Treatment of multiple sclerosis

Associate Editors-In-Chief:

Background
Although there is no known cure for multiple sclerosis (MS), several therapies for multiple sclerosis have proven helpful. Multiple sclerosis is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS).

The most common initial course of the disease is the relapsing-remitting subtype, which is characterized by unpredictable attacks (relapses) followed by periods of relative remission with no new signs of disease activity. After some years, many of the people who have this subtype begin to experience neurologic decline without acute relapses as the secondary progressive subtype. Other, less common, courses of the disease are the primary progressive (decline from the beginning without attacks) and the progressive-relapsing (steady neurologic decline and superimposed attacks). Different therapies are used for patients experiencing acute attacks, for patients who have the relapsing-remitting subtype, for patients who have the progressive subtypes, for patients without a diagnosis of MS who have a demyelinating event, and for managing the various consequences of MS.

The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects, and many possible therapies are still under investigation. At the same time different alternative treatments are pursued by many patients, despite the paucity of supporting, comparable, replicated scientific study.

This article focuses on therapies for standard MS; borderline forms of MS have particular treatments that are excluded.

Management of acute attacks


During symptomatic attacks, patients may be hospitalized. As of 2007, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the routine therapy for acute relapses. This is administered over a period of three to five days, and has a well-established efficacy in promoting a better recovery from disability. The aim of this kind of treatment is to end the attack sooner and leave fewer lasting deficits in the patient. Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery: steroids produce a rapid improvement from disability, but this improvement only lasts up to thirty days following a clinical attack and is not evident thirty-six months after the attack. This treatment does not reduce the number of patients who subsequently develop a clinical relapse.

Potential side effects include osteoporosis and impaired memory, being the latter reversible

Recent studies suggest that steroids administered orally are just as effective at treating MS symptoms as intravenous treatment. However, short term treatment with high-dose intravenous corticosteroids does not seem to be attended by adverse effects; on the contrary, gastrointestinal symptoms and psychiatric disorders are more common with oral corticosteroids.

Clinically isolated syndrome
The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS). During a CIS, there is a subacute attack suggestive of demyelination but the patient does not fulfill the criteria for diagnosis of multiple sclerosis. Several studies have shown that treatment with interferons during an initial attack can decrease the chance that a patient will develop MS. These results support the use of interferon after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Relapsing-remitting MS


As of 2007, six disease-modifying treatments have been approved by regulatory agencies of different countries, including the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMEA) and the Japanese PMDA. Three are interferons: two formulations of interferon beta-1a (trade names Avonex and Rebif; the first given weekly, the latter three times a week), and one of interferon beta-1b (U.S. trade name Betaseron, in Europe and Japan Betaferon). Interferons are medications derived from human cytokines which help to regulate the immune system. A fourth medication is glatiramer acetate (Copaxone), a mixture of polypeptides which may protect important myelin proteins by substituting itself as the target of immune system attack. The fifth medication, mitoxantrone, is an immunosuppressant also used in cancer chemotherapy. Finally, the sixth is natalizumab (marketed as Tysabri), a monoclonal antibody.

All six medications are modestly effective at decreasing the number of attacks and slowing progression to disability, although they differ in their efficacy rate and studies of their long-term effects are still lacking. Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab,. Mitoxantrone is probably the most effective of them all; however, its use is limited by severe cardiotoxicity. This is the reason why it is mainly used to treat MS patients who have worsening relapsing-remitting or secondary progressive multiple sclerosis despite prior therapy with interferons or glatiramer acetate.

Medications also differ in ease of use, price and side effects. All of these therapies are expensive and require frequent injections, with Tysabri given as intravenous infusions every four weeks, Avonex requiring weekly injections, Rebif three times a week, and Copaxone and Betaseron daily injections. Mitoxantrone is intravenously administered every three months as a slow infusion over at least thirty minutes.

Even with appropriate use of medication, most patients with relapsing-remitting MS still suffer from some attacks and subsequent disability.

Progressive MS


Treatment of progressive MS is more difficult than relapsing-remitting MS, and many patients do not respond to any available therapy. A wide range of medications have been used to try to slow the progression of the disease.

Mitoxantrone has shown positive effects in patients with a secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease and the frequency of relapses in patients in short-term follow-up. In 2007 it was the only medication approved for secondary progressive and progressive relapsing multiple sclerosis; however, it causes dose-dependent cardiac toxicity which limits its long-term use. Interferon-beta-1b slowed progression of the disease in one clinical trial for secondary progressive MS, but not in another. However, both studies demonstrated that interferon recipients had fewer relapses and less disease activity, as assessed by magnetic resonance imaging (MRI). Therefore, interferons show promise in treating secondary progressive MS, but more data is needed to support their widespread use.

Several trials have been designed specifically for primary progressive multiple sclerosis (PPMS), including trials with interferons and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole. Patients with PPMS have also been included in trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin, cyclophosphamide, and studies of haematopoietic stem cell transplantation. However, no treatment in these trials has been proven definitively to modify the course of the disease.

Side effects of treatments


Both the interferons and glatiramer acetate are available only in injectable forms, and both can cause irritation at the injection site.

Interferons are produced in the body during illnesses such as influenza in order to help fight the infection. They are responsible for the fever, muscle aches, fatigue, and headache common during influenza infections. Many patients report influenza-like symptoms when using interferon to fight MS. This reaction often lessens over time and can be treated with over-the-counter fever reducers/pain relievers like paracetamol (known in the U.S. as acetaminophen), ibuprofen, and naproxen. Rare, but potentially serious, liver function abnormalities have also been reported with interferons, requiring that all patients treated regularly be monitored with liver function tests to ensure safe use. Interferon therapy has also been shown to induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. However, the clinical consequences of the presence of antibodies are presently unclear: it has not been proved that these antibodies reduce efficacy of treatment. Therefore, any treatment decision should be based only on the clinical response to therapy.

Glatiramer acetate is generally considered to be better tolerated than the interferons, although some patients taking glatiramer experience a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.

Mitoxantrone therapy may be associated with immunosuppressive effects and liver damage; however its most dangerous side effect is its dose-related cardiac toxicity. Careful adherence to the administration and monitoring guidelines is therefore essential; this includes obtaining an echocardiogram and a complete blood count before treatment to decide whether the therapy is suitable for the patient or the risks are too great. It is recommended that mitoxantrone be discontinued at the first signs of heart damage, infection or liver dysfunction during therapy.

In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leukoencephalopathy (PML) were identified in patients who had taken it in combination with interferons. PML is a rare and progressive demyelinating disease of the brain that typically causes permanent disability or death. It is caused by infection by the JC virus (JCV), a virus thought to be present in most healthy individuals, and at first its symptoms may be similar to a MS relapse. There are no known treatments for PML; but the sooner the immune system returns to normal the higher the probabilities for recovery will be. As natalizumab was the suspected cause for these three cases of PML, it was withdrawn from the markets. An intensive safety evaluation was conducted which concluded that there was a potential risk of PML in patients taking natalizumab in combination with interferons. In 2006, natalizumab was finally re-approved as a monotherapy for patients with relapsing forms of MS.

Management of the effects of MS
Disease-modifying treatments only reduce the progression rate of the disease but do not stop it. As multiple sclerosis progresses, the symptomatology tends to increase. The disease is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap. Management of these deficits is therefore very important.

Both drug therapy and neurorehabilitation have shown to ease the burden of some symptoms, even though neither influence disease progression. For other symptoms the efficacy of treatments is still very limited.

Neurorehabilitation


Although there are few studies of rehabilitation in MS, its general effectiveness, when conducted by a team of specialists, has been clearly demonstrated in other pathologies such as stroke or head trauma. As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability; however there are particular difficulties in specifying a ‘core team’ because people with MS may need help from almost any health profession or service at some point. Neurologists will be the main physicians involved, but depending on the symptom, doctors of other medical specialties may also be helpful. Allied treatments such as physical therapy or speech therapy can also help to manage some symptoms and maintain quality of life. Treatment of neuropsychiatric symptoms such as emotional distress and clinical depression should involve mental health professionals such as therapists, psychologists, and psychiatrists, while neuropsychologists can help to evaluate and manage cognitive deficits. Although occupational therapy has shown its efficacy in other chronic neurologic conditions and some preliminary data suggests that it may be useful in MS, there are not sufficient randomized controlled studies to establish its effectiveness.

Medical treatments for symptoms
Multiple sclerosis can cause a variety of symptoms including changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, difficulty to move, difficulties with coordination and balance, problems in speech (known as dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or emotional symptomatology (mainly depression). The main clinical measure of disability progression and severity of the symptoms is the Expanded Disability Status Scale or EDSS. At the same time for each symptom there are different treatment options. Treatments should therefore be individualized depending both on the patient and the physician.


 * Bladder: pharmacological treatments for bladder problems vary greatly depending on the origin or type of dysfunction; however, some examples of medications used are: alfuzosin for retention, anticholinergics such as trospium and flavoxate for urgency and incontinence, or desmopressin for nocturia.  Non-pharmacological treatments involve the use of pelvic floor muscle training, stimulation, biofeedback, pessaries, bladder retraining, and sometimes intermittent catheterization.


 * Bowel: people with MS may suffer bowel problems in two ways: reduced gut mobility may follow from immobility and the drugs used to treat various impairments; and neurological control of defecation may be directly impaired. Pain or difficulty with defecation can be helped with a diet change, oral laxatives or suppositories and enemas.


 * Cognitive and emotional: neuropsychiatric symptomatology is not rare in the course of the disease. Depression and anxiety appear in up to 80% of patients, and can be treated with a variety of antidepressants; selective serotonin reuptake inhibitors (SSRIs) are the most commonly employed. Other neuropsychiatric symptoms are euphoria and disinhibition. This dyad was called "euphoria sclerotica" by the first authors that described the disease during the 19th century, and affects 10% of patients. On the other hand, cognitive deficits appear in approximately 50% of the people with the disease. Anticholinesterase drugs such as donepezil —commonly used in Alzheimer disease—although not approved yet for multiple sclerosis, have shown efficacy in improving cognitive functions.  Psychological interventions are also useful in the treatment of cognitive and emotional deficits.


 * Dysphagia and dysarthria: dysphagia is a difficulty with swallowing which may cause choking and aspiration of food or liquid into the lungs, while dysarthria is a neurological motor speech disorder characterized by poor control over the subsystems and muscles responsible for speech ("articulation"). A language therapist may give advice on specific swallowing techniques, on adapting food consistencies and dietary intake, on techniques to improve and maintain speech production and clarity, and on alternative communication systems. In the case of advanced dysphagia, food can be supplied by a nasogastric tube, which is a tube that goes through the nose directly to the stomach; or a percutaneous endoscopic gastrostomy (PEG), which is a procedure for placing a tube into the stomach and therefore administering food directly to it. This second system, although more invasive, has better results in the long term than nasogastric intake.


 * Fatigue: fatigue is very common and disabling in MS, and at the same time it has a close relationship with depressive symptomatology. When depression is reduced fatigue also tends to improve, so patients should be evaluated for depression before other therapeutic approaches are used. In a similar way, other factors such as disturbed sleep, chronic pain, poor nutrition, or even some medications can contribute to fatigue; medical professionals are therefore encouraged to identify and modify them. There are also different medications used to treat fatigue, such as amantadine or pemoline, as well as psychological interventions of energy conservation, but the effects of all of them are small. Fatigue is therefore a very difficult symptom to manage.


 * Pain: acute pain is mainly due to optic neuritis (with corticosteroids being the best treatment available), as well as trigeminal neuralgia, Lhermitte's sign, or dysesthesias. Subacute pain is usually secondary to the disease and can be a consequence of spending too long in the same position, urinary retention, and infected skin ulcers, amongst others. Treatment will depend on cause. Chronic pain is very common and harder to treat as its most common cause is dysesthesias. Acute pain due to trigeminal neuralgia is usually successfully treated with anticonvulsants such as carbamazepine or phenytoin.  Both Lhermitte's sign and painful dysesthesias usually respond to treatment with carbamazepine, clonazepam, or amitriptyline.  Sativex is approved for treatment of pain in MS in different countries, but due to its derivation from cannabis, it is currently not available in others, such as the USA. This medication is also being investigated for the management of other MS symptoms, such as spasticity, and has shown long-term safety and efficacy.


 * Spasticity: spasticity is characterised by increased stiffness and slowness in limb movement, the development of certain postures, an association with weakness of voluntary muscle power, and with involuntary and sometimes painful spasms of limbs. A physiotherapist can help to reduce spasticity and avoid the development of contractures with techniques such as passive stretching. There is evidence, albeit limited, of the clinical effectiveness of baclofen, dantrolene, diazepam, and tizanidine. In the most complicated cases intrathecal injections of baclofen can be used. There are also palliative measures like castings, splints or customised seatings.


 * Vision: different drugs as well as optic compensatory systems and prisms can be used to improve the symptoms of nystagmus.  Surgery can also be used in some cases for this problem.

Unfortunately, other symptoms, such as ataxia, tremor or sensory losses, do not have proven treatments.

Therapies under investigation
Scientists continue their extensive efforts to create new and better therapies for MS. There are a number of treatments under investigation that may curtail attacks or improve function. Some of these treatments involve the combination of drugs that are already in use for multiple sclerosis, such as the combination of mitoxantrone and glatiramer acetate (Copaxone). However most treatments already in clinical trials involve drugs that are used in other diseases. These are the cases of alemtuzumab (trade name Campath), daclizumab (trade name Zenapax), inosine, or BG00012. Other drugs in clinical trials have been designed specifically for MS, like fingolimod, laquinimod, or Neurovax. Finally, there are also many basic investigations that in the future may be able to find new treatments. Examples of these are the studies trying to understand the influence of Chlamydophila pneumoniae or vitamin D in the origin of the disease, or preliminary investigations on the use of helminthic therapy.

Alternative treatments
Different alternative treatments are pursued by many patients, despite the paucity of supporting, comparable, replicated scientific study.

Clinical and experimental data suggest that certain dietary regimens, particularly those including polyunsaturated fatty acids, and vitamins might improve outcomes in people with multiple sclerosis. Many diets have been proposed for treating the symptoms of the disease. Patients have reported a decrease in symptoms after long-term application of changes in diet; however, no controlled trials have been able to prove their efficacy. Even if these diets are genuinely beneficial for people with MS, it is uncertain whether this is due to any special traits of the diets or that they are simply beneficial for whole body health. Two examples of such diets are the Swank Multiple Sclerosis Diet and the Best Bet Diet.

Herbal medicine is another source of alternative treatments. Many patients use medical marijuana to help alleviate symptoms; however, the results of experimental studies are scarce. At least one subgroup experiencing greater disability appears to have derived some symptomatic benefit.

Hyperbaric oxygenation has been the subject of several small studies with heterogeneous results which, overall, do not support its use.

The therapeutic practice of martial arts such as tai chi, relaxation disciplines such as yoga, or general exercise, seem to mitigate fatigue and improve quality of life. Some studies also show benefits on physical variables but more investigation is needed as they are usually of low quality.

Notes and references
Tratamiento de la esclerosis múltiple