Multiple Sclerosis: Pathogenesis and Treatment Options

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Multiple Sclerosis: Pathogenesis and Treatment Options

Multiple Sclerosis, widely referred to as MS, is a lifelong, progressive medical condition that affects the central nervous system. There are currently around two million people worldwide that suffer from the condition and it is currently incurable. It affects both white and grey matters of the CNS and its underlying neuropathology leads to loss of myelin/oligodendrocyte complex, as well as neuronal and axonal degeneration. It can cause minor or serious disability, and although it may be possible to treat the symptoms, MS sufferers also have a slightly reduced average life expectancy. The condition is most commonly diagnosed within people in their 20s and 30s, however it may develop at any age, and it is more commonly found in women than men.

The National Institute of Neurological Disorders and Stroke in the United States report that vision problems are often the initial symptom of MS. This is due to inflammation affecting the optic nerves. Changes in vision include, blurriness, double vision, colour-distortion, loss thereof and pain when looking up or to the side. Other symptoms include; weakness and fatigue, tingling and numbing sensations within the arms, legs, fingers and face, pains (both short and long term) and spasms, and dizziness or loss of balance. The vast majority of people with MS also experience some degree of bladder dysfunction. Bladder issues occur when lesions affect nerve signals that control the bladder and urinary function.

Although the aetiology of multiple sclerosis is elusive, the pathogenesis has been derived from the basic CNS tissues of MS patients. There is still ongoing research into the autoimmune nature of MS, however it is well established that the immune system participates in the destruction of myelin and nervous cells. The destruction of myelin (demyelination), inflammation, and potential defects in synaptic transmission and putative circulating blocking factors are the main causes of the negative symptoms associated with MS.

Despite the disease process in multiple sclerosis appearing to be directed mainly against glial cells, the clinical features arise primarily from the electrophysiological consequences for axons. This can result in many different effects, from axonal hyperexcitability, spontaneous generation of spurious ectopic impulses, and even a complete conduction block. While the conduction block arises from factors such as demyelination, hyperexcitability represents a maladaptive response to demyelination, involving an inappropriate balance of ion channels across the segment of the demyelinated membrane. In MS, myelin-forming oligodendrocytes are the targets of inflammatory and immune attacks. OLG death by apoptosis or necrosis causes the cell loss seen in MS plaques.

Plaques of inflammatory demyelination within the central nervous system are the pathologic hallmark of multiple sclerosis, and the myelin destruction is a vital element of this plaque. Lesions are comprised of many pathologic and immunologic features. Acute MS plaque represents the earliest stage of lesion formation. It is characterised by inflammatory infiltration, combined with demyelination which is distributed throughout the lesion. Typical features of the acute plaque include ill-defined margins of myelin loss, infiltration of immune cells and parenchymal edema. The constituents of immune cell influx around vessels (termed perivascular cuffing) include lymphocytes (predominantly T cells), monocytes and macrophages. A portion of major histocompatibility class II (MHCII)-expressing cells that are distributed evenly throughout the lesion, are loaded with lipids and participate in actively stripping the myelin from axons. While oligodendrocyte apoptosis has been observed the degree of oligodendrocyte loss within active lesions can be variable. Complement C5 promotes axon preservation and new myelin formation, which protect OLGs from apoptosis. These findings indicate that activated complement C5b-9 plays a proinflammatory role in acute MS but may also protect OLGs from death in chronic MS. Glial reactivity throughout the lesion is noted, particularly hypertrophic astrocytes. However, dense glial scarring is not typical of the acute plaque.

Inflammatory mediators, such as axonal degeneration, and synaptic dysfunction resulting from cortical lesions are also large contributors towards the pathophysiology of multiple sclerosis. Specifically, these can be linked to some of the more major functional deficits, such as numbness, paralysis and blindness. The variety in the symptoms of multiple sclerosis can be partly explained due to the conduction properties of affected axons, though the explanation for these are mainly anatomical. This is due to the distribution of lesions in different patients, meaning that a magnitude of separate pathways are disturbed, which results in the diversity of the symptoms.

The main cause of relapse or remission of multiple sclerosis (loss of function) is the failure of axonal conduction at the site of a lesion. Function is lost frequently in inflammatory demyelinating lesions, as several mechanisms are operating, each of which can be a contributing factor towards conduction block. Other causes of remission can arise from a range of mechanisms. including restoration of conduction due to the resolution of inflammation, axolemmal plasticity restoring conduction to the demyelinated axon, adaptive synaptic changes, and repair by remyelination. Unfortunately, over time these compensatory processes become less effective and axonal degeneration becomes a more dominant issue.

Microglia are the intrinsic immune cells in the CNS; they play an important role in the processes of demyelination and remyelination in multiple sclerosis. Microglia can function as antigen-presenting cells and phagocytes. Microglia were once considered to be the same cell type as macrophages. Microglia express major histocompatibility (MHC) antigens I and II and secrete many proinflammatory and anti-inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-± (TNF-±), and IL-10.

It has been observed that the type of microglial cell and of astrocyte activation and proliferation observed suggests that CNS cells contribute and also may play a critical role in disease progression. Astrocytes could contribute to this process through several mechanisms. This could be as part of the innate immune system, as a source of cytotoxic factors, inhibiting remyelination and axonal regeneration by forming a glial scar, or by potentially contributing to axonal and mitochondrial dysfunction. Furthermore, regulatory mechanisms that are mediated by astrocytes can be affected by aging. Astrocytes may also limit the detrimental effects of pro-inflammatory factors, while providing both support and protection for the oligodendrocytes and neurons.

Interferon- ² 1b was introduced in 1993 as the first FDA-approved treatment for multiple sclerosis. This began an era of treatment for this incurable disease, and its natural course was permanently changed. Currently, there are seven different treatments for patients with multiple sclerosis with different mechanisms of action and dissimilar side effect profiles exist. These medications include interferon- ² 1a intramuscular (Avonex), interferon- ² 1a subcutaneous (Rebif), interferon- ² 1b subcutaneous (Betaseron/Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), Fingolimod (Gilenya), teriflunomide (Aubagio), and mitoxantrone aka Novatrone.

Avonex was approved by the FDA in 1996 in order to treat patients that were relapsing with MS. It came however with multiple side effects, including flu like symptoms, or less commonly the causation of the deterioration of psychiatric disorders.

Rebif is commercially available at two doses and is administered three times weekly.

In 1993, Betaseron was the first immunomodulatory agent approved by the FDA for the treatment of patients with RRMS ((Relapsing-Remitting Multiple Sclerosis.) It is also approved however, for the treatment of patients suffering with SPMS (Secondary progressive MS.) Copaxone is a synthetic polymer of random sequences of four naturally occurring amino acids and is used as one of the first line disease modifying agents for the treatment of RRMS.

Tysabri is a humanised anti-integrin monoclonal antibody that has been utilised in order to treat patients suffering with RRMS and it is administered once every 28 days via IV at a strength of 300mg. It works by targeting the ±4 chain of ±4- ²1 integrin. All leukocytes except for neutrophils express VLA 4 on their surface, which binds to the adhesion molecule on the surface of activated cerebral endothelial cells. This is a crucial step in the transendothelial migration of leukocytes to the CNS.

Gilenya was approved for treatment of MS in 2010. It is promoted as a second-line drug however, as it resulted in complications during the clinical trial, when two patients contracted herpes zoster infection. This resulted in two of the patients death. Novatrone has immuno-supressive features and intercalates with DNA, this in turn causes single and double stranded breaks. It also supresses the DNA repair by inhibiting topoisomerase.

In addition to the trove of medicines that are already available for patients suffering with MS, there are also a large number of clinical trials being conducted to assess the safety and efficacy of other experimental drugs. An example of one of these drugs is Rituximab. Rituximab (Rituxan) is a chimeric monoclonal antibody with IgG1 heavy-chain and kappa light chain constant region which depletes CD20+ B lymphocytes via cell-mediated and complement-dependent cytotoxic effects, while also promoting the apoptosis of these cells. In 1997, the FDA approved use of rituximab for the treatment of relapsing or refractory cases of low grade CD20+ B lymphocyte non-Hodgkin lymphomas. CD20 antigen is a 35 kDa transmembrane protein which is expressed by majority of B lymphocytes in patients with non-Hodgkin lymphomas. While normal B lymphocytes and its precursors express this antigen, plasma cells, T lymphocytes, and hematopoietic stem cells do not possess CD20 antigen. As a B lymphocyte depleting drug, administration of rituximab leads to rapid abolition of CD20+ B lymphocytes in the peripheral circulation. One phase 2 clinical trial assessed efficacy of rituximab in patient with relapsing-remitting MS, and results of this study indicated that treatment of MS with rituximab was associated with decline of contrast-enhancing lesions versus the placebo as well as significant reduction in risk for relapse.

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