The Symptoms, Pathophysiology and Therapy of Multiple Sclerosis
Introduction
Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory disease of the central nervous system (CNS) where specific types of leukocytes released by the immune system attack myelin producing cells, myelin itself and neuronal axons. MS is the most common cause of neurological disability amongst those who are 20-30 years of age and genetically predisposed to the disease. In England and Wales alone, incidence rates for MS are between 74-112 cases per 100,000 persons. The disease has three main stages: the pre-clinical stage, detectable only by MRI; the relapsing-remitting stage, in which patients will be subject to relapses of neurologic dysfunction followed by periods of resolve; and finally, a progressive stage, where patients experience irreversible disability. Characteristically following a relapse-remitting course over many years, MS is thought to be caused by a combination of genetic predisposition and environmental factors, such as exposure to the Epstein Barr virus, cigarette smoke and vitamin D deficiency. Although MS does not follow typical mendelian inheritance patterns, those with first-degree relatives suffering the disease have a 20 times higher risk of developing MS. Moreover, it has been uncovered through whole genome sequencing that the human leucocyte antigen region, located on chromosome 6, is unquestionably linked with the development of the disease.
MS has a low prevalence rate in Asian countries and generally, has higher prevalence in more affluent countries. This is thought to be dependent on distance from the equator and thus, amount of sunlight received, as vitamin D deficiency has been found to be a risk factor for MS. Studies by Cree have revealed that the expression of many genes involved in the development of MS are regulated by vitamin D and its binding agents.
MS is almost twice as common in women than in men and this is thought to be because of the elevated levels of S1PR2, a blood vessel receptor protein, in the female brain; the S1PR2 protein determines which immune cells may pass through the blood brain barrier and cause the areas of inflammation typically seen with this disease.
Pathophysiology
Currently, there are four known types of MS; Relapsing-remitting, secondary progressive, primary progressive and progressive relapsing, the most common being relapsing-remitting MS. In this subgroup, cognitive impairment, development of secondary progressive MS or failure of the body to completely recover from relapses can cause disability in up to 60% of sufferers. The second most commonly reported form of the disease, primary progressive MS, is characterised by the steady decline of neurological function from the onset. In this case, disability is prevalent in almost all sufferers, usually severe and starting early on. These subgroups are designed to show the common patterns of MS and should not be taken as four different diseases.
MS presents with many features typical to an auto immune disease, including the breakdown of the blood-brain barrier. The barrier, in healthy people, is surrounded by white matter in the form of myelin sheaths on neuronal axons and prevents the entry of immune cells that may cause damage to neurons. The Myelin sheath is a lipid and protein-based substance that forms the modified and extended membrane of oligodendrocytes the myelinating glia of the CNS, and encases the axon in intermittent sections. White matter connects different regions of the cerebellum to one another, effectively speeding up nervous transmission via saltatory conduction. In healthy individuals, nerve cells are coated in repeating sections of myelin, separated by nodes of Ranvier which speed up conduction greatly, but also ensures that the impulse does not prematurely leave the neuron.
During the early stages of MS, neuronal activity is recurrently silenced. To counteract this, sensitivity to glutamate, an excitatory neurotransmitter, is increased. Glutamate binding activates ion channels, allowing calcium, vital for neurotransmitter release, to enter the neuron terminal. This altered state can have detrimental effects on the CNS, namely where proinflammatory cytokines released from autoreactive lymphocytes and activated microglia cause synaptic abnormalities, as concentrations of excitatory and inhibitory neurotransmitters are no longer strictly controlled, causing a clear imbalance in GABAergic and glutamatergic transmission. As well as chemical imbalances, the synapses may undergo physical changes, including degeneration of the pre and/or postsynaptic sites as a result of inflammation, and overactivation of glutamate receptors. The more damage done to neurones and their synapses, the more progressed the symptoms of MS.
In MS, myelin antigen-specific DC4+ T cells are activated by myelin antigens presented on the surface of reactive microglia in inflammatory lesions. They then penetrate the blood brain barrier via intracellular adhesion molecules and enter the central nervous system. Once inside, activated T- cells release cytokines such as interleukin 1, and proteases such as TNF-α and nitrous oxide, which begin demyelination followed by axonal damage, , leaving the axons unprotected and uninsulated. In addition, astrocytes in the brain are responsible for the reactivation of microglia. Chemokines released by microglia are the key components of recruitment and subsequent activation of the autoreactive T- cells that trigger the disease. This abnormal immune response produces inflammation and areas of hardened scar tissue, called lesions, on the previously myelinated axon, which are detectable on magnetic resonance images (MRI’s). MRI’s help medical professionals to determine how progressed the patient’s case of MS is. There have also been studies conducted using MRI imaging that have confirmed the role of macrophages in the degradation of myelin.
The human body, however, does attempt its own repair of lesions. It may do this through the recruitment of oligodendrocyte progenitor cells to the area of damage, which can proliferate into myelinating glial cells when they come into physical contact with astrocytes so that they may be stimulated to produce new myelin. Furthermore, astrocytes can secrete chemokines such as CXCL1, recruiting additional oligodendrocytes to areas of demyelination, in which they may proliferate into mature oligodendrocytes. However, changes in the microenvironment of damaged nerves may cause proliferating oligodendrocytes to lose their ability to respond to damage and so their remyelinating ability is reduced with progression of the disease. This process is also too slow and incomplete to compensate for the loss of myelin but has paved the way for new research attempting different strategies of oligodendrocyte stimulation. In cases of severe immune attack, nerve fibres in the brain and/or spinal cord may also be damaged or destroyed. Signals originating from exposed nerve fibres may become distorted or delayed, giving rise to the symptoms of the disease.
Symptoms
MS presents with several symptoms, both invisible (primary symptoms) and visible (secondary), however, they are determined by the specific sites of nerve damage present in each individual. No two cases of MS are the same and symptoms will vary considerably, lasting days to weeks and lingering for months.
Surprisingly, one of the most disabling, primary symptoms of MS is fatigue, arising from sleep interruptions commonly caused by bladder and bowel control problems during the night. Fatigue may present either mentally or physically and often prevents sufferers from carrying out everyday tasks and activities as they simply lack the energy to do so. Carefully devised aerobic exercise may help to decrease the severity of fatigue and may also benefit those suffers whom have developed mental health issues, such as depression, as a result of living with such a disease.
Optic neuritis is another major primary symptom, which presents with visual problems and pain around the general eye area. Optic neuritis arises when the connecting nerve between the eye and brain becomes inflamed. Colour blindness may also present in some individuals. In 25% of cases, this was the first symptom noticed, and should therefore be high in a clinician’s assessment.
Pain is another common symptom of MS and often negatively impacts everyday life. Pain can come in two main forms; Neuropathic pain (primary symptom)- caused by damage to the pain-sensing nerves which may present as numbness, tingling or burning sensations as the signal will become distorted before reaching the brain, if at all, and nociceptive pain- caused by damage to the body tissues and muscles. Nociceptive pain may be caused by spasticity, another heavily disabling symptom of MS, which is associated with functional impairment and significantly worsens a patient’s quality of life, making limbs stiff and resistant to movement, severely limiting which daily activities are manageable.
Approximately one third of people living with MS experience neurogenic dysphagia and it is not uncommon for its complications to cause death in the later stages of the disease through dehydration, chest infections resulting from aspiration of food or saliva and uncoordinated breathing whilst swallowing. Studies have shown that patients with dysphagia seem to have a longer duration of disease and higher levels of neurological damage than those who do not this could potentially be due to their stilted ability to take oral medicines. Demyelination of nerves affecting muscles used in speech and lesions in the cerebellum are the two main causes of dysphagia.
Disabling limb ataxia and tremors are experienced by up to 85% of MS sufferers and it is reported that daily function is affected in 32% of cases. Limb ataxia is the simple loss of coordination or mobility in the limbs that are otherwise seemingly healthy and strong, and is a result of damage to the cerebellum and its connective parts. Limb ataxia gives rise to gait ataxia, a secondary symptom of MS in which patients walk with unequal, staggering steps that may increase the chance of accidents such as falling. Physiotherapy can be used to temporarily alleviate the symptoms of ataxia somewhat, including tasks that focus on coping with demanding conditions, such as walking on different types of surface with the eyes open and closed, however there is little clinical evidence to support the success of this treatment type.
Current and Future Therapies
Whilst MS is an uncurable disease there have been several treatments for MS, which focus on supressing the overactive immune system using immunosuppressive and immune-modulating substances. One example of a disease modifying-treatment (DMT) for relapsing-remitting MS is Interferon beta (IFNβ). IFNβ is licenced for use in the UK and has been found to significantly reduce both the rate of relapse and the severity of attacks by up to 50%. IFNβ slows progression of the disease by 12 months, however this is subject to each individual case, as some patients may not respond to this type of treatment. Unfortunately, IFNβ has side effects such as flu-like symptoms lasting up to 3 months, skin necrosis at the site of subcutaneous injection and is not available through the NHS, as it has been condemned as not cost-effective. A second example of DMTs is Glatiramer acetate, which blocks T-cell activation by mimicking fragments of myelin basic protein. This drug is administered subcutaneously daily and has been found to reduce relapse rate by 29%, however it has not been found to delay the development of disability.
Mitoxantrone is a generally well tolerated cytotoxic, commonly used for chemotherapy, which has immunosuppressive actions. It is used for secondary progressive MS and effectively inhibits activation of T-cells and macrophages, significantly reducing accumulation of disability and slowing relapse rate.
Corticosteroids are intravenously used for 3-5 days in treatment of acute relapses. There is a significant lack of studies on their effectiveness and ability to prevent disability, but they are generally thought to shorten symptoms and boost general health of patients via suppression of inflammatory pathways, leading to reduced inflammation, greater nervous transmission and restoration of the blood brain barrier.
