents.

    In an Italian study, people who worked in the shoes and leather industry had a higher prevalence ratio of MS ~4.9 compared to other people.

    Many other studies have shown that occupational chemical exposures somewhat increase the risk of developing MS. However, all of these cases were based on prevalent cases (those who already developed the disease) and may not directly prove cause and effect.

    https://selfhacked.com/blog/causes-s...ple-sclerosis/
    Last edited by Sherman Peabody; 11-06-2017 at 03:07 PM.

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