Multiple Sclerosis. Therapies
Which treatment options are there for multiple sclerosis?
In spite of all the progress which has been made in the development of new therapies, multiple sclerosis remains a condition for which there is no cure and which may cause a considerable reduction of the quality of life for people who have it and for their families. The primary goal of therapies currently available is to influence favourably the progress of the disease and to protect those affected by it from relapses or lasting disabilities. The existing symptoms can also be treated with a view to improving the patient's quality of life.
The following treatment options are available for multiple sclerosis:
- Pharmaceutical treatment of an acute relapse: This is almost always treated with cortisone. The objective is to achieve a faster and more effective remission of the symptoms.
- Pharmaceutical treatment of the disease progression: This is achieved by using immunomodulants and immunosuppressants. The treatment objective is the reduction of relapses and of the progression of disability in the relapsing remitting form of the condition and it can also sometimes be used with moderate effect in slowing down secondary progression. It does not have any effect, however, on primary progressive multiple sclerosis.
- Pharmaceutical treatment of symptoms: This refers to the pharmaceutical treatment of individual symptoms which have a diminishing effect on the patient's life, such as spasticity, pain, bladder disorders and fatigue. The treatment objective is to effect an improvement in the symptoms and in the patient's quality of life.
- Non-pharmaceutical treatment of symptoms: Training exercises, such as physical therapy are useful in treating balance disorders, ergotherapy for fine motor skill problems and psychotherapy is useful in treating depression. The treatment objective is to effect an improvement in the symptoms and in the patient's quality of life.
- Alternative remedies: There is a wealth of different procedures available which are aimed at both an improvement in the course of the disease as well as a reduction in the severity of the symptoms. It must be admitted, however, that there is a great dearth of scientific evidence to back the effectiveness of many of these treatments. Many treatment methods are potentially dangerous or are very expensive. Many of these treatments are not recognised, or are not funded by the German health insurance companies:
Multiple sclerosis. Diagnostics & Therapy
Diagnostics. How is a diagnosis of Multiple Sclerosis made?
The fundamental principle of multiple sclerosis diagnosis is the ability to demonstrate the existence of a process of inflammation which affects various locations in the central nervous system from time to time. The presence of this process is proven by taking into account the patient's previous medical history (anamnesis) and the results of various physical and neurological investigations as well as of other additional investigations using technically advanced investigative techniques. The diagnostic procedures must, however, also be able to exclude other conditions which have similar symptoms. These include, for example, auto-immune diseases and inflammations of the blood vessels (angiitis or vasculitis).
International diagnostic criteria for multiple sclerosis
There has been agreement on an international level on the exact criteria required for diagnosing multiple sclerosis. These criteria have been refined over the years, and the introduction of magnetic resonance imaging techniques has, in particular, allowed diagnoses of MS to be made much earlier and with much greater accuracy. For a long time the so-called "relapsing-remitting" or intermittent form of this disease could only be diagnosed if the patient suffered two episodes which were separated in time and which originated in different areas of the brain or spinal cord (under the so-called Poser criteria). Magnetic resonance imaging has, however, allowed physicians to discover that patients often have new incipient areas of inflammation (plaques) before they feel the symptoms of the new attack of MS. These plaques nonetheless indicate the progression of MS. In 2001 a new set of diagnostic criteria (the McDonald criteria) was therefore proposed under which the presence of a first possible attack (or clinical isolated syndrome - CIS) which is followed by the detection by MRI scan of a new plaque at least three months later is sufficient for the diagnosis of MS, even if no other symptoms are present. These criteria were revised again in 2005. Using MRI scanning it is now possible to confirm a diagnosis of multiple sclerosis just 30 days after the appearance of the first symptoms. The article below contains further information on some of the important diagnostic tools used in MS. The most important of these are magnetic resonance imaging (MRI scans) and lumbar puncture.
Nuclear magnetic resonance imaging (now usually referred to as magnetic resonance imaging - MRI scan) in multiple sclerosis
This process uses a strong magnetic field to pick up signals from the various soft tissues in the brain and the spinal cord which are converted into very high definition images of these body structures. This enables even the slightest changes to be seen. This type of examination is not dangerous to the patient. It must not, however, be performed on patients who have a cardiac pace maker or who have other forms of moveable magnetisable pieces of metal inside their body. This type of examination may be unpleasant for people who suffer from claustrophobia as they will have lie still in a relatively confined tubular structure in which there is also quite a lot of noise from the machine. It is often helpful for the patient to be given a mild form of tranquilising medication before going into the scanner. There are now also a few open MRI scanners which some patients will find less distressing. In multiple sclerosis the MRI scan images will show multiple plaques, especially in the brain structures where there are many myelinated nerve fibre bundles, i.e in the medullary layers of the cerebrum and of the cerebellum, in the corpus callosum which connects in the two hemispheres of the brain and in the brain stem. In certain sequences of MRI images these appear as white spots against the dark background of the other brain tissue. By injecting a contrast medium into one of the patient's veins prior to the scan it is possible to observe new plaques of inflammed nerve cell tissue, which appear particularly brightly when the blood-brain barrier has been breached in the more advanced stages of the disease. Over the course of the disease some of the plaques will disappear as the myelin sheath on the nerve cells repairs itself but if the damage to the myelin sheath takes the form of larger scars these will still be visible as large bright spots on the scans for may years to come. The extent of the damage to the nerve cells may be assessed by measuring the overall reduction in brain volume (atrophy) or locally by examining the smaller lesions which become filled with cerbrospinal fluid and which therefore show up on the MRI scan. These will appear as very dark on particular series of images and are known in the technical jargon as "black holes."
Lumbar puncture (cerebrospinal fluid analysis) in Multiple Sclerosis
Lumbar puncture is routinely carried out as part of the diagnostic investigations for many other neurological conditions. The risks of bleeding or inflammation, which are common to all puncture procedures, are extremely low. A fine needle is inserted a few centimetres through the back between the L3/L4 or L4/L5 interspace between the lumbar vertebrae and into the dura mater which contains cerebrospinal fluid (also sometimes called "liquor") which surrounds the brain and the spinal cord. Because in adults the spinal cord containing nervous tissue ends a good three vertebrae higher than the point at which a lumbar puncture is performed it cannot be damaged in this procedure. The colloquial name "spinal tap" used for this procedure may be somewhat misleading here, however. The procedure is carried out under local anaesthetic. Some patients experience transient headaches during lumbar puncture but these usually subside if the patient lies down for a while. This effect is caused by the temporary underpressure in the system and is harmless. Because of the modern use of so-called "atraumatic", i.e particularly fine, needles, this "post-lumbar puncture syndrome" has become rare. Where it does occur, it is not necessary, as used to be thought, for the patient to remain lying down for hours after the lumbar puncture. Lumbar puncture is used multiple sclerosis to demonstrate the presence of inflammation in the nervous system. Typically, it shows slightly increased levels of immunocytes and especially of particular bands of antibodies (oligoconal bands) which suggest the presence of inflammation. In rare cases an examination of the cerebrospinal fluid at the beginning of a case of this disease may reveal no abnormalities.
By making a small electrical, accoustic or visual stimulation at particular entry points to the nervous system and recording the effects with electrodes attached to appropriate points of the skin on the patient's head and neck, doctors are able to draw conclusions about the speed and integrity of nerve signals in the patient's central nervous system. These tests can therefore sometimes reveal the presence of damaged areas which were missed in the clinical examination or, more rarely, by the MRI scan. Visually evoked potentials (VEP) are another particularly important factor in diagnosing multiple sclerosis. While the patient watches a constantly changing chessboard-type patterns on a computer screen, electrodes attached to the scalp at the back of the head measure the electrical potential or response to the changing stimulus. This procedure can be used to test for such things as inflammation of the optic nerve.
Therapy. Treatment of multiple sclerosis
Treatment of a relapse in multiple sclerosis
A degeneration in a patient's condition caused by a relapse is usually treated with cortisone. This is not necessary, however, when the symptoms are very mild or have shown clear signs of remission. There is no evidence that the administration of cortisone affects the progression of the disease itself. Cortisone is usually administered in high dosages (500 – 2000 mg per day) as an infusion through a vein for 3–5 days. If the patient responds poorly to this medication it can be continued in tablet form in gradually reducing doses over the next one to two weeks. If the patient suffers any severe relapses which do not respond to cortisone, a procedure in which the patient's blood is removed and "washed" (plasmapharesis) may be considered.
Disease-modifying treatment: Basic therapy in Multiple Sclerosis
It is this area of treatment which has seen the most rapid advances over recent years, with many new drugs being licensed. Whereas in earlier years the only immunosuppressants which were available for the treatment of multiple sclerosis, such as Azathioprine, suppressed the immune system as a whole, there are now newer "immunomodulating" drugs act in a more specific, targeted way (Immunmodulation). Not all of these newer drugs are effective in tablet form, however, and they must therefore be administered as an injection of infusion. All of the disease-modifying drugs which are currently available are effective against relapsing remitting multiple sclerosis. Only a few of the drugs have been shown to be effective in secondary progression. There is currently no disease modifying therapy which is effective in the primary progressive form of MS.
Currently the first line treatment for multiple sclerosis are the following three types of Beta interferons (IFN β) and glatiramer acetate which are used as the so-called "basic therapy":
- IFN β-1a ( Avonex® ): is injected into the muscle once a week
- IFN β-1b ( Betaferon® ): is injected under the skin every other day.
- IFN β-1a ( Rebif® ) 22 + 44 µg: is injected under the skin three times a week.
- Glatirameracetat (Copaxone)®: is injected under the skin once every day
A clear superiority of one of the drugs over the others.
Even if as part of the fierce competitive battle between the various products in the market place, the manufacturers tend to always highlight the benefits of their own pharmaceutical drugs as compared with those of other companies, the results of the various clinical studies do not yet demonstrate the clear superiority of any one of these four drugs compared with the others. Each one of these drugs produces a reduction of approximately 30 percent in the occurrence of further attacks or "relapses" compared to the patients who were given placebos. Help and sometimes a training service too is provided for all of these drugs which means that most patients will be able to inject themselves. Possible side effects include localised irritation of the skin around the injection site and with the interferon therapies the patient may suffer flu-like complaints following an injection, especially at the beginning of the therapy.
If there are particular reasons why these drugs cannot be used, treatment may be switched to the following drugs:
- Azathioprine ( Imurek® ): To be taken in tablet form daily.
- Immunoglobulins (various manufacturers): Intravenous infusion every 4 weeks
Azathioprine has been used for a long time now as an immunosuppressant. Its effectiveness in treating relapsing-remitting multiple sclerosis is poorly attested in the study data but this is partly due to the fact that no manufacturer any longer has an economic interest in the drug so no new studies have been conducted on it.
In some smaller studies intravenous immunglobulins have proved very effective against relapsing remitting multiple sclerosis. They are, however, very expensive and, unlike other medications, they have not yet been officially licensed for use in multiple sclerosis. The drugs used in treatment must be discussed with the health care insurance providers on an individual basis. Immunglobulins may also be used in monotherapy as disease-modifying drugs for women during pregnancy and so their use should be especially considered for women who wish to have children at some stage.
Who should be considered for immune modulation?
The decision as to whether in individual cases treatment should begin with immunomodulation is a critical one. The treating physician and the patient must take their time and weigh up all the expected benefits and disadvantages of the treatment before making a decision. On the one hand early treatment of this kind may be the best way of preventing relapses as well as disease progression. On the other hand there is the argument that at the beginning of the disease it is not always possible to predict its future course with any accuracy. There therefore have to be very good reasons for going ahead with a therapy which has so many side effects associated with it, which is very limiting on the patient, which is very expensive and which has to be continued over such a long period of time. In view of the fact that the disease may take a rather idiosyncratic course, such a course of treatment may prove to have been unnecessary anyway. On this point there have been several recent studies which have all shown that the commencement of therapy immediately following a first possible attack (= CIS, see above) will help to delay significantly a second attack and may possibly also have a favourable influence on the later progression of disability. In general, medical opinion favours an early start to treatment. In the final analysis, the decision on what form treatment should take following an initial attack of MS must be weighed up on the individual factors of the case. The extent of the plaques which are revealed by MRI scanning will be one of the key factors in this decision making.
Therapy objectives in Multiple Sclerosis
It is important that realistic therapy objectives are set. The first objective should be to achieve a reduction in the frequency and severity of recurrent attacks or "relapses" and that the progression of disability is halted. As a rule it should not be expected that existing symptoms will improve under the effects of therapy. Because the course of the disease can take many different forms, it is not always easy to establish whether the therapy objectives have been attained. It may take up to six months before the drugs mentioned above become fully effective. If the patient suffers a relapse in his condition during the first few weeks of treatment with one of these drugs, this should not be taken as grounds for discontinuing the therapy because it does not appear to be working. Usually doctors must wait for at least one to two years before deciding on whether treatment is effective in each individual case.
What happens when multiple sclerosis cannot be stabilised?
In order to be able to evaluate the success of a course of treatment, clinical monitoring using magnetic resonance imaging scans should be carried out in addition to the other forms of clinical investigations. These scans will help to identify any disease progression which might otherwise go unnoticed. This information can then be included in the clinical decision making process. If it is found that the side effects of therapy either cannot be tolerated by the patient, or fails to stabilise the condition within the expected time frame, as compared with the previous course of the disease, the current therapy should be discontinued. In individual cases where the effectiveness of drug therapy is uncertain, the identification of antibodies which may have developed in the patient to neutralise the effect of interferon may help with further clinical decision making. Doctors will then also have to decide whether to switch to another type of drug for the basic therapy or, especially if there is a large amount of disease activity, whether to resort to the drugs used in escalation therapy (see below). If the patient's condition becomes well stabilised for several years under a particular therapy there are no exact guidelines on how long this therapy should be continued. After several years of relapse-free therapy it may be possible in individual cases to consider having a break in the therapy.
Disease-modifying treatment of multiple sclerosis: Escalation therapy
If treatment with standard drugs for this condition fails to stabilise the condition within the expected time frame or if their side effects make their continued use impossible, there are currently two other medications which should certainly be tried:
- Natalizumab ( Tysabri®): administered as an intravenous infusion every four weeks
- Mitoxantron ( Ralenova® ): administered as an intravenous infusion every three months
Mitoxantron is an immunosuppressant which has already been used for many years as a medication in cancer treatment. It is licensed as as a second choice medication for relapsing-remitting MS and for secondary progressive MS. In studies it has been shown that treatment with Mitoxantron can cause a reduction of around 60 percent in the relapse rate and that it also slows down the progression of disability. It must be noted, however, that in a very few cases patients being treated with Mitoxantron develop leukaemia (blood cancer). A further danger is that patients may develop a weakening of the heart muscle (cardiomyopathy). This effect depends on the dosage which the patient receives, however, and for this reason the total dosage of Mitoxantron which a person may receive in their life has been set at 140mg. Mitoxantron infusion is usually well tolerated by patients who are concurrently administered anti-emetic (anti-vomiting or nausea) medication.
Monoclonal antibody treatment in multiple sclerosis.
Natalizumab is a new type of medication. It is a humanised monoclonal antibody which targets particular types of structures in the body which produce inflammation as part of the bodies immune response system. In the studies conducting as part of the licensing procedure it was shown to produce a 60% reduction in further attacks or "relapses" as well as a reduction in the progression of disability. The infusions are generally well tolerated though they may occasionally cause allergic reactions. Though here too the ancient maxim holds good: There is no rose without thorns. Even during the original licensing studies on Natalizumab there were three reported cases of potentially fatal viral illness affecting the brain (progressive multifocal leukoencephalopathy = PML). It must be noted, however, that all the patients concerned were concurrently taking other immunosuppressive medications. The drug was therefore licensed only for use as a monotherapy (meaning that it must not be used in combination with other immunosuppressants or immunomodulants) for highly aggressive recurrent attacks or "relapses," and in cases where therapy with beta interferons has failed. In June 2008 around 30, 000 patients were being treated with Natalizumab across the world. At present there have been two more reported cases of PML associated with the drug.
Disease-modifying treatment: . What does the future hold?
Research into multiple sclerosis is continuing at full speed across the world. There are a great number of studies into new medications underway and it is expected that new preparations which have entirely new types of mechanism of action will be licensed for use in the next few years.
In particular, it is expected that in the next few years medications which can be taken orally and medications which have a more effective action on the progression of the physical disability caused by MS will become available.
There are currently several final stage (phase 3) studies underway for medications which can be taken orally, i.e. in tablet from, and for which the initial study results have shown that they are very effective:
- Fingolimod FTY720
In addition to Natalizumab which is already licensed there are other monoclonal antibody treatments which are at the advanced trial stage:
Here too the preliminary results have shown that these medications are remarkably effective. As is the case with Natalizumab, both of these medications have shown some rare but potentially fatal side effects.
Other lines of research are aimed at protecting the patient against degeneration of the nerve cells (neuroprotection). Studies are also currently being conducted to see whether it might be possible to develop a vaccination against multiple sclerosis.
Symptom-based treatment of Multiple Sclerosis
Despite all the progress which has been made in the treatment of multiple sclerosis, patients with this condition are often confronted with some symptoms which have a serious impact on their everyday activities. Symptom-based treatment strategies therefore continue to play a major role in therapy. In view of the very wide range of symptoms found in multiple sclerosis, as described above, this line of approach necessarily includes a very wide spectrum of treatments. The symptom-related treatment of multiple sclerosis, in particular, is far from being the preserve of pharmaceutical drug treatments; many non-pharmaceutical activity and training procedures can be of enormous benefit where drugs no longer have any real effect.
Some suggested possible treatment options for particular symptom complexes
- Fatigue: Structuring the day, activity therapies such as aerobic training, possible discontinuation of medications which cause or increase fatigue, where heat regulation is required cooling jackets may be used, pharmaceutical therapy: Amantadine, Modafinil, 4-Aminopyridin. If the patient suffers accompanying depression newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) may also be used. Studies are also currently underway to investigate the effectiveness of acetylsalicylic acid (aspirin).
- Spasticity: Various physical therapy treatment approaches may be used, including some in which the patient is supported by technical equipment (e.g. walking machines, robot assisted therapy). Redression treatment and use of splints. Pharmaceutical therapies: Oral Antispasticity drugs (e.g. Baclofen, Tizanidine). Administration of baclofen into the cerebrospinal fluid using a pump implanted under the skin (intrathecal pump). Botulinum toxin (Botox) injections into the muscle.
- Pain: Physical therapy, physiotherapy, relaxation techniques, hypnosis; According to the cause of the pains, in addition to conventional pain killers, for acute pain and especially in chronic nerve pain (neuropathic pain), antiepileptics such as carbamazepine and gabapentin may be used. Antidepressants, such as citalopram and amitryptiline etc. may also be used because of their pain-relieving action on the central nervous system.
- Depression: For pharmaceutical treatment the newer antidepressants (e.g. sertraline, citalopram, fluoxetine, mirtazapine) have fewer side effects than the older classical antidepressants (e.g. Amitryptiline, Imipramine) and are therefore to be preferred. Antidepressants must be given in an adequate dosage and usually require a period of 7-14 days before they reach their full effect. Psychotherapy, Discussions on coping with the condition, Relaxation techniques, Structuring the day, Sleep hygiene.
- Cognitive disorders: In a pharmaceutical study donepezil has previously been shown to be effective in the treatment of multiple sclerosis. Neuropsychological training therapy. The treatment of accompanying depression.
Rehabilitation of multiple sclerosis.
It is particularly in the symptom-oriented approach to the treatment of MS that wholistic thinking is especially required. Emotional wellbeing, social networking and individual goals are important elements of this approach. Ideally, rehabilitation treatment should be geared towards this goal of helping the patient to regain the skills of everyday life.
Aim: Improving the quality of life.
Rehabilitation measures may not be able to have any influence on the underlying disease progression in multiple sclerosis, but at least they are able to produce many important benefits in improving the patient's quality of life. Teaching patients to practise skills helps their brain to re-organise itself and helps the patient to relearn old skills. If patients have psychotherapy at the same time as their other treatments this can help them to deal with the disease and to minimise the risk of complications, such as depression, from arising. Social education workers help patients with MS to learn self-help skills and give them and their families advice about the possible social consequences of living with the condition. Rehabilitation treatment may either be provided on a completely in-patient basis in a hospital setting, on a partially in-patient basis in a day clinic or in an out-patient clinic. The most suitable rehabilitation setting for each individual patient must be discussed individually with the patient but also with their health insurance company or other body funding the treatment. Rehabilitation in an in-patient setting is necessary, above all, in cases where the patient is suffering severe disabilities, which do not permit treatment to be performed in a normal domestic setting, and in cases where the patient is also suffering from a complex accompanying condition.
Symptom-based, individual therapy methods.
Therapy procedures in rehabilitation are symptom-oriented. This means that an accurate diagnosis of the patient's physical deficits must be made at the beginning of the treatment in oder to enable the medical staff to select individualised therapy measures and to set individualised therapy objectives for the patient. This analysis is conducted in the clinical neurology examination and in the individual specialist areas of the members of the multidisciplinary rehabilitation team. The team normally consists of ergotherapists, neurophsychologists, physical therapists, speech and swallowing disorders therapists as well as social education workers. The medical co-ordination and supervision of the treatment programs will be conducted by neurologists. During the diagnostic process it is important that the symptoms of a disorder are not just described but that they are viewed against a background of the patient's own individual resources as well as on their daily and social activities. In doing this attention must also be paid to the individual's personal influencing factors (e.g. age, profession, individual living environment) as well as the environmental influencing factors (material possessions, social network etc.). The treatment objectives must primarily be relevant to the individual's everyday life. During rehabilitation it is therefore less important that a symptom changes in a way which can be measured than that the therapy helps patients to regain the ability to resume performing particular activities and to regain certain social skills.
Training procedures used in the treatment of multiple sclerosis.
The key component of rehabilitation is exercise training programs. It has been shown in studies that the regaining of physical skills and functions is decisively influenced by the intensity of the exercise training programs, the frequency with which the exercises are repeated and the relevance of the exercises to the patient's everyday activities. In recent years and especially in the field of motor rehabilitation, i.e. the regaining of movement, and study results have supported the superiority of the new "evidence based" therapy methods which are gradually replacing the ideas of the "empirical" schools of therapy, such as the Bobath and Vojta schools. The classical methods, for the efficacy of which there is no real proof in accordance with the criteria used in modern studies, will, however, certainly continue to be important as supplementary methods.
Re-learning lost functions in multiple sclerosis.
Naturally, the most important treatment goal is to help the patient to regain fully any abilities and functions which have been lost. This is, however, possible only for a limited number of patients with MS. This is why the teaching of compensation strategies can also play such an essential part in the rehabilitation process. These strategies include helping someone who has been paralysed on the tight hand side to learn to write with the left hand and making adaptations in the person's environment, e.g. providing external aids, such as a wheelchair which has been modified to suit the person's individual needs.
Multiple sclerosis (MS) is in these parts one of the most common disorders of the central nervous system.