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MSExplained A str aight forwar d guide to m ultiple sclerosis Simon Webster Alison Whittam 3rd Edition We hope you find the information in this book helpful. If you would like to speak with someone about any aspect of multiple sclerosis, contact the MS Trust information team and they will help find answers to your questions. MS Trust information service Helping you find the information you need The MS Trust offers a wide range of publications, including a newsletter Open Door, which provides an ongoing update on research and developments in MS management. This book has been provided free by In addition it contains articles from the Multiple Sclerosis Trust, a small people with MS and from health UK charity which works to improve professionals. the lives of people affected by MS. We rely on donations, fundraising For a full list of MS Trust and gifts in wills to be able to fund publications, to sign up to receive our services and are extremely copies of Open Door four times grateful for every donation received, a year, and much more, visit our no matter what size. website at www.mstrust.org.uk Freephone 0800 032 3839 (Lines are open Monday-Friday 9am-5pm) Phone 01462 476700 email [email protected] write MS Trust Spirella Building Bridge Road Letchworth Garden City SG6 4ET 2www.mstrust.org.uk Introduction Welcome to the third edition of ‘MS Explained’. Contents Introduction3 MS stands for multiple sclerosis which is a condition that affects the central nervous system (the brain and spinal cord). MS is a life long condition which affects different people in different ways. Who gets MS? MS Explained aims to give a basic introduction to what MS can do to the body, as well as an extensive look at research and areas where advances might be made in the future. An explanation of the terms highlighted in bold can be found in the extended glossary at the end of the book. The immune system Readers could include people with MS, their family and friends; people caring for someone with MS; and those simply interested in this most enigmatic condition. Future research This book purposely avoids discussing the treatment and management of symptoms as this is covered extensively by other MS Trust publications, details of which are given in relevant sections and on page 72. Index74-77 The possible causes of MS 4-9 10-15 The central nervous system16-19 20-23 What happens in MS? 24-25 Diagnosis26-29 Types of MS 30-33 The cause of symptoms34-53 54-63 Glossary64-71 More information from the MS Trust 72-73 Tel: 01462 476700 3 Who gets MS? How many people have MS? Multiple sclerosis is the most common disease of the central nervous system diagnosed in young adults. An estimated 2,500,000 people in the world have MS. There is currently no comprehensive register of people with MS in the UK and so the number of people with MS is an estimate based on a number of studies of local areas. The studies look at the number of people with the condition in a particular geographic area, which is referred to as the prevalence, and are usually expressed as the number of cases per 100,000 people. The prevalence rates from the studies are then applied to the national population, and from this it is estimated that around 100,000 people live with MS in the UK. Similarly, if the results of local area studies are applied nationwide it suggests that nearly 3,000 people are diagnosed with MS in the UK each year, or around 50 to 60 a week. The number of new cases in the population within a specified period of time is known as the incidence rate. 4www.mstrust.org.uk The University of Swansea is working with the MS Society to develop a UK MS Register that will combine personal information with clinical and NHS data to provide a more accurate picture of the number of people with MS in the UK. More information about the register, including how to join, can be found at: www.ukmsregister.org/ An incidence register of MS in Scotland has also been launched, which will collate data on all new cases of MS in Scotland from the 1st January 2010. As well as collecting data about the number of new cases of MS in Scotland each year, the register will examine patient management from referral to diagnosis. More information about the register can be found at: www.msr.scot.nhs.uk/ Age Most people with MS are diagnosed in their 20s or 30s, although it can be diagnosed in people who are older than this, and, less frequently, in teenagers and children. However, the number of cases of MS in this age group is rising and research suggests that somewhere between 1 in 37 and 1 in 50 people with MS are diagnosed in their teens or younger, although precise figures are unknown. Due to the age at which it is diagnosed, MS is often thought of as a condition that affects younger people. However, as it only has a small effect on life expectancy, most people live with the condition for a long time. Gender More women than men are diagnosed with MS. Roughly two women have MS for every man with the condition, although it has been suggested that the proportion of women with MS may be growing. Recent studies in North America indicate that the figure may be closer to three women to each man diagnosed. When MS is diagnosed in people in their teens, the proportion is about three women to one man. When MS is diagnosed in older people, or in whose MS is progressive from onset, the numbers of women and men are equal (see page 30 for more on types of MS). The reason for the larger proportion of women with MS is unknown but this pattern also occurs in most other autoimmune conditions (see page 10 for more on autoimmune conditions). Where is MS more common? The distribution of MS around the world is uneven. As a rough guide, the prevalence increases as you travel further north or south from the equator. Those parts of Asia, Africa and America that lie on the equator have extremely low levels of MS, whilst countries such as Canada and Scotland have particularly high rates. Studies in countries near the equator have shown a prevalence rate of about 4 cases per 100,000 in Peru, 8 in Saudi Arabia and just 1 amongst Indians in Mumbai. In contrast, studies in Australia show a range from 11 in the north to 68 in Tasmania in the south. This increasing prevalence is more marked in the northern hemisphere. Studies in the UK suggest that the rate in England and Wales is between 120 and 140 Tel: 01462 476700 5 Who gets MS? per 100,000, about 180 in Northern Ireland and as high as 210 in Scotland. Individual studies in Orkney have recorded rates of over 400 per 100,000. Race A simple geographical spread is not the whole picture. Studies show that some ethnic groups have a markedly lower prevalence of MS, despite living in countries where MS is relatively common. For instance, the Sami (Lapps) of northern Scandinavia and the Inuit in Canada have very low rates of MS. A similar pattern is observed amongst the Maoris of New Zealand. In contrast, a study in Kuwait showed that the rate in Kuwaitis was half that of the ethnic Palestinian population - many of whom had been born and raised in Kuwait. Similarly, the studies in India that showed very low rates for Indians also found that the rate in Parsis, an ethnic group that originated in Persia, was much higher and equivalent to the rates seen in areas in southern Europe. 6www.mstrust.org.uk Vikings and Scots The fact that MS is more prevalent in northern Europe, North America, Australia and New Zealand has led to speculation that it was carried around the world by European colonists and settlers. It has been suggested that the origins can be traced back to the Vikings who colonised those parts of Northern Europe where MS is now most pronounced and that ‘Viking’ genes can make people particularly susceptible to MS. It has also been noted that Scotland has a much higher rate of MS than England or Wales and that areas of high MS prevalence around the world have been settled by Scottish immigrants. In Ireland for instance, the national rate of MS in the Irish Republic was looked at in 2007 and was shown to vary from 145 per 100,000 in Wexford in the south, to 290 in Donegal in the northwest. In Northern Ireland, which was extensively settled by immigrants from Scotland from the 17th century, the rate was recorded in 2004 as 230 per 100,000. Migration Research looking at the effect of migration on the risk of developing MS suggests that the age someone moves is important. If someone moves from an area of low risk to an area of high risk as an adult, they retain the risk level of the location from which they originally came. People who move as children, and their subsequent offspring, have a risk of MS similar to that found locally. This explains the outdated belief that MS is a condition that only affects white people and is rare or unknown amongst black or Asian people. Whilst this might have been true for the first generation immigrants, it is not the case for successive generations born and brought up in the UK, with MS increasingly being seen in black and Asian communities. The geographic spread of MS suggests the genetic make up of people from different parts of the world has an impact on risk of MS; the migration studies point to there being an environmental element at play as well. Cases of MS <5/100 000 5-30/100 000 >30/100 000 Tel: 01462 476700 7 Who gets MS? Bibliography Alonso A, et al. Incidence of multiple sclerosis in the United Kingdom: findings from a population-based cohort. Journal of Neurology 2007; 254(12): 1736-41. Burgess M. Multiple sclerosis: theory and practice for nurses. London: Whurr; 2002. Canadian MS Society. International Pediatric MS Study Group’s Recommendations on Clinical Trials Published. 2013 Jun 10 [cited 2013 July 2]. Available from: URL: http://mssociety.ca/ en/help/msupdates/msupdate_20130610. htm Compston A, et al. McAlpine’s multiple sclerosis. 4th ed. London: Churchill Livingstone; 2006. Gray OM, et al. Factors in the rising prevalence of multiple sclerosis in the north-east of Ireland. Multiple Sclerosis 2008; 14(7): 880-6. Lonergan R, et al. Multiple sclerosis prevalence in Ireland: relationship to vitamin D status and HLA genotype. Journal of Neurology, Neurosurgery and Psychiatry 2011; 82(3): 317-22. Orton SM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurology 2006; 5(11): 932-936. Richard RG, et al. A review of the natural history and epidemiology of multiple sclerosis. Health Technology Assessment 2002; 6(10). Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurological Sciences 2001; 22: 117-139. 8www.mstrust.org.uk Thomas T, et al. Multiple sclerosis in children. Seminars in Neurology 2008; 28(1): 69-83. Visser EM, et al. A new prevalence study of multiple sclerosis in Orkney, Shetland and Aberdeen city. Journal of Neurology, Neurosurgery and Psychiatry 2012; 83(7): 719-24. Zajicek J, et al. Multiple sclerosis: a practical manual. Oxford: Oxford University Press; 2007. Tel: 01462 476700 9 The possible causes of MS Multiple sclerosis was first described as a distinct condition by the French neurologist JeanMartin Charcot in 1868. However, the cause of MS still remains a mystery. There has been a great deal of research looking for the solution to this problem and a number of theories have held sway as to what triggers MS. Over the years, speculation on the cause of the condition has included: acute fevers or exposure to damp or cold blood clots or poor circulation in the brain environmental poisons dietary factors such as a food allergy or food intolerance mercury leakage from dental amalgam fillings. Research has failed to prove any of these theories, but it has been widely held that MS is primarily an autoimmune disease. However, there is currently a debate going on as to whether MS may in fact be due to a neurodegenerative process, which in turn triggers a 10www.mstrust.org.uk secondary inflammatory response, but this theory is not yet universally accepted. Autoimmune disease An autoimmune disease is one in which the immune system, which should only target invading germs, instead targets the body’s own tissues. Other autoimmune conditions include diabetes mellitus type 1, in which the insulin making cells of the pancreas are destroyed; and rheumatoid arthritis, where the immune system primarily attacks the joints, but can also affect organs such as the lining of the lungs and the heart. In the case of MS, the immune system attacks myelin, the substance covering and protecting nerves in the central nervous system. The reason for this reaction is unknown but it is thought that the genetic make up of some people means that MS can be triggered by something in the environment, possibly an infectious agent or agents. In response to the infection, some cells from the immune system come into contact with the central nervous system and attack myelin. Genetics It is important to state that MS is not hereditary and the majority of people who develop MS have no previous family history of the condition. However, there is a slight increased risk of developing MS for someone with a relative with the condition. Whilst the rate of MS within families indicates that there is a genetic factor involved in developing the condition, studies of identical twins show that genes are not the whole story. Identical twins have exactly the same genetic make up. If MS were solely dependent on genes, it would be expected that if one identical twin developed the condition, so would the other. Studies have shown that rather than this 100% risk, the actual risk of developing MS for the identical twin of someone with MS is about 1 in 4. The risk of developing MS In the general population in the UK, the prevalence of MS is about 1 in 700. Studies have shown that the risk for first degree relatives (parents, children, siblings) of someone with MS is about 1 in 40. For second degree relatives (cousins, uncles/aunts, nephews/nieces) it is around 1 in 100. It is worth putting MS in context with other conditions: 1 in 3 people will develop some form of cancer 1 in 8 women will develop breast cancer at some point in their lives 1 in 9 men will develop prostate cancer 1 in 20 people over the age of 65 have dementia 1 in 33 people have diabetes 1 in 500 people have Parkinson’s disease 1 in 520 people in England and Wales have a stroke each year. 1 in 700 people have MS. Tel: 01462 476700 11 The possible causes of MS Which genes are involved in MS Genetic research has started to identify conditions such as cystic fibrosis that result from variations in a single gene. This is not the case with MS and it is believed that the interaction of a number of genes determines whether or not an individual is susceptible. The first gene to be identified as contributing to the risk of MS was discovered in the 1970s. With recent advances in gene technology, more than 50 genes have now been identified. In fact researchers suggest there might be a hundred or more genes that contribute to an individual’s risk of MS. On its own, each gene raises the MS risk by a negligible amount. However, if an individual has enough of these genes, the combined effect will make them more susceptible to MS. A major reason why the identification of genes has been so slow is that none of those found to be associated with MS is unique to people with the condition. For instance, one of the discovered genes, called IL7R, is carried 12www.mstrust.org.uk by nine out of ten people in the general population. Having the IL7R gene does not mean that an individual will get MS, but the bit of risk that it carries adds to an individuals susceptibility to MS. External factors Whilst a specific combination of genes can mean that an individual is at risk of developing MS, this in itself does not cause the condition. It is believed that other external factors are involved. When people with a particular genetic make up are exposed to a trigger, their body reacts in a way that starts the development of MS, although it may be years before any symptoms become apparent. Many people believe that one of the possible triggers is probably an infection of some sort. Infection Research into the role of an infection or infections in the onset of MS has been carried out since the 19th century. Initial work looked into the theory that MS was directly caused by an infectious agent, but failed to find any positive results. Subsequent research, has worked on the theory that an infection may act as a trigger, which sets off a train of events in some people that then develops into MS over a period of time. A number of common infections have been investigated, including chicken pox, measles, mumps, canine distemper and several herpes viruses. When someone is infected with a virus or bacteria, the immune system creates antibodies to help it fight off the invasion. The antibodies remain in the blood to help fight off subsequent infections. Researchers can identify antibodies in the blood that indicate infections to which someone has been exposed. It is not yet clear if there is a particular virus, or combination of viruses, that might trigger MS, or if this varies from person to person. This type of research is challenging because most adults carry evidence of common infections, even if their immune system prevented any symptoms developing. For example, a virus that has been a focus of investigation is the Epstein Barr virus (EBV), which causes glandular fever. Children have a lower level of exposure to some infections, so researchers in Canada compared exposure to EBV in a group of children with MS and a control group who did not have the condition. They found that 83% of the MS group had been infected with EBV compared to 42% of the controls. Whilst this suggests that EBV might have a role in the development of MS, almost one in five of the children with MS had no evidence of exposure. Vitamin D The role of vitamin D in multiple sclerosis has also been the focus of much debate and research has focused on two areas: Does vitamin D affect the risk of getting MS? Does vitamin D affect the course of MS? Vitamin D and risk of MS Recent reviews suggest that vitamin D may influence MS susceptibility. Vitamin D is manufactured by the skin when it is exposed to sunlight. Tel: 01462 476700 13 The possible causes of MS Many studies of the geographical distribution of MS have shown that the prevalence of MS increases with distance from the equator, supporting the link between lack of sunlight exposure, consequent lack of vitamin D production, and the development of MS. A review of blood samples taken from US military personnel found that levels of vitamin D in people who subsequently developed MS were lower than levels in people without the condition. This effect only seemed to occur in samples from white people, and was not demonstrated in the smaller set of samples from black or Hispanic people. Another study found that amongst sets of identical twins, where only one of the twins had MS, the twin who had engaged in less outdoor activity as a child and had been less exposed to sunlight was the twin more likely to have developed MS. A number of studies have drawn a connection between vitamin D levels in mothers and the subsequent risk of their children developing MS. Studies have found that more people with MS are born in spring than autumn, 14www.mstrust.org.uk suggesting that decreased maternal exposure to the sun during winter pregnancies results in low vitamin D levels, which in some way increases the risk of developing MS later in life for children who are genetically susceptible. Vitamin D and the course of MS Despite the accumulating evidence which suggests its importance in MS, so far there have only been a limited number of studies on the effect of vitamin D treatment in MS. These studies have been in relatively small numbers of people, and differing levels of supplementation have been tested. The results generated have been very variable, making it difficult to draw conclusions, but no significant association has been found. Studies are currently underway, or in the planning stages, to look at how common vitamin D deficiency is in people with MS and to establish the safety of high doses of vitamin D. Further studies are needed to evaluate the role of vitamin D during pregnancy and early years for reducing the risk of children developing MS in later life. Bibliography Alotaibi S, et al. Epstein-Barr virus in pediatric multiple sclerosis. JAMA. 2004; 291(15): 1875-1879. Burgess M. Multiple sclerosis: theory and practice for nurses. London: Whurr; 2002. Burton JM, et al. A phase I/II doseescalation trial of oral vitamin D3 with calcium supplementation in patients with multiple sclerosis. Multiple Sclerosis 2008; 14(Suppl 1): S34. Compston A, et al. McAlpine’s multiple sclerosis. 4th ed. London: Churchill Livingstone; 2006. Dobson R, et al. The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. Journal of Neurology, Neurosurgery and Psychiatry 2013; 18(4): 427-32. Goldberg P, et al. Multiple sclerosis decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Medical Hypotheses 1986; 21: 193-200. Goris A, et al. Progress in multiple sclerosis genetics. Current Genomics 2012; 13(8): 646-63. Islam T, et al. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 2007; 69: 381-388. James E, et al. The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis. Multiple Sclerosis 2013; May 22 [Epub ahead of print] Munger KL, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296(23): 2832-2838. Munger KL, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62(1): 60-65. O’Gorman C, et al. Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology 2013; 40(1): 1-12. Sawcer S. The genes jigsaw. MS Matters 2008; 77(Jan): 8-9. Trapp BD, et al. Multiple sclerosis: an immune or neurodegenerative disorder? Annual Reviews in Neuroscience 2008; 31: 1247-69. Wingerchuck DM, et al. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 2005; 76: 1294-1296. Statistics from Cancer Research UK – www. cancerresearchuk.org [cited June 2013]. Alzheimer’s Society - www.alzheimers. org.uk [cited February 2013]. Diabetes UK - www.diabetes.org.uk [cited February 2013]. Stroke Association - www.stroke.org.uk [cited February 2013]. Parkinson’s UK - www.parkinsons.org.uk [cited February 2013]. Tel: 01462 476700 15 The central nervous system MS is a condition in which damage occurs within the central nervous system. The nervous system The nervous system is the means by which the body communicates messages to and from muscles and organs and maintains awareness of the outside world through the senses. It controls every function in our body, all that we say, do, or think. The nervous system is divided into two areas the central nervous system (CNS), which consists of the brain and spinal cord and is enclosed within the skull and spine the peripheral nervous system (PNS) comprises all other nerves. brain spinal cord 16www.mstrust.org.uk The peripheral nervous system The peripheral nervous system is the cabling that transmits information to and from the central nervous system from the rest of the body. There are two main types of nerve in the peripheral nervous system: sensory nerves - collect information from the body’s sense organs responding to touch, temperature, pain, position, smell, sound and sight motor nerves - pass messages from the central nervous system. When information has been processed centrally, these nerves carry instructions for action to the muscles controlling movement, speech, internal organs, and to the various glands, such as the sweat glands in the skin. The part of the peripheral nervous system that regulates the function of our internal organs (heart, stomach, intestines) is known as the autonomic nervous system (ANS). Often we are not aware of the ANS as it is involved in involuntary or reflex functions such as breathing, dilation/constriction of blood vessels and increases/decreases in heart rate. The ANS also controls some of the muscles within the body. The central nervous system The central nervous system receives, processes and stores information from the peripheral nervous system and initiates instructions for the body’s responses. The central nervous system is divided into two major parts: the brain - analyses and stores information and directs the action of the body the spinal cord - passes information to the brain and is responsible for reflex reactions. The central nervous system is made up of two types of cells nerve cells and support cells. Nerve cells Nerve cells are called neurons. The human brain and spinal cord contain about 100 billion neurons. The brain develops rapidly in the unborn child and in the first years of life. By the age of two, a person has most of the neurons that they will have during their lifetime. Although cells in the body such as blood cells die and are replaced, many neurons are never replaced when they die. As a result, disease activity caused by MS that leads to the damage or destruction of neurons can cause permanent disabilities. dendrites cell body myelin sheath axon synapses Nerve cell nodes of Ranvier Tel: 01462 476700 17 The central nervous system Neurons have specialised extensions called dendrites and axons. A neuron usually has a number of dendrites but only one axon. Information enters the neuron via the dendrites, passes through the cell body and then along the axon. At the end of the axon, chemicals called neurotransmitters carry the message over a small gap, called a synapse, to the dendrite of another neuron. The axon can be as long as a metre, making neurons some of the longest cells in the body. The axon is surrounded by a protective sheath of fatty protein called myelin, which acts as insulation. The myelin sheath has short gaps about one micrometre apart known as nodes of Ranvier, which assist in the fast conduction of messages. Nerve messages pass along the axon from node to node. The thickness of the myelin sheath, and the size of the gap between nodes, determines the speed of messages, which can travel as fast as 120 metres/second (268mph). 18www.mstrust.org.uk Support cells About 40 per cent of the total volume of the brain and spinal cord is made up of cells that support neurons in various ways but which do not carry information themselves. The collective name for these support cells is glial cells. Glia comes from the Greek word for glue and one of the roles of these cells is to hold the nerve cells in place. Other functions include transporting nutrients to neurons, cleaning up debris and digesting parts of dead neurons. Glial cells also provide the insulation to neurons through the production of myelin. The specific glial cells that produce myelin in the central nervous system are called oligodendrocytes. Each oligodendrocyte can supply myelin for several axons and each axon can be supplied by several oligodendrocytes. The myelin produced by oligodendrocytes wraps around the axons in thin sheets like a Swiss roll. Damage to myelin, and the interruption or delay to nerve messages along the axon that this causes, leads to the symptoms of MS. If the protection of myelin is lost, the axon itself can be destroyed, which may cause permanent problems. Cerebrospinal fluid and the blood brain barrier The entire surface of the central nervous system is surrounded by a clear, colourless liquid called cerebrospinal fluid (CSF). This cushions the brain and spinal cord within the bony casing of the skull and spine and helps support the weight of the brain. Bibliography National MS Society. Multiple sclerosis information sourcebook. New York: National MS Society; 2006 - www. nationalmssociety.org/Sourcebook.asp Neuroscience for kids - http://faculty. washington.edu/chudler/neurok.html Zajicek J, et al. Multiple sclerosis: a practical manual. Oxford: Oxford University Press; 2007. The cerebrospinal fluid and the central nervous system are surrounded by a layer of cells called the blood brain barrier. This prevents large molecules circulating in the blood from reaching the central nervous system. In MS, the blood brain barrier is breached, allowing immune cells to move across from the blood stream and into the central nervous system. axons myelin oligodendrocyte Tel: 01462 476700 19 The immune system How does the immune process work? The immune system is the body’s main defence system against infection. It consists of a complex collection of special cells and chemicals that patrol the body, identifying and fighting off material that it identifies as foreign, such as bacteria and viruses. When a cell is attacked by a virus or other invader, it sends out a chemical as a warning signal. This alerts a type of white blood cell called macrophages which mount the initial immune response. When macrophages encounter foreign matter they encircle and digest it [1]. antigen helper T-cell 2. Macrophages use particles of the debris called antigens to tell T-cells which cells to attack. virus macrophage cells 1. When macrophages encounter foreign matter they encircle and digest it. 20www.mstrust.org.uk Once some of the invading germs have been destroyed, macrophages use particles of the debris, called antigens, to tell other immune system cells which cells to attack and to encourage a greater response to the invasion. When this happens, macrophages are known as antigen presenting cells [2]. The cells that are prompted to respond are a type of white blood cell called lymphocytes. There are two main groups of lymphocytes B-lymphocytes or B-cells, which mature in the bone marrow, are programmed to recognise a specific virus or bacterium. T-lymphocytes or T-cells, which mature in the thymus, respond to the antigen presenting cells. There are different types of T-cells: helper T-cells help to influence how the immune system responds, whilst killer T-cells (also known as cytotoxic T-cells) attack and destroy cells. Prompted by the antigen presenting cells, helper T-cells become activated and direct other immune system cells by producing ‘messenger’ molecules, called interferons, which tell other elements in the immune system how to act. Killer T-cells attack and destroy cells which contain the antigen – this includes both the invading cell and any of the body’s cells which have been infected. This prevents the germ from reproducing and infecting other cells. B-cells are tuned to specific invaders. When the germ is found in the body, the B-cell clones itself and produces millions of antibodies against that germ. Antibodies are proteins that lock onto the surface of the specific invading germ helping the body to kill it off [4]. At the start of an immune response, one of the molecules produced is gamma interferon which stimulates B-cells and killer T-cells to attack [3]. killer T-cell antigen helper T-cell 4. B-cells produce millions of antibodies, which lock onto an invader, helping the body to destroy it. 3. Helper T-cells produce gamma interferon to stimulate B-cells and killer T-cells. Tel: 01462 476700 21 The immune system The immune response causes inflammation in damaged or infected tissue. Inflammation causes local blood vessels to dilate, which increases blood flow to the injured site and allows more white blood cells to attack invaders in the affected area. Once the infection is under control, helper T-cells release a messenger molecule called beta interferon that helps to calm down the immune response. Once an infection is over, some of the antibodies developed to fight it remain in the immune system. This creates an ‘immune memory’, which means that should the same organism invade again, the body is already prepared to combat it. This is why many infectious diseases such as mumps or chicken pox usually only occur once. Vaccination uses this principle to forewarn the immune memory. A small amount of matter from a weakened version of an infection is injected into the body. Whilst this is not strong enough to cause illness, it allows the immune system to recognise the disease and to fight it off should it appear again. 22www.mstrust.org.uk Why does a white blood cell not attack every cell in the body? The antigen presenting cells are controlled by genes called the Major Histocompatibility Complex (MHC) or the Human Leukocyte Antigen (HLA). These genes, which are different in every person, allow the immune system to indentify which cells belong to the body and which are ‘foreign’. It is these genes that create the problems with rejection in organ transplantation. Unless the genes of the donor and the recipient are closely matched, the immune system will treat the new organ as an invader and start to attack it. In some conditions, for reasons that are unknown, this protective mechanism fails to work. The immune system turns on the body’s own tissue and attacks it as if it were an invader. These conditions are called autoimmune diseases. How this causes the symptoms of MS will be explored in more detail later in this book. Bibliography Coles A. The immunology of multiple sclerosis. Way Ahead 2003; 7(2): 4-5. Tel: 01462 476700 23 What happens in MS? It is widely believed that MS is an autoimmune and/or neurodegenerative condition. For some reason - possibly following exposure to an as yet unidentified infection - the body’s immune system starts to attack cells within the central nervous system. Activated T-cells pass through the blood brain barrier where they mistake the myelin sheath for a foreign body and start to destroy it. The process of damaging or stripping away myelin from an axon is called demyelination. Messages that pass along a demyelinated nerve become delayed or blocked. As the central nervous system controls processes throughout the body, a wide range of symptoms can occur, depending on where the nerve damage has happened. For example, damage to areas in the spinal cord can lead to problems with mobility or weakness. For reasons that are not yet understood, the attack by the immune system tends to stop after an indefinite period and scar tissue develops on the damaged nerve. The forming of scar tissue over an area of damaged myelin is 24www.mstrust.org.uk what forms the plaques, lesions or scarring (‘sclerosis’) that show up as white regions on T2 magnetic resonance imaging (MRI) scans. The name multiple sclerosis comes from the fact that it causes areas of sclerosis in multiple places in the central nervous system. Once the inflammation caused by the immune attack is over, it is possible for damaged myelin to be replaced, a process known as remyelination. Whether this happens or not depends on the level of damage to the surrounding oligodendrocytes, the supporting cells that produce myelin and which are also attacked by this process. Although the new myelin can work effectively, it tends to be thinner than unaffected myelin and so messages through the affected nerves may not be as fast as before the attack. If there are several periods of damage, the amount of remyelination is reduced. Remyelination tends to occur in the earlier stages of MS. Over time, with repeated attacks, oligodendrocytes are damaged and destroyed and myelin is not as easily replaced. If an axon is left without the nourishment and protection of myelin it is more vulnerable to damage. The central nervous system is able to overcome small areas of axon loss by finding ways to reroute messages around an area of damage through undamaged nerve cells. This ability to adapt to avoid areas of damage is called plasticity. Should the area of damage become too large, this rerouting process is no longer able to compensate and messages to or from that part of the central nervous system are permanently blocked, resulting in symptoms that do not improve. Remyelination and rerouting occur in the stage of MS where an attack of worsening symptoms, or relapse, is followed by a period of remission when some or all of the function returns. Remyelination, rerouting and the loss of axons can happen at the same time in different parts of the central nervous system. Bibliography Burgess M. Multiple sclerosis: theory and practice for nurses. London: Whurr; 2002. Compston A, et al. McAlpine’s multiple sclerosis. 4th ed. London: Churchill Livingstone; 2006. healthy nerve cell axon nerve cell with damaged myelin myelin an axon left without myelin will die Tel: 01462 476700 25 Diagnosis There is no single test that will conclusively show that someone has multiple sclerosis and diagnosis usually involves a combination of investigations. Similarly, none of the individual symptoms people can experience are unique to the condition. This means that in order to reach a diagnosis, a range of other possible explanations has to be ruled out and so the process can be difficult and take some time. The diagnosis of MS is made by a neurologist. To show that someone has MS, the neurologist is usually looking for evidence of two or more areas of scarring in different parts of the central nervous system that have occurred at different points in time. The diagnostic criteria used in MS are known as the McDonald criteria. Brain imaging or scanning is becoming more powerful and it is now technically possible to make a diagnosis based on information from one attack of symptoms and evidence of further disease activity from scans. However, it is still unusual to diagnose MS from 26www.mstrust.org.uk just a single attack of symptoms. In this instance it is more likely that a clinically isolated syndrome (CIS) would be diagnosed. A number of tests are used to try and find information to help a neurologist decide if someone has MS. Patient history As the neurologist needs to establish that different symptoms have occurred at different times, a discussion of someone’s previous symptoms and health is important in establishing a diagnosis of MS. Sometimes a previous episode of numbness or double vision, for instance, that might have passed of its own accord or been treated without thought of MS at the time, can prove significant. Neurological examination There are a number of simple tests that a neurologist can carry out that may suggest whether or not MS is a cause of symptoms. These include checks on movement, coordination, vision, balance, reflexes and other functions of the five senses. Information from these tests may also give an indication as to where in the central nervous system damage has occurred and which further tests might be useful. Blood may be taken for testing. There is no blood test that can determine whether someone has MS, but if there are abnormalities, it is an indication that another condition may be present and might be causing symptoms. Although the patient history and neurological examinations might suggest the diagnosis of MS, the process usually involves one or more tests to look for evidence of MS within the body. Magnetic resonance imaging (MRI) First used in MS in the early 1980s, MRI has become a key diagnostic test. monitor the behaviour of hydrogen atoms in the body. The nucleus at the centre of an atom spins like a top. The powerful magnetic field in an MRI machine (more than 10,000 times stronger than gravity) makes the atoms line up in the direction of the magnetic field. The machine then fires a pulse of radio waves that causes the atoms to spin in a different direction (causing ‘resonance’). When the pulse is turned off, the atoms return to their natural alignment within the magnetic field and release energy. The machine picks up this signal and sends it to a computer, which converts it into an image of a slice through the body. An MRI machine is essentially a large magnet, shaped as a tube, within which the person being scanned lies. The procedure is painless, although the machines can be noisy. Images are created by using magnetic fields and radio waves to Tel: 01462 476700 27 Diagnosis There are two main types of MRI scan: T1 weighted scans show areas of permanent axonal damage (black holes) T2 weighted scans show the total number of lesions, both active and non active. Typically a T2 scan is used for diagnosis, scars caused by MS show up as white patches on MRI images, giving a very clear picture of the effects of MS on the brain and spinal cord. White blood cells Generally the number of cells from the immune system in the cerebrospinal fluid is low. For many people with MS the count of white cells in cerebrospinal fluid is up to seven times higher than normal. A count that is even higher than this is probably due to an infection of some sort, such as Lyme disease and not MS. Oligoclonal bands In MS, cells from the immune system cross the blood brain barrier and attack the myelin that surrounds nerves. As a result, the level of proteins from the immune system in the cerebrospinal fluid of someone with MS is higher than it should be and is higher than the level in the blood. Some people may undergo a third type of scan. Here they are injected with a contrast enhancing agent called gadolinium before the scan. This allows the MRI to show damage to the blood brain barrier, which indicates areas of active MS lesions The test that shows the presence and ongoing episodes of inflammation. of immune system proteins in cerebrospinal fluid is called Lumbar puncture A lumbar puncture involves inserting electrophoresis. A sample of fluid a hollow needle into the base of the is placed on a gel and voltage is applied. This causes proteins of spine and drawing off a quantity of the same size to bunch together, cerebrospinal fluid (CSF), the fluid forming visible ‘bands’. A sample that surrounds the brain and spinal of serum from the blood is also cord within the skull and spine. analysed for comparison with the In the diagnosis of MS, analysis of CSF sample. cerebrospinal fluid is looking for: 28www.mstrust.org.uk One band (monoclonal) in the cerebrospinal fluid is normal. ‘Oligoclonal bands’ refers to the presence of two or more bands. If oligoclonal bands are seen in the CSF, but not in the corresponding serum sample, this is an indication of immune activity in the central nervous system. While this does not necessarily mean that someone has MS, more than 95% of people with MS do have oligoclonal banding in their cerebrospinal fluid. Evoked potentials Evoked potentials are tests that measure the speed of nerve messages along sensory nerves to the brain. The most commonly used test is called visual evoked potentials (VEP). Electrodes placed on the skin measure messages sent from the eyes in response to being shown a flashing chessboard pattern on a computer screen. Less frequently, tests of sensations from the skin (somatosensory evoked potentials), which involve tiny electric impulses, and of hearing (auditory evoked potentials), using clicks, can also be carried out. Visual evoked potentials work on the basis that it is possible to measure how long it takes for input from the eye to get to the visual cortex at the back of the brain where this information is processed. As damage to the optic nerve in MS can slow messages down, evoked potentials tests can indicate the presence of an area of scarring that is not causing any obvious symptoms (described as clinically silent). Delays of as little as 10 milliseconds can indicate that there is damage to the nerve pathway. Bibliography Burgess M. Multiple sclerosis: theory and practice for nurses. London: Whurr; 2002. Compston A, et al. McAlpine’s multiple sclerosis. 4th ed. London: Churchill Livingstone; 2006. How Stuff Works www.howstuffworks.com/mri.htm Link H, Huang YM. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. Journal of Neuroimmunology 2006; 180(1-2): 17-28. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 2011; 69(3): 292-302. Zajicek J, et al. Multiple sclerosis: a practical manual. Oxford: Oxford University Press; 2007. Tel: 01462 476700 29 Types of MS Typically MS is a condition in which there are periods of relapse - also called episodes or attacks - which initially improve but are then followed by episodes where recovery is not complete, and eventually a period of slow progression with more persistent symptoms. However, some people experience a slow progression of symptoms and disability from the outset. This is a broad generalisation of a wide spectrum of experiences of MS. The range of possible symptoms and the levels of severity of those symptoms mean the way MS affects one person may vary widely from someone else. Some people will live with MS for many years with few or very minor symptoms, whilst others find that they progress much more rapidly. The majority of people will fall somewhere in between these two ends of the spectrum. There are a number of ‘types’ of MS that are used to try to broadly group individuals in accordance with how the condition has developed. However, each type encompasses a wide range of experiences of MS and 30www.mstrust.org.uk it is sometimes difficult to ascertain what type an individual has. It is also difficult to predict how an individual’s MS will develop over time. Relapsing remitting MS The majority of people with MS are diagnosed with the relapsing remitting form. This means they will have periods when symptoms flare up - a relapse - followed by periods of recovery - remission. A relapse is the appearance of a new symptom, or the reappearance of old symptoms, which last more than 24 hours in the absence of an infection. A relapse often lasts for considerably longer than that and may persist for weeks or months. Many people also find that some of their symptoms will vary from day to day, being worse one day and better the next. This fluctuation is not classed as a relapse. As a very broad average, people with relapsing remitting MS have one or two attacks a year, although for the individual, the number and frequency of relapses and the nature and severity of symptoms experienced are unpredictable. Some people with relapsing remitting MS have very mild attacks separated by very long periods with no symptoms; this is sometimes referred to as ‘benign’ MS. However, the use of the term ‘benign’ is controversial as many people find that as the years pass their MS starts to follow a more typical relapsing remitting pattern, where the number of relapses increase and the period between relapses decreases, at which point their MS would no longer be considered ‘benign’. Secondary progressive MS Many people who are initially diagnosed with relapsing remitting MS find that over time the frequency of their relapses decreases but their disability increases. As this progressive phase follows a period of relapsing remitting MS it is known as secondary progressive MS. As with relapsing remitting MS, an individual’s experience of secondary progressive MS can vary widely. Some people find that the increase or progression of disability is very gradual, whilst for others it can occur more quickly. Studies that have monitored people with MS over a long period of time suggest that on average the relapsing remitting phase lasts around 19 years. secondary progressive MS disability disability relapsing remitting MS time time Tel: 01462 476700 31 Types of MS Primary progressive MS About 10-15% of people with MS are diagnosed with a form in which disability increases from the outset, usually with the absence of distinct relapses. As this type is progressive from onset, it is known as primary progressive MS. More women than men have the relapsing remitting and secondary progressive forms of MS. However, this gender difference is not seen in primary progressive MS, where similar numbers of men and women are affected. disability primary progressive MS time 32www.mstrust.org.uk Again, there is a variety of experience of primary progressive MS. Some people can have a persistent increase in disability, whilst others experience a more gradual worsening of symptoms, and many reach a plateau after a period of steady progression. Some people with MS which has been progressive from the outset can experience occasional relapses; some textbooks refer to this as progressive relapsing MS. Bibliography Burgess M. Multiple sclerosis: theory and practice for nurses. London: Whurr; 2002. Leray E, et al. Clinically definite benign multiple sclerosis, an unwarranted conceptual hodgepodge: evidence from a 30-year observational study. Multiple Sclerosis 2013; 19(4): 458-465. Lublin FD, et al. Defining the clinical course of multiple sclerosis. Neurology 1996; 46: 907-911. Sayao AL, et al. Longitudinal follow-up of ‘benign’ multiple sclerosis at 20 years. Neurology 2007; 68(7): 496-500. Tremlett H, et al. Natural history of secondary progressive multiple sclerosis. Multiple Sclerosis 2008; 14(3): 314-24. Tel: 01462 476700 33 The cause of symptoms In MS, only nerves in the brain and/or spinal cord are damaged. However, because these nerves control the functions of the whole body, MS can cause a wide variety of symptoms. The type, severity and duration of symptoms will vary from person to person. How MS affects an individual depends on where damage occurs and which nerve messages are interrupted or blocked. For example, some people can have an MRI scan that shows a number of areas of scarring, but they may not experience noticeable symptoms because the scarring has occurred in areas of the brain which are not associated with a major function. Conversely, a single scar that damages an area controlling bladder function, for instance, can have a serious impact. Similarly, the actual level of disease activity can remain constant with a consistent number of areas of scarring. However, if a new scar interrupts an important function, such as walking, it can seem to the individual as though the MS has accelerated. 34www.mstrust.org.uk Whilst the complexity of the brain and how it handles information are still far from fully understood, certain areas are associated with specific functions. The following pages give a very broad overview of how damage caused by MS to these areas can lead to certain symptoms being experienced. The following pages cover a range of symptoms that MS can cause, but it is important to stress that most people only experience a small number of these. Although there are no drugs to cure MS, there are treatments for many of the symptoms. There are also treatments that aim to modify the course of MS. Information on treatments can be found in other MS Trust publications or by contacting the MS Trust Information Service. MS Trust Information Service Spirella Building, Bridge Road, Letchworth Garden City, SG6 4ET T: 0800 032 3839 or 01462 476700 e: [email protected] www.mstrust.org.uk/publications 5 3 2 4 1 Site of damage Symptom 1 Spinal cordSpasticity Bladder problems Bowel problems Weakness 2 Brainstem Double vision and nystagmus 3 Optic nerve Optic neuritis 4 Cerebellum Balance and dizziness Tremor 5 Areas involved with thought Cognition and emotionDepression Symptoms not associated with a single area Fatigue Speech and swallowing Pain Tel: 01462 476700 35 The cause of symptoms 1. Spinal cord Most nerves in the peripheral nervous system are not connected directly to the brain but to the spinal cord, which acts as the main route for nerve messages to and from the brain. The spinal cord also controls reflex reactions. Reflex reactions are automatic responses to stimuli, such as pulling the hand away if it touches something hot. Spasticity This causes the affected limb to feel stiff or tight and often to be difficult to move. The instruction to contract a muscle can be triggered by sensory signals from peripheral nerves in a muscle. When the signal reaches the spinal cord, it responds with an automatic, reflex response and also by passing the message to the brain. The brain assesses the situation and sends a message back down the spinal cord telling the muscle how to respond. The whole process is normally almost instantaneous. Spasticity is a condition in which muscle tone becomes greatly increased. Muscle tone refers to the level of tension or resistance to movement in a muscle and is what enables people to move limbs or hold a position. For instance, to bend your arm, you must shorten or contract the bicep muscle at the front of the arm (increasing the tone) and at the same time lengthen or relax the tricep muscle at the back of the arm (reducing the tone). In MS, spasticity occurs if there is an area of scarring between the brain and the point where the nerve from the muscle joins the spinal cord. The reflex action still takes place, but the message to or from the brain is interrupted. Thus no message to relax the muscle is received, or it is delayed, and the muscle remains contracted and stiff. When someone has spasticity in a limb, the signals from the brain are interrupted and the muscle remains in its shortened, contracted state. Depending on the area of damage in the process, spasticity can occur in any muscle in the body. This can lead to a number of problems 36www.mstrust.org.uk including difficulties with walking, speech or swallowing, and bladder control. The degree of spasticity can vary from mild muscle stiffness to severe, painful muscle spasms. More information from the MS Trust: Spasticity factsheet Spasticity triggers Bladder problems Types of bladder problem Frequency - an increase in the number of times someone needs to urinate in a day Urgency - the feeling of having to empty the bladder immediately, an inability to ‘hold on’ Hesitancy - difficulty in starting to urinate Incontinence - the inability to hold urine in the bladder until an appropriate time The wall of the bladder consists of muscle called the detrusor muscle, which stretches to store urine. At the base of the bladder is a valve called the urethral sphincter, which opens to let urine out. The average capacity of the bladder is between 300 and 500ml (about three quarters of a pint). On average, people produce about 1ml of urine every minute. The urge to empty the bladder usually occurs when it contains about 200ml. At this point the bladder is expanded enough to stimulate nerve endings in the detrusor muscle. This triggers a message to an area of the spinal cord that controls the reflex action that causes the bladder to contract. A message is also sent to the brain, signalling the need to urinate. When the brain assesses that it is appropriate to do so it passes simultaneous messages back through the spinal cord telling the valve to open and the detrusor muscle to contract, and urine is passed. Normally this occurs six to eight times a day. Tel: 01462 476700 37 The cause of symptoms Damage to areas of the spinal cord or brain that control the phases of this process can cause different types of problem. Failure to store In this situation, damage occurs to the spinal cord between the area controlling the bladder reflex and the brain. When this happens, the controlling message from the brain is interrupted and the reflex action means the bladder will empty automatically. For the individual this means they will need to go to the toilet often (frequency), but usually with little or no notice (urgency), resulting in incontinence. Failure to empty This happens when the scarring occurs in the reflex area of the spinal cord interrupting the instruction to empty the bladder. This means that even when someone goes to the toilet, they find it difficult to pass urine (hesitancy). The bladder does not empty properly and keeps filling beyond its normal level until it overflows. This leads to frequent, urgent needs to go to the toilet, often accompanied by overflow incontinence. 38www.mstrust.org.uk Combination of failure to store and failure to empty This occurs when scarring causes a loss of coordination between the contracting of the bladder and the opening of the valve. Depending on where the damage occurs this can either mean: the bladder contracts but the valve remains closed, so that urine can not be released – the individual feels a strong urge to go to the toilet (urgency) but is unable to properly empty their bladder (hesitancy) brain spinal cord reflex urine urine Normal function The bladder triggers a message to the reflex area of the spinal cord and a message is also sent to the brain. The brain passes instructions to the bladder the bladder relaxes and the valve opens resulting in an inability to store any urine which causes incontinence. Rather than helping the problem, reducing fluid intake can in fact make bladder symptoms worse. If the body does not have sufficient fluid, urine becomes concentrated and flow slows down. This allows painful crystals to form and bacteria to grow, which can lead to infections. Difficulty with both bladder control and walking often go together in MS. The wiring of the nervous system means that the connections to the bladder from the spinal cord are below those to the legs. If there is damage to the nerves further up the spinal cord, both functions can be affected. More information from the MS Trust: Bladder management factsheet brain brain spinal cord spinal cord reflex reflex urine urine Failure to store Failure to empty Damage occurs between area controlling the bladder reflex and the brain Scarring occurs in the reflex area of the spinal cord interrupting the instruction to empty the bladder Tel: 01462 476700 39 The cause of symptoms Bowel problems In the healthy bowel, once food has passed through the digestive system, waste material is collected in the colon where it forms into stools. When the colon is stretched to a certain size, nerve responses trigger a reflex process that causes a bowel movement. The stool is passed into the rectum - the area occupying the last six inches of the digestive system. As the rectum fills, it triggers another reflex action that causes the stool to pass to the anal canal. The anal canal is about an inch long with a valve, or sphincter, at each end. The internal sphincter, which separates the anal canal from the rectum, is opened by an involuntary reflex action under the control of the spinal cord. The external sphincter can be controlled to prevent inappropriate defecation. When someone wishes to defecate, the external sphincter is relaxed and they ‘bear down’ - increasing the pressure in their abdomen to help push the stool out. Although the causes of bowel disorders in MS are not fully known, it is thought that damage to nerves controlling different parts of this process can lead to different bowel problems. stomach rectum interior sphincter small intestine rectum colon (large intestine) anus exterior sphincter 40www.mstrust.org.uk Constipation Constipation can be caused by interruptions to the sensory messages from the colon or rectum that signal fullness. The body does not realise that there is a need to move the stool on to the next stage in the process. Constipation can also be due to the slowing down of the digestive process that can occur in people who do not undertake much physical activity or who cannot bear down with sufficient pressure due to weakness. Not drinking enough can also cause constipation. As food passes through the body, water is extracted. If there is not enough fluid in the diet, by the time food reaches the end of the process, it has become a dry, hard stool which does not move as easily through the system. Faecal incontinence Faecal incontinence is the inability to control defecation. This happens when damage to nerves occurs between the reflex area in the spinal cord and the areas of the brain that give voluntary control to bowel movements. This does not necessarily mean that the individual experiences diarrhoea, but if this lack of coordination affects the parts of the process where stools are formed, it can result in ill formed and runny stools. Faecal incontinence can also be caused by constipation. A build up of constipated matter can sometimes mean that the sphincters in the anus and the rectum do not close properly, allowing runny stools to escape around the blockage. More information from the MS Trust: Bowel management factsheet Weakness One of the causes of weakness in muscles in MS is the poor transmission of messages by damaged nerves, mainly within the spinal cord. It is often associated with fatigue. As the nerve damage makes muscles less responsive, it requires more energy to carry out actions. Feeling weak can cause Tel: 01462 476700 41 The cause of symptoms an individual to become less active in an attempt to conserve energy, but this can cause weakness to increase. An already weak muscle that is not used will become weakened further, a process known as atrophy. However, as muscle weakness in MS is primarily due to problems with nerves rather than within muscles, expending a great deal of energy by exercising to the point of exhaustion can also make weakness worse. For many years people with MS were advised to avoid exercise due to the impact it could have on weakness and fatigue. It is now felt that exercise is beneficial if it works on gently building up endurance and strength in muscles without increasing weakness and fatigue. More information from the MS Trust: Move it for MS DVD Exercises for people with MS www.mstrust.org.uk/exercise 42www.mstrust.org.uk 2. Brainstem The brainstem is the area at the base of the brain that connects to the spinal cord. It contains areas responsible for basic functions such as breathing, heart rate, blood pressure and control of the bladder. Many of the processes controlled by the brainstem are outside conscious control. The peripheral nerves that maintain processes such as breathing and digestion are referred to as the autonomic nervous system. The midbrain area of the brainstem controls vision, hearing, body movement and the movement of the eyes. Visual problems Visual problems are common in MS and are often one of the first symptoms people experience. Double vision Visual disturbances in MS can be caused by damage to the nerve pathways that connect to the 12 muscles that control the movement of the eyes. A reduction of coordination in the eyeballs leads to double vision (diplopia). Nystagmus Sometimes nerve damage can result in a flickering or jerking motion of the eyeballs, often when moving the eyes to a certain position. This disorder is called nystagmus. 3. Optic nerve Another common visual problem experienced by people with MS is due to damage to the optic nerves, which carry information from the back of the eyes to the brain. optic nerve eye ball Uhthoff’s phenomenon Some people find that an increase in temperature affects their vision in some way. This effect is known as Uhthoff’s phenomenon or Uhthoff’s sign. These symptoms lessen or disappear when the individual cools down again. visual cortex Optic neuritis Inflammation of the optic nerve is called optic neuritis. Optic neuritis can cause a sudden, usually temporary, loss of vision. An attack usually occurs on one side only and is often accompanied by pain behind the affected eye. The effects of an Tel: 01462 476700 43 The cause of symptoms attack of optic neuritis can include complete loss of sight, partial blind spots (called scotomas), blurred or foggy vision, or the loss or worsening of colour vision. More information from the MS Trust: A to Z of MS optic neuritis www.mstrust.org.uk/atoz/ optic-neuritis.jsp 4. Cerebellum The cerebellum controls movement, balance and posture. Balance problems and dizziness The body uses the complex interaction of a variety of sources to maintain an idea of how it fits in with its environment, such as whether it is upright or maintaining balance. This requires the coordination of information from vision, from the balance systems in the inner ear and information from movement, touch and joint sensors throughout the body. 44www.mstrust.org.uk For instance, when someone turns their head, their eyes, neck muscle sensors and two inner ears all give matching information to the brain. If something causes a mismatch in the information, it affects the sense of orientation and causes feelings of dizziness, vertigo or loss of balance. These outgoing and incoming messages are coordinated in the cerebellum. If MS causes damage to the nerves in this part of the brain, balance can be affected. More information from the MS Trust: A to Z of MS balance www.mstrust.org.uk/atoz/ balance.jsp Ataxia and tremor Disruption to the coordination of movements is called ataxia. In its mildest form this can be mistaken for clumsiness. If damage to the cerebellum is more severe, the disruption to coordination can lead to shaking or tremor. Tremor in MS usually does not happen in completely relaxed limbs, but is triggered by a mismatching of messages when trying to perform a function. This makes tremor in MS distinct from that found in Parkinson’s disease, where shaking occurs in muscles at rest. There are two main types of tremor that can affect people with MS. Intention tremor This occurs when someone tries to carry out a task. For instance, an arm can start to shake as it moves to pick up a teacup or the telephone, with the shaking worsening as the hand approaches the object. 5. Areas of the brain involved with thought and emotion Cerebral cortex The cerebrum makes up nearly 70 per cent of the brain. It is the outer layer of the brain which has the familiar walnut like bumps and grooves (called gyri and sulci). The cerebral cortex controls thought, voluntary movement, language, reasoning and perception. cerebral cortex limbic system Postural tremor This occurs when the body has been held in a particular position for a period of time. It usually affects the head, neck and trunk. More information from the MS Trust: A to Z of MS ataxia w ww.mstrust.org.uk/atoz/ ataxia.jsp A to Z of MS tremor www.mstrust.org.uk/atoz/ tremor.jsp hypothalamus Tel: 01462 476700 45 The cause of symptoms Hypothalamus The hypothalamus is a small structure at the base of the brain that controls body temperature, emotions, hunger, thirst and the circadian rhythms - the natural variations in the body’s activities throughout the day. Limbic system The limbic system (or the limbic area) is important for controlling the emotional response to situations. It includes the hippocampus, which is important for memory. Cognition As well as affecting the control of muscles and actions in different parts of the body, damage to the brain caused by MS can also affect mental processes. These are called cognitive or cognition problems. Generally, cognition problems in MS affect the speed or ease with which someone can process information, and do not indicate a loss of underlying intelligence. 46www.mstrust.org.uk Memory difficulties Memory difficulties are primarily related to the recall of recent events or information and forgetting to carry out planned actions. Information processing problems This results in difficulties when following complicated instructions or a series of instructions, especially if the information is given rapidly. Problem solving difficulties When there is an inability to hold a number of pieces of information in the head at once and being unable to mentally structure thoughts to carry out a series of separate actions. Word finding The inability to find the word you need when speaking, also called the ‘tip of the tongue’ phenomenon, is a short-term recall problem rather than the loss of memory for that word. Concentration and attention span problems This tends to occur when a lot of information is being delivered to a person at once, for example where several people are talking or in a noisy, bustling environment. Cognitive problems can fluctuate from day to day and can worsen during relapse or periods of fatigue. Some medications, including those used to counteract pain, fatigue and depression, may also have an impact on these problems. Although research suggests that these symptoms can affect almost half of all people with MS, many people may not recognise them as symptoms of MS or may find ways to compensate for the problems without seeking treatment. Difficulties can arise early in the course of someone’s MS, although the greater the disease duration and severity the more likely problems are to occur. More information from the MS Trust: Cognition factsheet Mood swings and depression The effects of MS can cause alterations in an individual’s mood and many people with MS experience depression. Depression involves persistent sadness lasting more than two weeks, accompanied by other symptoms such as an altered sleep pattern, feelings of hopelessness, guilt and low self esteem, thoughts of death, reduced energy and the inability to concentrate and to take pleasure in anything. Mood swings and depression in MS can be due to a number of factors. The uncertainty and frustrations of living with the condition can have a negative effect on mood and the side effects of some medication, such as steroids, can also affect emotional responses. Episodes of fatigue can be particularly associated with affected mood. Depression may also be caused directly by MS damage to the nerves in the brain. MS can also directly affect emotional responses and cause episodes of uncontrolled laughter or crying. Referred to as ‘pseudobulbar affect’, ‘emotional lability’ or Tel: 01462 476700 47 The cause of symptoms ‘pathological laughter and crying’, the exaggerated response will have little or no relationship to actual events or the individual’s feelings. Recognition of these disorders as symptoms of MS has only occurred relatively recently and the precise causes are poorly understood. More information from the MS Trust: A to Z of MS emotionalism www.mstrust.org.uk/atoz/ emotionalism.jsp Depression factsheet 6. Symptoms not associated with a single area of damage For some symptoms it is not possible to identify a single area of the central nervous system that is the chief area of damage. In other cases, the cause of the symptom remains unclear. Fatigue Fatigue is one of the commonest symptoms of MS and one that can often cause major problems to a person’s life. The cause of fatigue in MS is not well understood. It is thought to result from a combination of factors, partly caused by MS itself (known as primary fatigue) and partly by other factors (secondary fatigue) that affect the person with MS more significantly than those without the condition. Primary fatigue is thought to be a combination of slowed nerve messages from the brain and spinal cord and a build up of weakness in muscles due to lack of stimulation. The level of fatigue 48www.mstrust.org.uk does not reflect the severity of someone’s MS and people can experience fatigue that prevents them from working, or which interrupts their daily life, whilst having no other symptoms. MS fatigue or ‘lassitude’ is very different from the tiredness or exhaustion that people without MS experience following strenuous exercise or a busy day at work. Fatigue is described as interfering with normal activity and being out of all proportion to any activity undertaken. It is characterised by the sudden loss of energy and the inability to continue an activity. MS can also cause ‘shortcircuiting’ or neuromuscular fatigue. This happens if nerve messages to muscles become confused when someone is performing repeated movements. Messages start to ‘leak’ into other nerve cells and it becomes harder for the brain to get instructions through. For example, the legs may become increasingly heavy and difficult to move when walking, or the arms may be affected when writing for a period of time. Secondary fatigue is fatigue that results from another symptom or cause, rather than being caused by the condition directly. Factors that can add to fatigue include lack of sleep, low mood or depression, stress, inadequate diet, lack of exercise, infections or side effects of medication. Heat can increase fatigue in MS and some people with MS find that symptoms get worse during spells of hot weather. This was first observed in the late nineteenth century, and for a time, one of the diagnostic tests for MS was to put the patient into a hot bath and observe if this made symptoms worse. More information from the MS Trust: Living with fatigue Tel: 01462 476700 49 The cause of symptoms Speech and swallowing There are a number of different speech and swallowing problems that can affect people with MS. Damage to the various parts of the brain that control thought, memory, verbal fluency or attention can lead to difficulty in finding words or forming sentences. This disorder is called dysphasia. soft palate Speech requires the complicated interaction and coordination of several parts of the body including the lungs, diaphragm, vocal cords, lips, tongue and nasal cavity. Damage to areas of the central nervous system that control any of these elements can have an effect on speech. Similarly, fatigue or weakness can affect any part of the process. When a speech disorder is due to damage affecting the muscles used in speech, it is called dysarthria. This can lead to slurred speech, or difficulty in controlling volume, articulation or intonation. epiglottis Many of the muscles used in speech also have a role in swallowing and a lack of coordination can cause difficulties when a person is eating or drinking. This is known as dysphagia. nasal cavity tongue lips larynx vocal cords windpipe (trachea) 50www.mstrust.org.uk oesophagus If the various processes involved in holding food in the mouth, chewing and swallowing are not synchronised, a number of different problems can occur. Food may get stuck in the throat, which causes choking; may move too slowly in the oesophagus (the tube connecting the mouth to the stomach), which causes coughing and spluttering; or may go into the windpipe (which should be closed during swallowing) or the lungs, which is known as aspiration. More information from the MS Trust: A to Z of MS speech problems www.mstrust.org.uk/ speech.jsp A to Z of MS swallowing problems www.mstrust.org.uk/ swallowing.jsp Pain For many years, the medical world considered MS to be a pain free condition. This idea has now been completely overturned and studies suggest that the majority of people with MS experience some form of pain as a symptom at some stage. There are two main types of pain in MS. Muscle pain Muscle pain (called nociceptive pain or musculoskeletal pain) is generated by damage to the muscles, tendons, ligaments and soft tissue of the body. This is the sort of pain that is felt when someone falls over or cuts themselves. In MS, this pain is not caused directly by damage to the nerves but develops as a result of other symptoms. For instance, spasticity in a leg can cause someone to alter the way they walk or alter their posture, which can result in added strain on the back, legs or arms. Nerve pain Pain that results from damage to nerves is known as neurogenic, neuropathic or nerve pain. With this type of pain, nerve messages are interrupted, or blocked, and the brain interprets the incomplete information it is receiving as pain. Whilst the pain experienced can be severe or long lasting, unlike muscle pain, there is no physical cause of the symptom. Tel: 01462 476700 51 The cause of symptoms Examples of nerve pain include: Paraesthesia or dysaesthesia Persistent, uncomfortable, abnormal sensations are experienced differently from person to person. The pain can be described as sensations such as pins and needles, burning and crawling feelings, numbness or tightness. L’hermitte’s sign Sometimes referred to as the ‘Barber Chair’ phenomenon, this is caused by damage to the spinal cord in the neck. Movements of the neck cause a brief but sharp, painful, buzzing, electric shock feeling running down the spine and into the legs. Trigeminal neuralgia The trigeminal nerve controls movements and sensation in the face and mouth. Damage to this nerve at the point where it meets the central nervous system at the base of the brain can lead to episodes of sharp pain in the face triggered by actions such as talking, chewing, smiling or brushing teeth. 52www.mstrust.org.uk More information from the MS Trust: Pain factsheet Bibliography Burgess M. Multiple sclerosis: theory and practice for nurses. London: Whurr; 2002. Burks JS, et al. Multiple sclerosis: diagnosis, medical management and rehabilitation. New York: Demos; 2000. Fowler CJ. Pathophysiology of micturation disturbances in multiple sclerosis. Sexuality & Disability 1996; 14(1): 7-12. MS Trust. Multiple sclerosis information for health and social care professionals. Letchworth: MS Trust; 2011. National MS Society. Multiple sclerosis information sourcebook. New York: National MS Society; 2006. Neuroscience for kids. Available from: URL: http://faculty.washington.edu/chudler/ neurok.html [Accessed 21 Feb 2013] Schapiro RT. Managing the symptoms of multiple sclerosis. 4th ed. New York: Demos; 2003. Tel: 01462 476700 53 Future research Where will we find an answer? Despite being first described in 1868, MS still remains a condition of many mysteries: no known cause, no means of prevention, and no cure - but there have been significant advances. Until the 1990s, there were no drugs that had any effect on the underlying disease activity of MS, and treatment was focused on medication and management techniques for the various symptoms that people experienced. Whilst symptomatic treatment remains at the core of the medical management of MS, the last few decades have seen breakthroughs that have shown the possibility of developing therapies that may effectively tackle MS itself. Typically in the past, research has primarily focused on the relapsing remitting form of MS, however today more and more resources are being directed at research into progressive MS. Very broadly, there are three main focuses of research for altering the course of MS: 54www.mstrust.org.uk immune system - altering the processes that cause damage to nerves neuroprotection - protecting nerves to prevent any further damage repair - repairing or replacing damaged nerve cells to reverse disability. Immune system Initial experimental therapies for modifying the course of MS were based on attempts to control the activity of the immune system. The first drug to be licensed was beta interferon - a commercially produced version of a substance that occurs naturally in the immune system. The role of beta interferon is to calm down the immune system once an infection has been dealt with. As a drug it was hoped that this would limit the effect of the immune cells that mistakenly attack the myelin surrounding nerves (see page 20). Several different beta interferon drugs are now available (Avonex, Betaferon, Extavia, Rebif). Another drug called glatiramer acetate (Copaxone) was developed at the same time as beta interferon. This is a synthetic combination of four molecules that resembles the myelin protein surrounding nerve fibres. Studies showed that on average both the beta interferon drugs and glatiramer acetate helped to slow the relapse rate of someone with MS by a third and to reduce the severity of those relapses that did still occur. Attempts to produce more powerful drugs that reduce the immune response further have come up against the problem that this approach is not focused on any specific part of the system. As a result these drugs can attack aspects of the immune system needed to fight infections as well as the elements that might be involved in MS. Targeting antibodies Some researchers have looked at ways of targeting specific elements within the immune system that play a role in MS, while leaving the remaining immune system intact. This approach has led to the development of a new class of drugs called monoclonal antibodies. Antibodies are proteins in the immune system that bind onto an invading cell or germ and help to destroy it (see page 21). Each antibody has a single target, when that target is found in the body millions of antibodies are produced against it from a single B-cell. This means that if antibodies can be identified that bind to cells involved in attacking nerve cells and causing disease activity in MS, maybe drugs can be developed that will only affect those cells. Monoclonal antibodies are created by cloning a cell that produces a single antibody and this has led to the creation of several new drugs that may be used to treat MS. Examples of monoclonal antibodies include: natalizumab (Tysabri), which binds to and disables the area of white blood cells that allows them to cross the blood brain barrier, effectively keeping cells that might attack myelin from coming into contact with the brain or spinal cord Tel: 01462 476700 55 Future research alemtuzumab (Lemtrada), which binds to proteins on the surface of the white blood cells associated with attacking the myelin on nerves. The World Health Organisation’s standards for naming drugs means that all monoclonal antibodies end with -mab. Research has shown that these drugs are more effective than beta interferon and glatiramer acetate at reducing the number of relapses. However, the research has also shown that there are also more serious side effects and so treatment requires regular monitoring for, and treatment of, these effects. Oral treatments All of the drug treatments mentioned so far have to be injected or given intravenously. If taken as tablets, the active ingredients would be digested before they could work. More recently a number of drugs have been developed that provide a disease modifying effect in tablet form: 56www.mstrust.org.uk BG-12 (Tecfidera) is thought to work by reducing the inflammation caused when the immune system attacks myelin and by protecting the nerve cells from damage caused by chemicals released during the immune attack fingolimod (Gilenya) works by binding to the surface of white blood cells in the immune system, trapping them in the lymph nodes and preventing them from attacking cells in the central nervous system laquinimod is thought to work by affecting the levels of certain substances released by immune cells to reduce the inflammation caused when the immune system attacks myelin. Thus preventing immune cells that cause the damage in MS from entering the brain and spinal cord and by triggering the production and release of brain-derived neurotrophic factor (BDNF) which plays a key role in nerve survival and growth teriflunomide (Aubagio) is thought to work by reducing the number of white blood cells (T-cells and B-cells) involved in the MS immune response. More information from the MS Trust: Disease modifying drug therapy: what you need to know Alemtuzumab (Lemtrada) factsheet BG-12 (Tecfidera) factsheet Laquinimod factsheet Teriflunomide (Aubagio) factsheet Future drug development All of the current disease modifying drugs treat the relapsing remitting type of MS. Increasingly, research suggests that early, aggressive treatment of MS, effectively before someone is showing any signs of disability, may prevent or greatly reduce subsequent damage from occurring. If treatment is carried out once MS has started to attack and destroy nerve cells, then drugs are much less effective in controlling progression. The disease modifying drugs work by altering some of the processes within the body that cause MS relapses to happen and thus protect nerves from damage. The following are just some of the drugs that are currently in research: Relapsing remitting MS daclizumab – a monoclonal antibody that interferes with the activation and growth of lymphocytes ocrelizumab - a monoclonal antibody that targets a marker on the surface of B-cells which are thought to influence the abnormal immune response that causes the immune system to attack myelin Secondary progressive MS masitinib – a drug that targets a type of cell involved in allergy and inflammation, which is known as a mast cell, leading to a reduction in immune response and inflammatory processes natalizumab (Tysabri) – already licensed for use in RRMS siponimod – belongs to the same class of drugs as fingolimod and works by binding to the surface of white blood cells in the immune system, trapping them in the lymph nodes and preventing them from attacking cells in the central nervous system Tel: 01462 476700 57 Future research Primary progressive MS natalizumab (Tysabri) – already licensed for use in RRMS and also being tested in SPMS fingolimod (Gilenya) – already licensed for use in RRMS masitinib – also being tested in SPMS ocrelizumab – also being tested in RRMS The processes that cause MS to become progressive, once nerves have been damaged or destroyed, are less well understood than the processes that occur in relapsing remitting MS. To date there is no disease modifying treatment for progressive MS. In the past a number of different drugs have been studied as treatments for progressive MS, but any positive results were very modest. As can be seen from the list above, many drugs are currently being investigated to determine whether they have any modifying effect on progressive MS. However, alternative approaches will probably also be needed to protect existing nerves and to repair or replace those that have been lost. 58www.mstrust.org.uk Neuroprotection Neuroprotection is a relatively new area of research in MS. The permanent symptoms of the progressive types of MS develop when nerve cells are destroyed. This is thought to occur when nerve fibres are exposed to chemicals produced by the inflammation of tissue that MS causes. The theory of neuroprotection is that, if the nerve cells can be protected from these chemicals, destruction - and thus further permanent problems - can be lessened or prevented. Different aspects of neuroprotection are being examined, concentrating on different elements that lead to loss of nerve cells. Inflammation leads to the increase in levels of nitric oxide, calcium and sodium. Contact with high levels of these chemicals can damage nerve cells and research is underway to examine the impact of blocking their effects. Another approach is looking at a type of drug called glutamate receptor blockers. Glutamate is one of the chemicals involved in transmitting messages from nerve cell to nerve cell, but excessive glutamate can also damage nerves. Research in this area is at a relatively early stage and many studies are exploring the potential of neuroprotection as a strategy rather than the possibility of bringing a particular drug to market in the short-term. Neuroprotective drugs will not be able to reverse progression or restore function that has already been lost. However, if suitable drugs can be developed, it is hoped that the progression of MS can be significantly slowed down. Repairing and replacing myelin Whilst drugs that alter the action of the immune system or that protect nerves may help to limit the accumulation of damage, neither will reverse the progressive effects of MS. Exploration of processes that might repair areas of damage and thus allow people to recover function that has been lost is another important area of MS research. From observing areas of the central nervous system that have been damaged by MS it is known that, in the earlier stages of the condition, the body can replace lost myelin to some extent. If the affected area Tel: 01462 476700 59 Future research is no longer being attacked by the immune system, new myelin can be formed, which will repair damage to nerve cells and reverse, at least to a degree, some of the disability caused. Various strategies for repairing and replacing myelin have been investigated. For instance, chemicals within the immune system have been identified that can accelerate the growth of myelin. There is a large body of work going on in this field in the UK at centres in Cambridge and Edinburgh, but the research is still at a very early stage. Repurposing drugs Another approach that is currently being explored is the ‘repurposing’ of drugs. This is where treatments whose safety profile is known due to their use in other medical conditions are being looked at to see if they could be useful in MS. If this approach is successful it has the potential to speed up the development of drugs, as the treatments are already known to be safe in humans. 60www.mstrust.org.uk Teams in London and Edinburgh are using this approach to test three neuroprotective drugs which have shown early promise in small studies in secondary progressive MS (SPMS). Amiloride (a blood pressure tablet), ibudilast (asthma) and riluzole (motor neurone disease) will be tested against a placebo (dummy pill) to see if one or more of these drugs could be helpful in slowing SPMS. More information from the MS Trust: Treatments in development www.mstrust.org.uk/ research/ drugsindevelopment Stem cells Interest has also focused on the possibility of using stem cells to repair damaged cells in the central nervous system. Stem cells are unspecialised cells that can develop, or differentiate, into any of the specialised cells of the body, such as those in heart muscle or the insulin-producing cells of the pancreas. Stem cells are the first cells to develop in embryos and allow the foetus to develop the specialised functions and mechanisms that occur in the human body. Stem cells derived from an embryo are capable of developing into all the cell types that make up the tissues and organs, such as the heart, skin and brain. The use of stem cells from embryos is the cause of much ethical debate. This has also affected the issue of ‘hybrid’ embryos in which human genetic material is implanted into animal cells that have had most of their own genetic material removed. After six days, stem cells can be extracted for research and the hybrid is destroyed. Not all stem cell research involves the use of embryos. Stem cells also occur in adults and are used by the body to replace areas of damage. For instance, stem cells in bone marrow produce the different types of blood cells. Although more limited in the types of cells into which they can differentiate, research is now looking at how stem cells can be stimulated to turn into oligodendrocyte cells that produce myelin or into nerve cells in sufficient quantity to be used in treatment. Work is also looking at how best to deliver stem cells so that they go to the appropriate places to carry out repair, and also at ways to ensure that transplanted stem cells do not harm the recipient or grow into unwanted tissue. Stem cell treatment is still at the experimental stage in MS. In the UK, pilot studies in humans have focused principally on safety rather than effectiveness, although trials looking at efficacy are due to begin soon. If processes can be developed, it opens the possibility that cells destroyed by MS might be replaced and disabilities caused by the loss of nerve pathways reversed. More information from the MS Trust: Stem cells factsheet Tel: 01462 476700 61 Future research Genetics As we have seen earlier, it is thought that there is a genetic element to MS and that people with MS have a particular genetic make up that can be triggered by an as yet unidentified virus or toxin in the environment. Advances in biotechnology mean that genes are now far better understood. Although any treatments may be some way off, greater understanding of the genetic basis of MS means researchers will be able to identify how it develops and theoretically create the opportunity to target genes that are malfunctioning. It will also allow for the potential evolution of treatments that may prevent those with a genetic risk from developing the condition. However, this approach is made more complicated by the fact that MS is not a single gene condition. Environmental factors There is also a large body of work that is looking at environmental factors which may be implicated in the development of MS, including research on vitamin D, 62www.mstrust.org.uk the protective effect of hormones such as oestrogen, the effect of smoking on progression, and possible viral triggers such as the Epstein Barr virus. More information from the MS Trust: Vitamin D factsheet Summary Although the nature of MS remains unclear, new areas of research offer the chance to increase understanding of the condition. Increasing levels of research since the 1990s have seen some major advances. This period has witnessed the arrival of the first drugs to have some effect on the underlying disease activity of MS and new ones in the pipeline; continuing discoveries about the nature of the immune system and how it can be manipulated; knowledge of the involvement of genes in the development of disease; and breakthroughs in stem cell technology. This momentum offers the hope that multiple sclerosis will eventually be controlled. More information from the MS Trust: Medicine 2012; 367: 1098-107. Gold R, et al. Daclizumab high-yield process (HYP) in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013; 381(9884): 2167-75. MS Trust website Research section www.mstrust.org.uk/ Kapoor R. Neuroprotection in multiple research Bibliography Bruck W, et al. Insight into the mechanism of laquinimod action. Journal of the Neurological Sciences 2011; 306: 173-9. Claussen MC, et al. Immune mechanisms of new therapeutic strategies in MS – teriflunomide. Clinical Immunology 2012; 142: 49-56. Coles AJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380: 1829-1839. Compston A, et al. Multiple sclerosis. Lancet 2002; 359: 1221-1231. Compston A. MS research - theories and areas for progress. Open Door 2007; Feb: 8-9. Fassas A, et al. Stem cell transplantation for multiple sclerosis: what is the evidence? Blood Reviews 2003; 17: 233240. sclerosis: therapeutic strategies and clinical trial design. Current Opinions in Neurology 2006; 19(3): 255-259. Kappos L, et al. Ocrelizumab in relapsingremitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378(9805): 1779-87. Reingold SC. Research directions in multiple sclerosis. New York: National MS Society; 2004. Selmaj K, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurology 2013 June 11. [Epub ahead of print] Vermersch P, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurology 2012; 12: 36. Yuen TJ, et al. Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. Brain 2013; 136(Part4): 1035-47. Gold R, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. New England Journal of Tel: 01462 476700 63 Glossary Aetiology (or etiology in American English) - the study of the causes of a disease Axon - the long extension of a nerve cell along which the nerve message is passed Antibody - proteins in the immune system that help target the attack on invaders B-lymphocytes (B-cells) - a type of white blood cell which mature in the bone marrow and are programmed to recognise a specific virus or bacterium Antigen - a substance that causes the formation of an antibody and reacts specifically with that antibody Aspiration – the entry of secretions or foreign bodies, for example food, into the trachea or lungs Ataxia – disruption to the coordination of movement Autoimmune disease - a condition in which the immune system attacks the body’s own tissue Autonomic nervous system (ANS) - the part of the peripheral nervous system that regulates the function of our internal organs (heart, stomach, intestines). The ANS is involved in involuntary or reflex functions such as breathing, dilation/ constriction of blood vessels and increases/decreases in heart rate. 64www.mstrust.org.uk Benign MS – a form of relapsing remitting MS where there are very mild attacks separated by very long periods with no symptoms. Can only be diagnosed retrospectively Blood brain barrier - the layer of cells that keeps cells in the blood from coming into contact with the central nervous system Bone marrow - the spongy tissue found in the hollow centre of some bones. It contains stem cells which produce red blood cells Brainstem - the area at the base of the brain that connects to the spinal cord. It contains areas responsible for basic functions such as breathing, heart rate, blood pressure and control of the bladder Central nervous system - the brain and spinal cord Cerebellum – the part of the brain that controls movement, balance and posture Cerebrospinal fluid (CSF) - the fluid that surrounds the brain and the spinal cord Cerebrum - the outer layer of the brain which has the familiar walnut like bumps and grooves (called gyri and sulci) Circadian rhythms - the natural variations in the body’s activities throughout the day Clinically isolated syndrome (CIS) – a single episode of demyelination in one area of the central nervous system (a monofocal episode) or several areas of the central nervous system (a multifocal episode) which lasts for at least 24 hours Constipation - the passage of hard stools, less frequently than the patient’s usual bowel pattern Cognition - the entire range of mental skills and abilities that each of us possess. This includes memory, concentration, planning, thinking things out, decisionmaking and understanding Demyelination - the destruction of myelin Dendrite - extensions of the nerve cell body through which incoming messages are received Depression - persistent sadness lasting more than two weeks, accompanied by other symptoms such as an altered sleep pattern, feelings of hopelessness, guilt and low self esteem, thoughts of death, reduced energy and the inability to concentrate and to take pleasure in anything Detrusor muscle – the bag-like muscle of the bladder wall Differentiation – the process by which a less specialised cell (stem cell) develops or matures to possess a more distinct form and function Tel: 01462 476700 65 Glossary Diplopia – double vision Dysaesthesia - abnormal skin sensations, such as tingling or tickling or itching or burning Dysarthria – a speech disorder caused by damage to the muscles involved in speech, often leads to slurred speech, difficulty in controlling volume, articulation or intonation Dysphagia – a lack of coordination of the muscles involved in speech and swallowing that causes difficulties when eating and drinking Dysphasia – a condition arising when the parts of the brain that control thought, memory, verbal fluency or attention are damaged. Can lead to difficulty in finding words or forming sentences Electrophoresis - a method of separating substances, especially proteins, based on the rate of movement of each component in a suspension while under the influence of an electric field 66www.mstrust.org.uk Emotional lability - an excessive emotional response to a minor stimulus, for example laughing or crying with minimal provocation or at inappropriate times Epidemiology - the study of the geographical distribution of a condition and patterns of disease as it affects groups of people Faecal incontinence - having no control over when the bowel opens Frequency – an increase in the number of times someone needs to urinate in a day Glial cells - support cells in the central nervous system Hereditary - determined by genetic factors and therefore able to be passed directly on from parents to their offspring Hesitancy – difficulty in starting to urinate Hippocampus – part of the brain which is important for memory Hypothalamus - a small structure at the base of the brain that controls body temperature, emotions, hunger, thirst and the circadian rhythms Incidence - the number of new cases of a condition within a set period of time, usually a year Inflammation - a localised protective reaction of tissue to irritation, injury, or infection, characterised by pain, redness, swelling, and sometimes loss of function Interferon - a chemical generated by the immune system to alter the response to an invasion Lassitude - a state or feeling of weariness, diminished energy, or listlessness Lesion - the scar tissue over an area of damaged myelin that shows up as white regions on T2 magnetic resonance imaging (MRI) scans L’hermitte’s sign - a brief but sharp, painful, buzzing, electric shock feeling running down the spine and into the legs Limbic system – the area of the brain responsible for controlling the emotional response to situations Lumbar puncture – the insertion of a hollow needle into the lower region of the spinal cord to withdraw cerebrospinal fluid or to introduce drugs Lymphocyte – type of white blood cell involved in the immune system Lymph nodes - small bean-shaped structures scattered along the vessels of the lymphatic system, particularly at the neck, armpit and groin. The lymph nodes produce white blood cells and filter bacteria and cancer cells that may travel through the system Macrophage - immune system cell that attacks foreign particles in the body Tel: 01462 476700 67 Glossary Magnetic resonance imaging (MRI) – a test used in the diagnosis of MS. Images of the brain and/or spinal cord are created by using magnetic fields and radio waves McDonald criteria – the criteria used to diagnose MS Muscle atrophy - the wasting of muscle tissue, especially resulting from lack of use Muscle tone – the level of tension or resistance to movement in a muscle which enables you to move a limb or hold a position Myelin - the substance covering nerve axons in the central nervous system Neuron - nerve cell Neurogenic pain – pain that results from damage to nerves Neurotransmitter - chemicals that pass messages from one nerve cell to the next Nodes of Ranvier - a small gap in the myelin sheath of a myelinated nerve axon Nociceptive pain – pain caused by damage to the muscles, tendons, ligaments or soft tissue of the body Nystagmus - a repetitive, involuntary, to-and-fro oscillation of the eyes Oesophagus – the part of the alimentary canal between the mouth and the stomach Oligoclonal bands - proteins (called immunoglobulins) which suggest inflammation of the central nervous system Neuropathic pain – see neurogenic pain Oligodendrocyte - cells in the central nervous system that make myelin Neuroprotection - a therapeutic strategy intended to slow or halt the progression of nerve cell loss and thereby alter the natural history of disease Optic nerve – the nerve which carries information from the back of the eye to the brain 68www.mstrust.org.uk Optic neuritis – inflammation of the optic nerve Primary fatigue – fatigue caused by the condition itself Overflow incontinence - urinary incontinence that occurs when the bladder is so full that it continually leaks urine Progression - a period of gradual increase in disability unrelated to relapses Paraesthesia - abnormal skin sensations, such as tingling or tickling or itching or burning Peripheral nervous system nerves other than the brain and spinal cord Plaque - the scar tissue over an area of damaged myelin that shows up as white regions on T2 magnetic resonance imaging (MRI) scans Plasticity - changes in neural pathways and synapses which are due to changes in behaviour, environment or neural processes, as well as changes resulting from bodily injury Prevalence - the number of people with a condition, usually measured in cases per 100,000 Progressive relapsing MS – MS that is progressive from the outset, but with occasional relapses Pseudobulbar affect - an excessive emotional response to a minor stimulus, for example laughing or crying with minimal provocation or at inappropriate times Reflex reaction - physical response automatically generated by the spinal cord with no involvement from the brain Relapse - an episode of new or worsened symptoms that lasts more than 24 hours in the absence of an infection Remission - a period of partial or complete recovery from symptoms Remyelination - the replacement of myelin Tel: 01462 476700 69 Glossary Scotoma – a partial loss of vision or a blind spot in an otherwise normal visual field Secondary fatigue – fatigue caused by another symptom or cause rather than the condition itself, for example lack of sleep, depression, stress, infection Serum - the clear yellowish fluid obtained upon separating whole blood into its solid and liquid components after it has been allowed to clot Spasticity – a condition in which muscle tone becomes greatly increased Spinal cord - the long, cordlike part of the central nervous system that is enclosed within the vertebral column (spine) and descends from the base of the brain. The spinal cord branches to form the nerves that convey motor and sensory impulses to and from the tissues of the body Stem cells - an unspecialised cell which has the ability to divide and self-renew while it is in an undifferentiated state, and the capacity to give rise to various 70www.mstrust.org.uk specialised cell types by cell differentiation Synapse - the gap between nerve cells across which nerve messages are passed from one cell to the next Thymus - a lymphoid organ located in the chest cavity behind the breastbone and above the heart. It is central to the development and function of the immune system. It is not directly involved in the immune response, but a population of lymphocytes which become known as T-cells travel from the bone marrow to mature here T- lymphocytes (T- cells) – a type of white blood cell which mature in the thymus, they respond to the antigen presenting cells Trachea - the tube which extends from the larynx to the bronchi, which conveys air to and from the lungs; also known as the windpipe Trigeminal nerve – the nerve that controls movements and sensation in the face and mouth Trigeminal neuralgia – facial pain caused by damage to the trigeminal nerve which can be triggered by actions such as talking, chewing and smiling Visual evoked potential – a diagnostic test that measures the speed of the nerve message from the eye to the visual cortex at the back of the brain Uhthoff’s phenomenon (or sign) - the worsening of neurologic symptoms in multiple sclerosis and other neurological, demyelinating conditions when the body gets overheated Urethral sphincter – the valve at the base of the bladder which opens to let urine out Urinary incontinence – the inability to hold urine in the bladder until an appropriate time Urgency – the feeling of having to empty the bladder immediately, an inability to ‘hold on’ Vaccination – the administration of a preparation of a weakened or killed pathogen, such as a bacterium or virus, or of a portion of the pathogen’s structure that upon administration stimulates antibody production or cellular immunity against the pathogen, but is incapable of causing severe infection Tel: 01462 476700 71 More information from the MS Trust MS Trust publications All our publications are free Books Disease modifying drug therapy: what you need to know Living with fatigue MS: what does it mean for me? Primary progressive MS exposed Spasticity triggers DVD Move it for MS A DVD of exercises for people with MS Factsheets Alemtuzumab (Lemtrada) BG-12 (Tecfidera) Bladder management Bowel management Cognition Depression Laquinimod Pain Spasticity Stem cells Teriflunomide (Aubagio) Vitamin D 72www.mstrust.org.uk Website The MS Trust website includes: A comprehensive A to Z of MS covering a wide range of information about symptoms, treatments and more Sections on exercises for people with MS and Staying Active with MS A complete list of MS Trust publications, which can also be downloaded or read online A section discussing ongoing research and developments Videos from people with MS and health professionals. Tel: 01462 476700 73 Index A Abnormal sensations....................52 Aetiology.......................................64 Age at diagnosis.............................4 Antibodies....... 13, 20-22, 55-58, 64 Antigen............................. 20-21, 64 Antigen presenting cells......... 20-21 Aspiration...............................51, 64 Ataxia......................................44, 64 Attention span........................47, 50 Auditory evoked potentials...........29 Autoimmunity...............5, 10, 24, 64 Autonomic nervous system.................. 16, 42, 64 Axon...................... 17-18, 24-25, 64 B Balance...................................35, 44 Barber chair syndrome.................52 Benign MS....................................31 Beta interferon........................22, 54 Bladder symptoms........... 35, 37-39 Blood brain barrier......19, 24, 28, 64 B-lymphocytes or B-cells.21-22, 64 Bowel symptoms........ 35, 40-41, 64 Brainstem................... 35, 42-43, 64 Burning sensations.......................52 C Calcium........................................58 Cause of MS........................... 10-15 Central nervous system.... 16-19, 65 Cerebellum................. 35, 44-45, 65 74www.mstrust.org.uk Cerebral cortex.............................45 Cerebrospinal fluid (CSF).......28, 65 Clumsiness...................................44 Cognition.................... 35, 46-47, 65 Concentration...............................47 Constipation.................................41 Crawling sensations.....................52 D Demyelination................... 24-25, 65 Dendrites.......................... 17-18, 65 Depression.................35, 47, 49, 65 Detrusor muscle............... 37-39, 65 Diagnostic tests...................... 26-29 Diplopia............................35, 42, 66 Dizziness................................35, 44 Double vision..........................35, 42 Dysaesthesia..........................52, 66 Dysarthria...............................50, 66 Dysphagia...............................50, 66 Dysphasia...............................50, 66 E Emotional lability.............. 47-48, 66 Environmental factors......... 7, 12-14 Epidemiology........................ 4-7, 66 Epstein Barr virus.........................13 Evoked potentials.........................29 Exercise........................................42 F Fatigue........................ 35, 42, 48-49 G Gadolinium...................................28 Gamma interferon.........................21 Gender differences...................5, 32 Genes..................... 6, 11-12, 22, 62 Geographic spread of MS.......... 5-7 Glatiramer acetate.................. 54-55 Glial cells................................18, 66 Glutamate............................... 58-59 L Lassitude................................49, 67 Lesion.....................................24, 67 L’hermitte’s sign.....................52, 67 Life expectancy..............................5 Limbic system........................46, 67 Low mood..............................47, 49 Lumbar puncture.............. 28-29, 67 Lymphocytes.................... 20-22, 67 H Heat sensitivity.......................43, 49 Helper T-cells.......................... 20-22 Hot bath test.................................49 Human leukocyte antigen (HLA)...22 Hypothalamus........................46, 67 M Macrophage...........................20, 67 Magnetic resonance imaging....................... 27-28, 34, 68 Major histocompatibility complex (MHC).............................22 Memory..................................46, 50 Messenger molecules............ 21-22 Migration........................................7 Monoclonal antibodies........... 55-56 Mood swings.......................... 47-48 Motor nerves................................16 MRI............................. 27-28, 34, 68 MS Trust Information Service..................2, 34 Muscle pain..................................51 Muscle stiffness...................... 36-37 Musculoskeletal pain....................51 Myelin.....................................18, 68 I IL7R..............................................12 Immune memory..........................22 Immune system................ 20-22, 28 Incidence..................................4, 67 Incontinence, bladder....... 35, 37-39 Incontinence, faecal......... 35, 40-41 Infection (as trigger).......... 12-13, 24 Inflammation...........................22, 67 Intention tremor......................35, 45 Interferons..................21, 22, 54, 67 K Killer T-cells..................................21 Tel: 01462 476700 75 Index N Nerve cells........................ 17-18, 68 Nerve pain........................ 51-52, 68 Nervous system...................... 16-17 Neurogenic pain............... 51-52, 68 Neurological examination....... 26-27 Neurologist...................................26 Neuromuscular fatigue.................49 Neuron ............................. 17-18, 68 Neuroprotection............... 58-59, 68 Neurotransmittors.............18, 58, 68 Nitric oxide...................................58 Nociceptive pain.....................51, 68 Nodes of Ranvier....................18, 68 Numbness..............................26, 52 Nystagmus.......................35, 43, 68 O Oligoclonal bands............. 28-29, 68 Oligodendrocytes.............18, 24, 68 Optic nerve.............................43, 68 Optic neuritis..........................43, 69 P Pain.................................. 35, 51-52 Paraesthesia...........................52, 69 Pathological laughter and crying................. 47-48 Patient history........................ 26-27 Peripheral nervous system..........16, 36, 42, 69 Pins and needles..........................52 Plaque....................................24, 69 76www.mstrust.org.uk Plasticity.................................25, 69 Postural tremor.......................33, 45 Prevalence........................ 4, 5-6, 69 Primary progressive MS...............32 Problem solving difficulties..........46 Progressive MS........... 31-32, 57-60 R Racial variations.............................6 Reflex reaction........................16, 42 Relapse....................... 25, 30-31, 69 Relapsing remitting MS................31 Remission................... 25, 30-31, 69 Remyelination................... 24-25, 69 Risk of developing MS.................11 S Secondary progressive MS..........31 Sensory nerves.............................16 Short-circuiting fatigue.................49 Somatosensory evoked potentials.........................29 Spasticity and spasms................ 35, 36-37, 70 Speech....................... 35, 37, 50-51 Spinal cord.................16, 35, 36, 70 Stem cells......................... 60-61, 70 Support cells..........................18, 66 Swallowing.......................35, 37, 50 Synapse..................................18, 70 T T-lymphocytes or T-cells..................... 21-22, 24, 70 Tremor.............................. 35, 44-45 Trigeminal neuralgia................52, 71 Twins.......................................11, 14 U Urethral sphincter...................37, 71 Urinary tract infections.................39 Uhthoff’s phenomenon or sign...............................43, 49, 71 V Vertigo..........................................44 Viking genes...................................6 Visual evoked potentials (VEP)......................29, 71 Visual problems................ 35, 42-44 Vitamin D................................ 13-14 W Weakness......................... 35, 41-42 White blood cells.............. 20-21, 28 Word finding.................................46 Tel: 01462 476700 77 About the authors Simon Webster, Information Officer, MS Trust; Alison Whittam, Information Officer, MS Trust The MS Trust is a UK charity for people with MS, their family and friends. The MS Trust Information Service offers a personalised enquiry service; produces a wide range of publications including Open Door, a quarterly newsletter; and provides web based information. We would like to thank the people with MS and health professionals who reviewed this book and provided invaluable comments, without which this revision would not have been possible. Please contact the MS Trust information team if you would like any further information about the reference sources used in the production of this publication. This publication will be reviewed in three years. Simon Webster, Alison Whittam MS Explained ISBN 1-904156-28-2 © 2013 Multiple Sclerosis Trust Registered charity no. 1088353 All rights reserved. No part of this book may be produced, stored in a retrieval system or transmitted in any form by any means, electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise without written permission of the publisher. 78www.mstrust.org.uk Tel: 01462 476700 79 We provide: • information that is tailored to what people want to know • education for health professionals about what people with MS need • research into better management of MS • support for anyone affected by MS Multiple Sclerosis Trust Spirella Building, Bridge Road Letchworth Garden City Hertfordshire SG6 4ET T 01462 476700 E [email protected] www.mstrust.org.uk Registered charity no. 1088353 MSExplained.07.13.12K The MS Trust is a charity working with and for the 100,000 people in the UK with multiple sclerosis (MS). Our vision is to enable people with MS to live their lives to the full.