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Clinical Features
Clinical Features
What is Multiple Sclerosis?
Multiple sclerosis is an autoimmune disorder in the central nervous system (CNS) in which the patient's own immune system attacks primarily the white matter and causes multiple sclerotic lesions. The cause of MS is unknown, but it is believed to be a cause of both genetic and environmental factors.
Neurons have cells that support them called glial cells. One of these glial cells named the oligodendrocyte forms projections and wrap its membrane around the axon of multiple neurons up to 100 times (Fig. 1). Once wrapped around the axon, the membrane is caused myelin. Myelin is crucial for providing support to the neuron and maintaining homeostasis. The myelin is made mostly of lipids, and it also insulates the axons to lower their capacitance and allow electrical signaling to pass more quickly down the axons. In multiple sclerosis, the immune cells target and destroy the myelin, leading to the death of the oligodendrocyte. Since it is no longer able to assist in maintaining homeostasis of the neuron, it eventually dies as well. Recall that a single oligodendrocyte supports many neurons at once, so the death of even one oligodendrocyte can cause the death of many neurons, resulting in a sclerotic lesion. In multiple sclerosis, these autoimmune attacks are acute and focal, meaning that one attack does not cause widespread damage of neural tissue.
Signs and Symptoms
An autoimmune attack can occur anywhere in the CNS, so symptoms can vary greatly from patient to patient depending on the locations of their lesions. However, because the attacks are localized, the symptoms are focal and representative of the specific locations of the affected neurons.
One common symptoms of MS are vision changes. If the attacks happen in the optic nerve or other areas of the visual pathway, it can lead to symptoms such as diplopia, blurred vision, and optic neuritis that can also include painful eye movements. The patient can also experience other sensory deficits such as tingling, numbness, dizziness, or abnormal pain throughout the body. MS can also affect motor areas, leading to fatigue and weakness, especially in the extremities. It can also lead to rigid muscles and myalgias. If the lesions occur in the spinal cord, it can also lead to bladder or sexual dysfunctions. Of course, cognition can also be affected by MS. A patient may experience mood changes, brain fog, poor memory, poor judgement, or difficulty concentrating [1].
Diagnosis
Due to the nature of MS, symptoms can vary widely, so diagnosis involves ruling out other possible ailments through various tests. For example, a blood test may be performed and rule out any electrolyte abnormalities. For neurological symptoms, a physician may perform a lumbar puncture, in which they tap into the cerebrospinal fluid in the spine to test it. A lumbar puncture may rule out infection, however, the cerebrospinal fluid can also contain biomarkers for MS [2]. Lastly, MRI is a common tool for diagnosing MS. In fact, MS is usually diagnosed through recognizing symptoms and performing repeated MRIs to monitor the progression of the lesions, as shown in Fig. 2.
Along with ruling out differential diagnoses, MS is often diagnosed by employing the McDonald Criteria. These criteria explains that dissemination in space and dissemination in time must be observed to make a diagnosis of MS. Dissemination in space describes the presence of sclerotic lesions in at least two of the four CNS regions described in McDonald Criteria. Dissemination in time describes the appearance of new lesions on MRI over time. Along with these criteria, the number of clinical attacks (appearance or worsening of symptoms) and the number of lesions with clinical evidence (lesions that can be linked to specific symptoms) will also play a role in determining which and how many of these criteria are needed for a diagnosis to be made. Some examples of the criteria needed in specific situations can be seen in Fig. 3.
Clinical Course
MS always begins with the presence of sclerotic lesions in the CNS. A person may experience a pre symptomatic phase of the disease where autoimmune attacks are occurring, but the patient has yet to experience any symptoms. Once the patient does begin to experience symptoms, they may seek treatment and be diagnosed with clinically isolated syndrome (CIS). As the name alludes to, CIS refers to a short bout of neurological deficits (also referred to as clinical disabilities) that coincide with the formation of sclerotic lesions in the CNS. Recall that a diagnosis of MS requires dissemination in space and time, along with clinical attacks and lesions with objective clinical evidence. Without all of these factors, a diagnosis of MS cannot be made, and the person is diagnosed with CIS in the meantime. Once dissemination in time and space do occur, a diagnosis of MS can be made, and the disease can progress in various directions.
Relapse-remitting MS is by far the most common form of MS. It is characterized by events of clinical disability (flare ups) that are followed by periods of remission. Throughout the course of the disease, the baseline for remission remains the same. In other words, the disease does not worsen unless it progresses into a more severe form of MS. However, the severity of the flare ups can vary from mild to severe.
About 50% of relapse-remitting MS evolve into secondary-progressive MS. In this worsened form of the disease, there are still periods of flare ups, however, the baseline during the remission stage continuously gets worse throughout the course of the disease. Eventually, the baseline becomes just as severe as the flare ups, and the patient's condition consists of continued and severe neurological deficits.
Another form of MS is primary-progressive MS. In this form, the severity of the patient's baseline steadily rises with no clear periods of flare ups or remission. In other words, the patient's condition becomes increasingly worse with no periods where the patients' symptoms become significantly better or worse.
The last form of MS is progressive-relapsing MS. This form is similar to secondary-progressive MS. It involves a gradually worsening baseline with intermittent flare ups. The main distinction between the two is that progressive-relapsing MS includes flare ups that only occur occasionally and much less frequently that in secondary-progressive MS.
Epidemiology
Epidemiology
MS affects 2.8 people worldwide with the onset normally occurring in the age range of 20-40.
MS affects females significantly more than males with only one male diagnosed for every three females diagnosed. Females consistently experience a higher incidence and prevalence of MS as shown in Fig. 5-6. Fig. 6 also shows that there is a higher prevalence of middle aged and elderly people with MS. This can be attributed to sometimes slow progression of the disease and high-quality treatments that target the mechanisms of the disease.
In the United States: about 3 in every 1000 people are diagnosed with MS [4]. There is a total of about 1 million people affected with the disease in the country [5].
Worldwide: Among countries that reported, the global incidence is 2.1 people per 100,000 per year. About 2.8 million people worldwide live with MS. [6] Fig. 4, shows North America and Europe are some of those most affected by MS while those in Asia, Africa, and South America aren't affected at as great a rate.
Risk Factors
Risk Factors
Genetic Susceptibility
While MS is not considered to be an inheritable disease, there does appear to be a genetic predisposition. In a set of identical twins, if one twin has MS, 33% of the time the other twin is also affected. In fraternal twins, if one twin has it, the other twin is also affected 5% of the time. If one of your first-degree relatives (mom, dad, etc.) has MS, there is a 2-5% risk you will get it. [7]
Gender
As mentioned before, females are three times more likely to develop MS. This is likely attributed to normal physiological events like menopause that result in fluctuations and drops in estrogen, which explains the increase of prevalence in MS in women as they age which can be seen in Fig. 6. Relapses are also seen less in women in the second and third trimesters of pregnancy and while breastfeeding when levels of estrogen are high. On the other hand, as estrogen decreases, such as right after giving birth and during pre-eclampsia, higher number of relapses occur.
Infectious Agents
In the Faroe Islands from 1900-1943 there were no reported cases of MS, however from 1943-1960 (after troop occupation of the islands), there were 24 reported cases of MS.
A study published in 2022 took over 10 million blood samples and over 62 million serum samples and found that, out of 801 of them who developed MS, all of them had tested positive for Epstein-Barr Virus at some point, and there was no correlation with herpesvirus [8]. Although over 90% of the population has been exposed to the virus, and most people do not get MS.
Latitude and Vitamin D
The latitude where you live is the most consistent risk factor for MS, with the latitude where you spent the first 15 years of your life having the largest impact. The risk comes to people who live above 45 degrees latitude. As you move away from the equator, the UV density decreases. UV is needed to create Vitamin D from cholesterol. Vitamin D has neuroprotective factors as it can influence T cells and microglia converting them into an anti-inflammatory state, which is opposite from the mechanism in MS.
Biology of Disease
Biology of Disease
Immune System and Autoimmune Response
The first step leading to the autoimmune response is lymphocytes (T and B cells) crossing the blood brain barrier into the CNS.
There are two relevant types of T cells, the CD4+ T cells and CD8+ T cells. Once in the CNS, the CD4+ T cells will recognize the myelin antigen that is presented to them by the microglia. The CD4+ T cells will then release pro-inflammatory cytokines. These will in turn activate CD8+ T cells, which are cytotoxic and will attack the myelin.
B cells also contribute to the destruction of myelin, but they do not directly attack them. They produce and release antibodies attracted to the myelin antigen. These antibodies will recruit other immune cells to attack and destroy the myelin.
Oligodendrocytes and Myelin
Oligodendrocytes are the glial cell in the CNS that provide the myelin to the neurons. One oligodendrocyte will grow multiple projections and wrap its membrane around multiple axons up to 100 times. Myelin has several roles in assisting neuronal function. The first function is to allow for saltatory conduction, which greatly increases the speed of the action potential down the axon. In a myelinated axon, all of the membrane bound proteins are highly expressed between the myelin at the Nodes of Ranvier. The action potential will move from node to node so quickly that the signal will appear to skip down the axon as it opens the highly concentrated voltage gated ion channels. In an unmyelinated axon, the voltage gated ion channels are evenly distributed along the axon, and in order for the signal to propagate down the axon it must open each channel step by step as it moves down the axon. These difference in conduction can be seen in Fig. 7. Myelin also decreases membrane capacitance of the neuron, which also helps to speed up the action potential. Without myelin, the positive ions on the outside of the cell attract the negatively charged molecules inside the cell, causing them to cluster near the membrane. When myelin is present, it creates a larger space between these opposite charges, and it prevents the intracellular molecules from gathering near the membrane, shown in Fig. 8. Because of this, when sodium ions enter at the Node of Ranvier, they will not be impeded by other molecules as much as they would be if the myelin was not present.
By wrapping around the axon, myelin also as provides physical support to the relatively fragile axon. For proper support of the neuron, the oligodendrocyte only needs to wrap around the axon a few times, but with it wrapping up to 100 times, it means that the oligodendrocyte can withstand attack and extracellular stress to keep providing support to the neuron. The oligodendrocyte also offers trophic support for the neuron. It can release neurotrophic factors that support the growth and plasticity of the neurons.
The last role of myelin is to assist with energy efficiency of the axon. Because the voltage gated ion channels are only present in the Nodes of Ranvier in myelinated axons, they need to use much less energy since the ATPase pumps only need to be present at these nodes, rather than all of the way down the axon in unmyelinated cells. These pumps use huge amounts of glucose so needing less of them along the axon is import for energy efficiency.
The Kir4.1 transporter is found on the oligodendrocyte and helps with the reuptake of extracellular K+. This reuptake of K+ leads to glycolysis occurring within the oligodendrocyte and producing lactate. This is then transported to the neuron where it is converted into pyruvate which is used to complete the rest of cellular respiration and the mass production of ATP. This is beneficial to the neuron because glycolysis takes 2 ATP molecules to run, and with the support of the oligodendrocyte, it does not need to spend this ATP to run glycolysis.
Virtual Hypoxia
There is a distinction between an unmyelinated axon and a demyelinated axon. As mentioned before, an unmyelinated axon never had myelin on it, and it has an even distribution of membrane bound proteins (ion channels, ATPases, etc.) all the way down the axon. A demyelinated axon, on the other hand, is relatively bare where the myelin once was. The cell begins to express proteins once the myelin is gone, but the ion channels are relatively weak and leaky, resulting in poor conduction in those areas of demyelination.
Recall in MS, the axon becomes demyelinated as the myelin is attacked by the immune system. In order to continue action potential propagation, the high concentration of transporters found in the Nodes of Ranvier are distributed across the axon. Also recall that myelin and the oligodendrocyte provide an energy source to the axon: lactate. In MS, the oligodendrocyte is damaged or killed and can no longer supply this source of energy to the neuron. The lack of energy leads to a buildup of intracellular Na ions as there is not enough ATP for the Na/K pumps to maintain the ion gradient. To help facilitate Na+ moving with its concentration gradient, the Na/Ca exchanger (which runs passively) reverses its normal flow and starts pumping Na ions out of the cell and Ca ions into the cell. Excess calcium in the cell is cytotoxic, and it triggers several cascades that lead to neurodegeneration and cell death. This process is known as virtual hypoxia because it mimics ischemic conditions when the cell does not have an adequate supply of oxygen and glucose. In virtual hypoxia, the cell still has a supply of glucose and oxygen, but lack of support from the oligodendrocyte leads to the death of the neuron.
The symptoms that correlate with the lesions are going to depend on where the lesions occur. For example, if lesions present in the occipital lobe, a person may experience vision changes. This is because these lesions are focal and will only cause symptoms correlated to their location. Another example would be with the primary motor cortex. This area of the brain sends motor commands to the muscles. A lesion in the left primary motor cortex will not have widespread effects. Since MS is focal in nature, this lesion in the left hemisphere would only affect motor function on the right side of the body, and even then, it will only affect certain areas depending on the size and severity of the lesion.
Remyelination
After oligodendrocyte damage, oligodendrocyte precursor cells (OPC) are differentiated into new oligodendrocytes. These new oligodendrocytes remyelinate the axons. Although this remyelination is not as strong as the original as the new myelin sheath is thinner and covers a smaller portion of the axon. This process of remyelination is the cause for remission in those with relapse-remitting MS as the brain is able to temporarily repair the damage. Unfortunately, as the person ages and uses up these OPCs, their supply dwindles, and the myelin will get progressively weaker each time remyelination occurs. Once the supply runs out, the affected person's MS will progress into secondary-progressive MS because repairs can no longer be made, and the person's condition continually worsens without getting any better.
Treatments and Outlook
Treatments and Outlook
Medications
Interferon beta is a first line defense medication for MS. Interferon beta is a cytokine that has anti-inflammatory properties. It also inhibits the activation of T cells, meaning they do not enter the CNS and cause damage. Because of this, interferon beta can lead to a lower rate of remission and formation of new lesions.
Fingolimod is a drug that works by targeting immune cells and prevents them from entering circulation. Immune cells, oligodendrocytes, and neurons express S1P receptors, which have various effects. Fingolimod modulates these receptors. By modulating S1P receptors on T cells, it forces them to remain sequestered in the lymph nodes, meaning they cannot enter the CNS and attack myelin. By targeting S1P receptors on oligodendrocytes and neurons, it promotes cell survival and can even result in possible myelin repair.
Glatiramer Acetate is an amino acid polypeptide that mimics a specific antigen that is present on myelin and baits the T cells into binding to it. Normally when T cells are exposed to myelin antigens, it causes them to release pro-inflammatory cytokines, which lead to the damage of the oligodendrocytes. However, when T cells are exposed to glatiramer acetate in circulation, the T cells cross the blood brain barrier, and they release anti-inflammatory cytokines, rather than pro-inflammatory ones that are released normally [9].
Monoclonal antibodies are synthetic antibodies that mimic the immune response. This method of treating MS can be different in that, rather than passively suppressing the immune response, it causes the destruction of immune cells. They work by binding to the antigens of T and B cells and recruit other immune cells to destroy them. Natalizumab is a type of monoclonal antibody that works by binding to antigens on T and B cells and prevents them from entering the blood brain barrier. Because of this, they are unable to target myelin and cause damage in the CNS. Mitoxantrone is an anti-cancer drug that can also be used to treat MS. It works by disrupting the proliferation of T and B cells, effectively reducing the amount of them that exist in circulation.
Experimental Treatments
The outlook for MS is generally good because we have a number of these medications that target the mechanisms of the disease rather than simply treating the symptoms. However, it should be noted that these medications are specially made and are incredibly expensive. Because of this, they may not be accessible to people who do not have medical insurance or populations who experience disparities in medical care. Luckily, there are a number of experimental treatments that could serve as cheaper alternatives. Not only this, but they also work without compromising the patients' immune systems.
Sodium channel blockers are one of these experimental treatments. Recall from the biology section that demyelinated segments of the axon express sodium channels that are leaky and allow an excess of sodium into the cell, which eventually leads to the entrance of excess calcium into the cell and cytotoxicity. Also recall that microglia are partly responsible for the release of inflammatory cytokines. Sodium plays a role in this process as well. Blocking sodium channels would not only support the maintenance of the ion gradient in the neuron, but it would also play a role in suppressing the release of harmful cytokines.
Estriol is an estrogen, and it is known that estrogen has neuroprotective properties. It is particularly beneficial to reducing inflammation. Clinical trials have shown that giving estriol in conjunction with glatiramer acetate has been shown to reduce relapse.
Potassium channel blockers such as Dalfampridine are also being studied to treat MS. When myelin is removed from the axon, the action potential may not be strong enough to pass through the demyelinated segments. Potassium channel blockers prevent potassium from leaving the cell, effectively broadening the action potential by insulating the axon. This act allows the depolarization step of the action potential to occur for longer, allowing it enough time to pass through the demyelinated segment before repolarization occurs. This does not target the mechanism of the disease, but it could be beneficial in treating the symptoms, especially in patients who no longer have the ability to replace destroyed oligodendrocytes.
Maintaining a low body temperature is another experimental treatment for MS. This is another method that will mainly treat the symptoms, rather than target the mechanism of the disease. It has been shown that maintaining a lower body temperature slows the action potential, effectively broadening it and allowing it to pass through demyelinated segments without dying out. This may be the most affordable option, as a person can avoid hot climates, stay in air-conditioned areas, and take cold showers to remain cool. Another method to remain cool is to wear active cooling devices such as cooling vests or umbrellas. Lastly, a person can use cannabis to lower their body temperature. The THC component of cannabis has been shown to not only reduce body temperature, but it can also treat spasticity and muscle stiffness caused by MS. Another component of cannabis, CBD, can reduce the psychoactivity of the THC. Because of this, THC and CBD should be given in a one-to-one ratio to treat MS.
References
Images
Fig. 1 The Electrospinning Company. (2022, July 5). Myelination Assay | The Electrospinning Company. https://www.electrospinning.co.uk/case-studies/myelination-assay/
Fig. 2 Multiple sclerosis - Diagnosis and treatment - Mayo Clinic. (n.d.). https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/diagnosis-treatment/drc-20350274
Fig. 3 Jakimovski, D., Bittner, S., Zivadinov, R., Morrow, S. A., Benedict, R. H., Zipp, F., & Weinstock-Guttman, B. (2023). Multiple sclerosis. The Lancet, 403(10422), 183–202. https://doi.org/10.1016/s0140-6736(23)01473-3
Fig. 4 Dobson, S. (2023, November 29). New prevalence and incidence data now available in the atlas of ms. MS International Federation. https://www.msif.org/news/2023/08/21/new-prevalence-and-incidence-data-now-available-in-the-atlas-of-ms/
Fig. 5-6 Grytten, N., Aarseth, J. H., Lunde, H. M., & Myhr, K. M. (2016). A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway. Journal of neurology, neurosurgery, and psychiatry, 87(1), 100–105. https://doi.org/10.1136/jnnp-2014-309906
Fig. 7 Encyclopædia Britannica, inc. (n.d.). Encyclopædia Britannica. https://kids.britannica.com/students/assembly/view/66781
Fig. 8 Neurophysiology part 3 flashcards. (n.d.). https://quizlet.com/513873406/neurophysiology-part-3-flash-cards
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