Multiple Sclerosis Overview: Symptoms, Causes and Treatments

Phenotypes

MS is most prevalent in young adulthood, with a higher percentage of females than males diagnosed, most commonly between the ages of 20-40 years (Garg and Smith, 2015). There are four clinical types of MS; relapse remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS).

These different clinical types are important for prognosis of disease and treatment pathway for each patient. RRMS, classified as discrete attacks occurring over a few days followed by periods of recovery with no attacks, is the most common clinical type found in 87% of patients (Loma and Heyman, 2011). No decline neurological function is shown during recovery periods.

During RRMS, lesions are formed in the central nervous system (CNS) by activated immune cells, and inflammatory attacks on the myelin and nerve fibres occur. Most patients progress gradually from RRMS to SPMS after a period of recurring relapses and gradual neurological deterioration as an effect.

PPMS is seen only in around 10% of patients, classified as progressive accumulation of disability from onset with no or minor relapses. There is a large effect on nerves of the spinal cord and fever brain lesions (Gholamzad et al., 2018). Less commonly, around 15% of patients skip straight from RRMS to PRMS stage, expressing a fast decline of disability from onset with clear relapses with or without full recovery (Ghasemi et al., 2017). PPMS and PRMS can only be distinguished at later stages when relapses occur.

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With no single diagnostic test for MS, diagnosis of disease is based on symptoms and clinical presentation. More recently neuroimaging, a form of brain imaging used to image the structure and function of the nervous system, and cerebrospinal fluid (CSF) analysis, a group of tests used to evaluate the substances in the CSF are used to help diagnosis. CSF analysis looks for oligoclonal bands, IgG index and inflammatory markers (Garg and Smith, 2015). Abnormalilities in CSF include positive oligoclonal bands and inflammatory markers, found present in 85% patients with MS (Garg and Smith, 2015).

Symptoms

MS patients may express a broad range of symptoms over the course of their disease and lifetime, resulting from the involvement of sensory, motor, visual and brainstem pathways in the course of disease.

The extent of tissue damage and location of the lesion in the CNS express different symptoms ranging in severity and location in the clinical types of MS. The most common symptom, found in 90% of patients if clinically isolated syndrome (CIS) (Tullman, 2013). CIS is the first episode of neurological symptoms shown by a patient, usually lasting 24 hours or more.

An episode of damage is either monofocal, which expresses symptoms at a single site of the CNS, or multifocal, resulting in a wide range of symptoms across multiple sites (Tullman, 2013). Monofocal damage includes optic neuritis and other direct problems of the eye, whereas multifocal expresses broad symptoms including dizziness and numbness.

Symptoms range from primarily changes in vision (diplopia, blurred, pain), walking difficulties (due to weakness fatigue), to more severe and disabling symptoms including intestinal and urinary system dysfunction (constipation and bladder dysfunction), cognitive and emotional impairment (inability to learn and depression), dizziness and sexual problems (Ghasemi et al., 2017).

The harsh associated symptoms of sexual, intestinal and urinary symptom dysfunction are shown in 5% of patients, most commonly from PRMS category (Ghasemi et al., 2017). Without treatments these symptoms can cause unalterable and tough alterations to a patient’s everyday lifestyle.

Causes/Influencing factors/Aetiology

The aetiology of MS is thought to be caused by immune dysregulation triggered by genetic and environmental factors. Although MS is not defined as an inherited disease, there is evidence of strong genetic components to the aetiology shown by family aggregation and clustering. The low risk of 2-5% for developing MS in the general population increases by 10-50 times in first degree relatives of patients (Garg and Smith, 2015). There is also a high concordance rate in monozygotic twins of 1/3 (Garg and Smith, 2015). Several gene loci have also been expressed as risk factors, with the major histocompatibility complex (MHC) human leukocyte antigen (HLA).

The definite role of genetic factors remains undefined, with a larger emphasis on environmental factors which show more direct links to risks of developing the disease. There are multiple environmental factors linked to MS.

The Epstein Barr Virus (EBV) is a speculative risk factor, the link starting on the basis that both MS and infectious mononucleosis (an infection caused by EBV) occur roughly at the same age and coincide geographically. The risk of developing MS is approximately 15-fold higher in individuals with a history of EBV in childhood, and 30-fold higher in individuals infected with EBV in later life (Garg and Smith, 2015).  Although EBV seropositivity is seen frequently in MS, patients can also be seronegative, concluding EBV to be a strong risk factor but not a direct cause (Tselis, 2012).

The active form of vitamin D, 1,25 di-hydroxyvitamin D (1,25(OH)₂D), has effects on gene expression at the nuclear level, as well as a wide range of effects in the human body (O’Gorman et al., 2012). Observational epidemiological studies have shown beneficial roles of vitamin D in MS. A study by Munger in 2004 examined dietary vitamin D intake directly in relation to risk of MS in two large cohorts of women (Munger et al., 2004). The results showed a correlation of low vitamin D intake with increased risk of developing MS, with 173 cases with onset symptoms confirmed in follow ups (Munger et al., 2004).

The geographical location of countries across the world has shown a trend of increasing prevalence of MS with increasing latitude north and south of the equator. Latitude effects are thought to be related to decreasing gradients of sunlight and therefore decreased production of vitamin D. Geographical location is also dependant on lifestyle changes, diet and life expectancy. Dietary sources of vitamin D such as oily fish may compensate the lack of UV exposure.

More recently, lifestyle factors such as smoking have emerged as associated risks for MS. Cigarette smoke contains many unidentified components, some known effects of these substances include pro-inflammatory actions, direct tissue damage and increased apoptosis and anti-oestrogen effects (O’Gorman et al., 2012). The smoke also acts on the cellular and humoral components of the immune system, which can cause immunosupression and inhibitory effects, causing damage and therefore vulnerability to a person’s immune system. (O’Gorman et al., 2012). Smoking is viewed as general lifestyle risk with important but modest implications with MS and other autoimmune disorders.

Treatments

There is currently no cure for MS, with treatments designed to suppress symptoms and prevent progression of disease by targeting inflammation and immune activation.

Corticosteroids are the preliminary treatment, used to shorten duration of relapses and accelerate recovery for acute exacerbations. These steroids have anti-inflammatory effects, and are associated with immunomodulation, reduction of cerebral edema, and restoration of the blood brain barrier (BBB) (Loma and Heyman, 2011). Methylprednisolone is the commonly prescribed corticosteroid, with a course of  500 to 1000 mg/day for 3 to 10 days recommended for patients suffering acute attacks (Calabresi, 2004). Corticosteroids however do not alter the long-term course of MS or improve the overall degree of recovery.

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Disease modifying treatments (DMT’s) aim to reduce frequency of relapses and number of lesions, slowing disability progression and therefore help to alleviate symptoms. DMT’s are used in all phases of the disease, however have shown most success for patients with RRMS and CIS (Garg and Smith, 2015). Currently there are 8 self-ijnected medications, 4 infused medications and 3 oral mediacations FDA approved as DMT treatments for MS (Garry et al., 2018).

Self-injected DMT’s include Beta Interferons and Glatiramer Acetate. Beta Interferons were first approved by the FDA for MS treatment in 1993 (Ghasemi et al., 2017).

Interferon beta-1a (Avonex, Plegridy, Refib) is a once weekly intramuscular interferon, whereas Interferon beta-1b (Betaseron, Extavia) is a subcutaneous interferon injected 3 times a week during treatment (Calabresi, 2004).

These naturally occurring cytokines account for therapeutic effects through their variety of immunomodulation and antiviral activities.

In multiple randomised, double-blind placebo-controlled trials conducted by  Li and Paty, the use of beta interferons resulted in a 50 to 80 percent reduction in inflammatory lesions visualised on brain MRI scans (Li and Paty, 1999) (Paty and Li, 1993).

Common side effects of beta interferons include flu-like symptoms and injection site reactions, with less common effects of thyroid abnormalities, liver enzyme elevation, depression, and leukopenia or anaemia (Garg and Smith, 2015).

Glatiramer Acetate (GA) is a synthetic complex of 4 amino acids that mimics myelin basic protein (MBP), using structural similarity of MBP to block the formation of myelin reactive T cells, and produce GA-specific regulatory T-cell expression and Th2 anti-inflammatory cytokines (Garg and Smith, 2015).

This alteration of T cell differentiation and production of Th2 cells with inflammatory properties helps to slow brain atrophy and protect the brain from axonal damage (Gholamzad et al., 2018). GA’s are well tolerated with common symptoms limited to mild pain and itching from injection site reactions (Gholamzad et al., 2018).

Infused medications consist of monoclonal antibodies (mAb), with different types differentiated by their structural similarity to the human antibody structure.

Monoclonal antibodies Alemtuzumab, Ocrelizumab and Natalizumab are used for MS treatment, with each mAb developed to bind to a specific target molecule (Garry et al., 2018). Natalizumab is a humanised mAb immunoglobulin (Ig)G4 antibody that targets CD49, 4 subunit of antigen-4 (VLA-4) receptor (Loma and Heyman, 2011). Binding of the (Ig)G4 antibody to CD49 prevents adhesion between the endothelial wall and the immune cell, blocking migration of leukocytes into the CNS (Loma and Heyman, 2011).

Side effects include headaches, fatigue, infections of urinary and respiratory tract. Cases of progressive multifocal leukoencephalopathy (PML) reactivation have also been reported  due to prolonged and severe immunosupression (Rommer et al., 2014). Ocrelizumab has shown good efficacy in clinical trials for RRMS patients, with ongoing phase III trials in PPMS (Rommer et al., 2014).

There are 3 oral therapies for MS treatment; Fingolimod, Teriflunomide and Di-methylfumarate. In comparison to injectable therapies, phase III studies have showed better or comparable effect on relapse rate reduction, MRI lesions and disability progression, with fewer and less severe side effects.

HSCT

Hematopoietic stem cell transplantation is the transplantation of multipotent stem cells, derived autologously from the patient’s own bone marrow or peripheral blood.