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Editors
Multiple Sclerosis (Ms)
Essentials
- Multiple sclerosis (MS) is an autoimmune disease of unknown aetiology that mainly affects the white matter of the central nervous system (CNS).
- The symptoms of multiple sclerosis are diverse, depending on the location and size of the CNS inflammatory lesions (plaques).
- MS is divided into subtypes: relapsing-remitting, secondary progressive and primary progressive. The relapsing-remitting form is the most common, and it manifests itself as exacerbations (relapses).
- MS is diagnosed on the basis of clinical presentation, cerebrospinal fluid (CSF) examination and magnetic resonance imaging (MRI).
- Pulse glucocorticoid therapy is used to manage acute exacerbations. Several different medications, that can be administered in various ways, are nowadays available for long-term therapy, depending on the activity of the disease.
- No curative therapy exists as yet. Disease progress is individual. On average, the prognosis has clearly improved in the course of the last 20 years, resulting from changes in diagnostic criteria and developments in pharmacotherapy.
Epidemiology
- Globally, the prevalence of MS was in 2016 about 30.1 cases per 100 000 persons.
- Prevalence rates vary widely in different parts of the world. The prevalence is clearly higher e.g. in North America and in some northern European Countries.
- In Finland, the prevalence of MS is about 200/100 000 and MS is the most common CNS disease leading to disability in young adults; it is also the most common demyelinating disorder.
- MS is in women 2.5 times as common as in men.
- MS is usually diagnosed at the age of 20-40 years, on average at 30 years of age.
Aetiopathology
- According to the prevailing theory, T and B lymphocytes able to recognise CNS structures are formed in the body in childhood. Normal immunological tolerance towards CNS antigens is thus not formed. A later infection may activate these circulating lymphocytes which are able to cross the blood-brain barrier.
- Once the activated T lymphocytes enter the CNS they damage myelin which is formed by oligodendrocytes. Several types of tissue damage have been described, e.g. antibody- and complement-mediated, CD4+ T cell-/microglia-mediated and CD8+ cytotoxic T cell-mediated demyelination. The location and extent of the myelin loss, i.e. demyelination, dictate the type of clinical symptoms that result.
- In the early stages of the disease, oligodendrocytes are preserved and remyelination takes place;neuropathological changes are dominated by the inflammatory process. The disease is in the relapsing-remitting phase.
- Later on, destruction of oligodendrocytes and scarring starts to appear and remyelination decreases which leads to the more persistent motor and functional impairment. In far advanced disease the inflammatory reaction is minimal, and the disease picture is dominated by degeneration of neurons and glial cells which leads to permanent disability.
- Both environmental and genetic factors play a role in the susceptibility to the disease.
- Of environmental factors, the risk of MS is increased e.g. by EBV infection, especially mononucleosis which is the most significant single risk factor. In addition, low intake of vitamin D in childhood, smoking, obesity in one's teens and organic solvents increase the risk of MS.
- Of genetic factors, the most important is a HLA complex located in chromosome 6. The HLA-DR15-DQ6 haplotype is associated with a 3-4-fold risk of the disease and HLA-A2 with decreased risk of the disease.Siblings of a patient with MS have a 25-fold increased risk of developing MS compared with the rest of the population. About 20-30% of identical twins and about 5% of non-identical twins are concordant for the disease, i.e. both have the disease.
Clinical picture
- In relapsing-remitting MS, demyelination takes place in inflammatory foci, or plaques, that may be located in the white matter of the cerebrum, optical nerve, brain stem, cerebellum and spinal cord. Symptom appearance is dictated by the location and size of the lesions. The relapsing-remitting course results from the formation of new lesions or activation or inactivation of old lesions.
- Anything that activates the immune system, such as infections, surgical procedures, childbirth, accidents and stress may give rise to exacerbations (relapses).
- In secondary progressive MS, permanent motor and functional decline has already developed along with the corticospinal tract damage. The damage shows a steady, slow progress (neurodegeneration). Exacerbations may still occur.
- Primary progressive MS (about 10% of patients) is characterised by a steady progression of motor and functional decline (typical corticospinal tract damage) from onset, without obvious exacerbations. The abnormal activation of microglial cells is thought to be a central mechanism carrying out the progression of the disease.
Symptoms
- Blurred vision in one or both eyes (optic neuritis)
- Paresis of one or more limbs
- Ataxic gait Treatment for Ataxia in Multiple Sclerosis
- Sensory disturbances
- Eye movement disorders (ophthalmoplegia, internuclear ophthalmoplegia, nystagmus) Neurological Eye Symptoms
- Vertigo and nausea
- Speech dysfunction; dysarthria in most cases
- Bladder and bowel dysfunction (urgency, constipation)
- Fatigue
- Other symptoms
- Cognitive disturbances
- Trigeminal neuralgia Trigeminal Neuralgia and other Facial Pain and other neuralgias
- Paroxysmal dysarthria and ataxia
- Lhermitte's sign (sensations resembling an electric shock felt in the back and limbs, elicited by movements of the cervical spine)
- Mere fatigue, psychiatric symptoms, headache, or paraesthesias or other sensory disturbances, that are not unambiguously of CNS origin are not valid as initial symptoms (the so-called clinically isolated syndrome, CIS) suggesting MS diagnosis.
- The McDonald criteria are applied in the diagnostics, and the diagnosis of relapsing-remitting MS is based on the clinical picture (history and presentation), CSF examination and MRI. MRI findings are nowadays strongly emphasized in the diagnostics, but, on the other hand, more systematic criteria than before are used in the interpretation of the MRI.
- MRI reveals inflammatory MS lesions in the brain and spinal cord.
- MS can be diagnosed after a single episode if dissemination in time can be demonstrated by consecutive MRI recordings.
- Oligoclonal bands in CSF (in over 90%) and sometimes also a raised leukocyte count and immunoglobulin concentration in the CSF support the diagnosis (see Lumbar Puncture). These abnormalities in the CSF are, however, not specific to MS, but rather occur also in other chronic inflammatory diseases of the central nervous system.
- ENMG cannot be used in the diagnostics, not even for exclusion of the disease. It is used for the investigation of diseases affecting the nerve roots and the peripheral nervous system, while MS only affects the central nervous system.
- An incidental MRI finding in the absence of clinical signs or symptoms suggestive of MS (e.g. a patient with a history of headaches) does not warrant the diagnosis of MS. In this case the diagnosis is R90.8, i.e. Other abnormal findings on diagnostic imaging of the CNS. CSF analysis is not worthwhile as an additional investigation.
- The best results are achieved by combining drug therapies, rehabilitation and adjusting the patient's lifestyle.
- Aggressive management of bacterial infections is of the upmost importance. The most common conditions that need to be considered are infections of the urinary tract, maxillary sinuses and dental roots. If left untreated, they may trigger a relapse.
- Smoking should be avoided as it increases the risk of both the initial onset and of a more rapid progression of MS.
- Intravenous methylprednisolone Corticosteroids or Acth for Acute Exacerbations in Multiple Sclerosis is used to manage an exacerbation sufficient to cause functional impairment , i.e. it limits the patient's mobility, activity or vision (optic neuritis). In some cases, methylprednisolone can also be given by mouth Oral Versus Intravenous Steroids for Treatment of Relapses in Multiple Sclerosis.
- Bacterial infections must be excluded or treated before the glucocorticoid treatment (it is possible to administer antimicrobials in uncomplicated urinary tract infection concomitantly with the glucocorticoid therapy).
- Low-dose oral glucocorticoids should not be used in the treatment of an exacerbation.
- The immunomodulating therapies primarily used are interferon betas, glatiramer acetate, teriflunomide Teriflunomide for Multiple Sclerosis and dimethyl fumarate Dimethyl Fumarate for Multiple Sclerosis.
- Intravenous natalizumab Natalizumab for Relapsing Remitting Multiple Sclerosis, ocrelizumab or alemtuzumabAlemtuzumab for Multiple Sclerosis, or fingolimodFingolimod for Relapsing-Remitting Multiple Sclerosis as oral capsules or cladribine can also be used if the disease appears as very active immediately in the beginning or if relapses have occurred during first-line therapies.
- Cytotoxic chemotherapy (mitoxantrone Mitoxantrone for Multiple Sclerosis, azathioprine Azathioprine for Multiple Sclerosis) can be used in special cases.
- Symptomatic treatment must be given sufficient consideration.
- The presence of spasticity may actually give vital support to a lower extremity with poor muscle power and facilitate movement. Medicines that can reduce spasticity include baclofen, tizanidine, clonazepam, diazepam and gabapentinoids; see Spasticity. Fampridine relieves walking difficulties in some patients, but reimbursement may not be available.
- The key form of treatment for mobility problems and spasticity is physiotherapy.
- Bladder function disorders come in several forms, and treatment will be the most successful if based on urological studies. Poor bladder function predisposes the patient to urinary tract infections, and the emergence of relevant symptoms must be actively monitored.
- Anticholinergic medicines are the drugs of choice if the residual urine volume is less than 100 ml with co-existing incontinence or a continuous urge to urinate. The most commonly used drugs include tolterodine, solifenacin and trospium chloride; these induce less central adverse effects than the older preparations. Mirabegron which is a beta-3 adrenergic receptor agonist may be used as an alternative to an anticholinergic drug.
- Pelvic floor exercises are beneficial in stress incontinence.
- Alpha receptor blockers (alfuzosin, tamsulosin) may sometimes be useful in problems of bladder emptying. They are usually worthwhile trying before assessing the need of intermittent catheterization.
- If the residual urine volume is repeatedly more than 100 ml, intermittent catheterization 2-4 times daily is recommended. This will offer relief of symptoms, prevent upper urinary tract complications and improve the quality of life. Drug prophylaxis to prevent urinary tract infections is not indicated.
- If the symptoms of an overactive bladder continue, an anticholinergic medicine may be added.
- In severe urinary incontinence, botulinum toxin injected directly into the bladder muscle is also used. This treatment requires intermittent catheterizations in order to empty the bladder.
- Constipation may be managed pharmacologically and by diet. The patients often restrict their fluid intake because of the bladder symptoms.
- The diet should include sufficient amounts of fluids and fibre.
- Exercise increases bowel motility.
- A regular bowel emptying programme is an important tool in self management.
- Laxatives that increase the faecal bulk or stimulate peristalsis may also be used, and in severe cases enemas or suppositories are necessary.Metoclopramide increases the motility of the entire digestive tract.
- Fatigue is one of the most common symptoms in MS, and some patients report it as one of the main problems interfering with the ability to work and manage everyday life.
- AmantadineAmantadine for Fatigue in Multiple Sclerosis and some antidepressants (e.g. bupropion, venlafaxine, milnacipran, duloxetine and reboxetine) may relieve fatigue. Responses are very much individual.
- Fatigue usually increases as the day progresses, and physical exertion, stress and heat may increase it.
- When treating fatique, it is essential to identify and eliminate all factors that aggravate the situation, especially those with a negative effect on the amount and quality of sleep. Decreasing body temperature is an important part of treatment (reduction of clothing and room temperature, etc.).
- One in four patients with MS suffer from pain. Painful sensory disturbances may be alleviated e.g. with different types of pain-relieving antiepileptics. Pregabalin, gabapentin and lamotrigine are nowadays the most often prescribed drugs as they are better tolerated than the older preparations. Carbamazepine and oxcarbazepine are still used in the treatment of trigeminal neuralgia. Pain-relieving antidepressants (amitriptyline, nortriptyline) and some of the newer mood-altering drugs (venlafaxine, duloxetine) may also be helpful in alleviating chronic neuropathic pain in patients with MS.
- MS is a chronic disease in which lifestyle and psychological factors play a crucial role Psychological Interventions for Multiple Sclerosis.
- Treatment of depression improves the prognosis.
- In order to prevent social isolation, active physical exercise Exercise Therapy for Multiple Sclerosis and hobbies are to be recommended.
- A recommendation regarding sufficient intake of vitamin D should be given to the patient.
- It can be difficult for a newly diagnosed patient to take in disease-related information. It is recommended that family members are present when advice regarding the care and rehabilitation is given. Information and rehabilitation must be correctly timed.
- The patient should be given information about local support organisations and rehabilitation services. Individually tailored rehabilitation programmes, including e.g. physiotherapy, neuropsychological rehabilitationNeuropsychological Rehabilitation for Multiple Sclerosis, occupational therapy and appropriate aids will boost the patient's coping at work and home.
Evidence Summaries ⬆