Multiple sclerosis is difficult to diagnose in its early stages. In fact, definite diagnosis of MS cannot be made until there is evidence of at least two anatomically separate demyelinating events occurring at least thirty days apart. The McDonald criteria represent international efforts to standardize the diagnosis of MS using clinical data, laboratory data, and radiologic data.[6]
Clinical data alone may be sufficient for a diagnosis of MS. If an individual has suffered two separate episodes of neurologic symptoms characteristic of MS, and the individual also has consistent abnormalities on physical examination, a diagnosis of MS can be made with no further testing. Since some people with MS seek medical attention after only one attack, other testing may hasten the diagnosis and allow earlier initiation of therapy.
Magnetic resonance imaging (MRI) of the brain and spine is often used to evaluate individuals with suspected MS. MRI shows areas of demyelination as bright lesions on T2-weighted images or FLAIR (fluid attenuated inversion recovery) sequences. Gadolinium contrast is used to demonstrate active plaques on T1-weighted images. Because MRI can reveal lesions which occurred previously but produced no clinical symptoms, it can provide the evidence of chronicity needed for a definite diagnosis of MS.
Testing of cerebrospinal fluid (CSF) can provide evidence of chronic inflammation of the central nervous system. The CSF is tested for oligoclonal bands, which are immunoglobulins found in 85% to 95% of people with definite MS (but also found in people with other diseases). [7] Combined with MRI and clinical data, the presence of oligoclonal bands can help make a definite diagnosis of MS. Lumbar puncture is the procedure used to collect a sample of CSF.
The brain of a person with MS often responds less actively to stimulation of the optic nerve and sensory nerves. These brain responses can be examined using visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs). Decreased activity on either test can reveal demyelination which may be otherwise asymptomatic. Along with other data, these exams can help find the widespread nerve involvement required for a definite diagnosis of MS.[8]
Another test which may become important in the future is measurement of antibodies against myelin proteins such as myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP). As of 2007, however, there is no established role for these tests in diagnosing MS.
The signs and symptoms of MS can be similar to other medical problems, such as neuromyelitis optica, stroke, brain inflammation, infections such as Lyme disease (which can produce identical MRI lesions and CSF abnormalities[9][10][11][12]), tumors, and other autoimmune problems, such as lupus. Additional testing may be needed to help distinguish MS from these other problems.
Disease course and clinical subtypes
Graph representing the different types of multiple sclerosisThe course of MS is difficult to predict, and the disease may at times either lie dormant or progress steadily. Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. A person diagnosed with a particular subtype may, for unclear reasons, switch from one subtype to another over time. Subtypes are important not only for prognosis but also for therapeutic decisions. In 1996 the United States National Multiple Sclerosis Society standardized the following four subtype definitions:
Relapsing-remitting
Relapsing-remitting describes the initial course of 85% to 90% of individuals with MS. This subtype is characterized by unpredictable attacks (relapses) followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during the attacks may either resolve or may be permanent. When deficits always resolve between attacks, this is referred to as "benign" MS.
Secondary progressive
Secondary progressive describes around 80% of those with initial relapsing-remitting MS, who then begin to have neurologic decline between their acute attacks without any definite periods of remission. This decline may include new neurologic symptoms, worsening cognitive function, or other deficits. Secondary progressive is the most common type of MS and causes the greatest amount of disability.
Primary progressive
Primary progressive describes the approximately 10% of individuals who never have remission after their initial MS symptoms. Decline occurs continuously without clear attacks. The primary progressive subtype tends to affect people who are older at disease onset.
Progressive relapsing
Progressive relapsing describes those individuals who, from the onset of their MS, have a steady neurologic decline but also suffer superimposed attacks.
Treatment
There is no known definitive cure for multiple sclerosis. However, several types of therapy have proven to be helpful. 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 attacks. Treatment is aimed at returning function after an attack, preventing new attacks, and preventing disability.
Currently only relapsing-remitting multiple sclerosis has treatments approved by the USA's Food and Drug Administration (FDA); as of 2006 there are six such treatments. Three are interferons: Interferon beta-1a (Avonex and Rebif) or beta-1b (Betaseron [in Europe and Japan Betaferon]). The interferons are medications derived from human cytokines which help regulate the immune system. A fourth medication is glatiramer acetate (Copaxone), a synthetic medication made of four amino acids that are found in myelin. This drug stimulates T cells in the body's immune system to change from harmful, pro-inflammatory agents to beneficial, anti-inflammatory agents that work to reduce inflammation at lesion sites. The fifth medication, mitoxantrone, is effective but is limited by cardiac toxicity. Finally, the sixth medication is natalizumab (marketed as Tysabri). Relapsing-remitting symptomatic attacks can be treated. Patients in the United States are typically given high doses of intravenous corticosteroids, such as methylprednisolone, to end the attack sooner and leave fewer lasting deficits. Patients' self-reporting indicates that many find benefit from a number of other medicines.[3]
Currently there are no approved treatments for the progressive varieties, though several medications are being studied and are described at Therapies for multiple sclerosis.
Therapies for multiple sclerosis
There is no known definitive cure for multiple sclerosis (MS). However, several types of therapy have proven to be helpful. 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 attacks. Treatment is aimed at returning function after an attack, preventing new attacks, and preventing disability.
Alternative treatment can involve nutritional supplement, and/or dietary measures. For example, some patients may adhere to mainstream pharmaceutical treatment options while others may also choose to apply a form of precautionary principle, where potentially helpful and/or preventive measures are employed despite a paucity of supporting, comparable, replicated scientific study.
This article focuses only in therapies for standard MS. The borderline forms of MS (Devic's disease, Balo concentric sclerosis, Schilder disease, Marburg multiple sclerosis, Autoimmune Peripheral neuropathy, and Acute disseminated encephalomyelitis) are explicitely excluded, as they have their own particular treatments.
Management of acute attacks
During symptomatic attacks, patients may be hospitalized. In some countries, patients are given high doses of intravenous corticosteroids, such as methylprednisolone, to end the attack sooner and leave fewer lasting deficits. When given to treat optic neuritis, although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery. Despite this fact, some neurologists recommend aggressive steroid treatment at the first signs of any worsening to reduce the duration in which inflammation persists in order to minimize the opportunity for damage to the nerves. Oral steroids tend to be given more often to patients in European nations, and they are frequently the only treatment offered to patients in countries where it is difficult to obtain the expensive disease-modifying medications. Recent findings suggest that oral steroid pills are just as effective at treating MS symptoms as intravenous treatment; the primary factor in the effectiveness of the treatment appears to be the high dosage over a short period of time, regardless of how the steroid is administered.
Management of relapsing-remitting MS
In the United States, as of 2006 there are six Food and Drug Administration (FDA)-approved treatments for patients with relapsing-remitting MS. Three are interferons: Interferon beta-1a (Avonex and Rebif) or beta-1b (Betaseron [in Europe and Japan Betaferon]). The interferons are medications derived from human cytokines which help 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 effective but is limited by cardiac toxicity. Finally, the sixth medication is Natalizumab (marketed as Tysabri). Natalizumab was finally approved in May 2006 after a long process, due to cases of progressive multifocal leukoencephalopathy (PML) in some patients who had taken it in combination with interferons.
All six medications have been proven to be modestly effective at decreasing the number of attacks and slowing progression to disability. They differ primarily in ease of use, price, side effects, and the likelihood that extended use will decrease their effects. All these therapies are expensive and require frequent injections, with Tysabri is given as intravenous infusions every four weeks, Avonex requiring weekly injections and Copaxone daily injections. All of the interferons can lose effectiveness after continued use, with Avonex being the least likely and Betaseron the most likely. This is the result of neutralizing antibodies against the interferons. The interferons all require laboratory monitoring of blood tests. Even with appropriate use of medication, most patients with relapsing-remitting MS still suffer from some attacks and subsequent disability. Side effects are covered below.
Management of progressive MS
Treatment of progressive MS is more difficult than relapsing-remitting MS, and many patients do not respond to any therapy. A wide range of medications have been used to try to slow the progression of disease. Many therapies have been shown to have some effect on disease progression and resulting disability, but most therapies have significant side effects which limit their long-term use. Therefore they are often appropriate only for the most rapidly progressive cases. Azathioprine, cladribine, and ciclosporin have all shown small benefits, which in most cases are outweighed by side effects such as an increased cancer risk. Mitoxantrone, a chemotherapy drug, offers a significant reduction in progression to disability, but causes dose-dependent cardiac toxicity which limits its long-term use. Bone marrow transplant, plasmapheresis, and total lymphoid irradiation (exposure to high doses of radiation in order to kill parts of the immune system) have been studied and are currently reserved for the most dire cases. Cyclophosphamide and methotrexate are chemotherapy drugs which can slow the progression of MS, but which also have a number of side effects. Frequent courses of high-dose corticosteroids, often given weekly or monthly, are also commonly employed to good effect. Interferons show promise in secondary progressive MS, but more data is needed to support widespread use.
Management of demyelination without a diagnosis of MS
Several studies have shown that starting treatment with interferon beta-1a during the initial attack (and prior to the second attack required for a definite diagnosis of MS) can decrease the chance that a patient will develop MS. A separate medication, intravenous immunoglobulin (IVIG) has also shown promise in reducing progression to MS in this set of patients. Therefore, in certain patients, it is important that therapy be started prior to definite diagnosis.[1][2]
Management of the effects of MS
Because much of the damage caused by MS is irreversible, management of the resulting deficits is very important. As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability. Physical therapy, occupational therapy, and supportive equipment such as wheelchairs and standing frames may be helpful. Speech therapy can help maintain quality of life. Treatment of emotional distress and depression should involve mental health professionals such as therapists, psychologists, and psychiatrists. Neurocognitive testing is important for determining the extent of cognitive deficits. Management of cognitive defects relies on lifestyle strategies, but also may respond to donepezil. Medications such as baclofen, tizanidine, dantrolene and Sativex have been shown to improve spasticity. Depression can be treated with a variety of antidepressants; selective serotonin reuptake inhibitors (SSRIs) are most commonly employed. The anticonvulsant drugs gabapentin and carbamazepine and the antidepressant amitriptyline can improve pain and tingling sensations in certain cases. Fatigue can often be managed by amantadine, pemoline, methylphenidate, and modafinil. Bladder spasms can be treated by oxybutynin and trospium chloride. Erectile dysfunction may respond to sildenafil, vardenafil, or tadalafil.
Electrical stimulation underneath the skin, electroacupuncture, can relieve bladder problems caused by multiple sclerosis.[3]
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. Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.
At this time, one of the most promising MS research areas involves a new class of molecules called sphingosine-1-phosphate receptor modulators. Recently, such a compound, fingolimod, showed impressive results in a phase II trial.[4]. A phase III trial is ongoing.
A family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS. However, as of 2005 there is not sufficient evidence that statins are beneficial in the treatment of human MS patients with normal cholesterol levels.
A recent study found that women who took vitamin D supplements were 40% less likely to develop MS than women who did not take supplements. However, this study does not provide enough data to conclude that vitamin D has a beneficial influence on ongoing MS. Furthermore, it could not distinguish between a beneficial effect of vitamin D and that of multivitamin supplements including vitamin E and various B vitamins, which may also exert a protective effect.[5]
A compound called inosine has had good results in phases I and II.[6] [7]. Three different ways of action have been proposed. First, it produces uric acid after ingestion[8], which is a natural antioxidant and a peroxynitrite scavenger[9] (peroxynitrite has been correlated with the axons degeneration[10]). Second, it has been shown to induce axonal rewiring and is used as a treatment for stroke,[11] and spinal cord injury [12] and third, it has shown neuroprotective and anti-inflammatory effects independently of the other two, [13] and as like any other antioxidant, it is supposed to reduce the blood-brain barrier permeability[14]. Currently it is being investigated by Boston Life Sciences under the name axosine. Of course, uric acid can also be raised by dietary treatment.
A few doctors have begun experimenting with antibiotic protocols targeted against Chlamydophila pneumoniae. These protocols involve the use of at least three antimicrobial agents, and often more, to cover all the phases of the life cycle of that pathogen, and are applied for extended periods; they are thus not likely to be arrived at by chance. Anecdotal reports are favorable, but only one double-blind placebo-controlled trial[15] has been published, in which the number of patients studied was too small (four in each arm of the trial) to reach statistical significance in the primary outcome measure (volume of gadolinium-enhancing lesions, as viewed on MRI).
A recent study in the United Kingdom revealed promising results when using a combination of mitoxantrone (an immunosuppressive drug normally used in cancer) and Glatiramer acetate (Copaxone). In an 'open' study of 27 patients with Relapsing Remitting MS, the combination was found to provide a rapid and sustained suppression of relapses in MS patients experiencing frequent, recurrent and disabling attacks (90% reduction in annualised relapse rate maintained, to date, for a mean of 36 months). A three year controlled study is now being launched at 10 centres across the UK.[16].
[Side effects of medications for relapsing-remitting MS
The two most common types of medications used to treat relapsing-remitting MS have significant side effects which warrant further discussion. 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 (acetaminophen), ibuprofen, and naproxen. Many patients choose not to take interferon due to the unpleasant experience of frequent injections and their subsequent side effects, citing a loss in their quality of life. Neurologists advocating for the use of these medications in modifying the progression of disease believe the long term benefits outweigh the short-term side effects. Interferons can cause liver damage, and laboratory blood tests must be monitored to ensure safe use. Some patients taking glatiramer acetate experience a "post-injection" reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety.
Alternative treatments
Decades of studies and research have also contributed to a popular following for treating the symptoms of the disease by diet. One such alternative treatment is the Swank Multiple Sclerosis Diet by Dr. Roy Swank who details the specifics of his diet guidelines in a book. The main restriction is the complete elimination of saturated fats and hydrogenated oils. Numerous patients have reported a decrease and even a complete elimination of symptoms after long-term application of the diet. Neurologists' acceptance of this treatment is mixed, though most will agree the rigors of the diet are beneficial for whole body health, and should be used in conjunction with MS treatments, and not as a replacement.
In Poland, Jan Kwasniewski's The Optimal Diet has been claimed to partially or fully cure Multiple Sclerosis. If the disease has lasted more than 5 years, it is difficult to obtain a cure, although improvements in symptoms and a stop of the progression is often observed. At several health clinics in Poland, patients are given this diet together with electromedicine (or "selective currents). In addition to implementing the diet - which is very rich in animal fats and egg yolks and limits carbohydrates to approximately 50 grams daily - people with MS are also often served brains several times per week.
It should be noted that although various health clinics and doctors in Poland have reported promising results for the treatment of MS (and other diseases) with "The Optimal Diet", no results have yet been published in any peer-reviewed journal, and therefore these reports have a questionable value. Even if the diet really was able to partially or fully cure MS, it is uncertain whether this fact is due to some special traits of the diet or simply that it is a low carbohydrate diet.[17]
As of 2007, the first clinical trial involving a dietary treatment has been started [3] by a canadian charity. They will compare the outcome of The best bet diet (their own proposal) versus the MS society of Britain recommended diet.