a 2021 cochrane review, ocrelizumab may reduce worsening of symptoms for primary progressive ms and probably increases unwanted effects but makes little or no difference to the number of serious unwanted effects. in 2019, siponimod and cladribine were approved in the united states for the treatment of secondary progressive multiple sclerosis (spms). subsequently, ozanimod was approved in 2020, and ponesimod was approved in 2021, which were both approved for management of cis, relapsing ms, and spms in the u.s., and rrms in europe. adverse effects irritation zone after injection of glatiramer acetate. the disease-modifying treatments have several adverse effects. one of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections). over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop. interferons may produce flu-like symptoms; some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, and anxiety, which usually lasts less than thirty minutes. more dangerous but much less common are liver damage from interferons, systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone, and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated). fingolimod may give rise to hypertension and slowed heart rate, macular edema, elevated liver enzymes, or a reduction in lymphocyte levels. tentative evidence supports the short-term safety of teriflunomide, with common side effects including: headaches, fatigue, nausea, hair loss, and limb pain. there have also been reports of liver failure and pml with its use and it is dangerous for fetal development. most common side effects of dimethyl fumarate are flushing and gastrointestinal problems. while dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials. associated symptoms both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease. some symptoms have a good response to medication, such as bladder spasticity, while others are little changed. equipment such as catheters for neurogenic bladder dysfunction or mobility aids can be helpful in improving functional status. a multidisciplinary approach is important for improving quality of life; however, it is difficult to specify a 'core team' as many health services may be needed at different points in time. multidisciplinary rehabilitation programs increase activity and participation of people with ms but do not influence impairment level. studies investigating information provision in support of patient understanding and participation suggest that while interventions (written information, decision aids, coaching, educational programmes) may increase knowledge, the evidence of an effect on decision making and quality of life is mixed and low certainty. there is limited evidence for the overall efficacy of individual therapeutic disciplines, though there is good evidence that specific approaches, such as exercise, and psychological therapies are effective. cognitive training, alone or combined with other neuropsychological interventions, may show positive effects for memory and attention though firm conclusions are not possible given small sample numbers, variable methodology, interventions and outcome measures. the effectiveness of palliative approaches in addition to standard care is uncertain, due to lack of evidence. the effectiveness of interventions, including exercise, specifically for the prevention of falls in people with ms is uncertain, while there is some evidence of an effect on balance function and mobility. cognitive behavioral therapy has shown to be moderately effective for reducing ms fatigue. the evidence for the effectiveness of non-pharmacological interventions for chronic pain is insufficient to recommend such interventions alone, however their use in combination with medications may be reasonable. non-pharmaceutical there is some evidence that aquatic therapy is a beneficial intervention. the spasticity associated with ms can be difficult to manage because of the progressive and fluctuating course of the disease. although there is no firm conclusion on the efficacy in reducing spasticity, pt interventions can be a safe and beneficial option for patients with multiple sclerosis. physical therapy including vibration interventions, electrical stimulation, exercise therapy, standing therapy, and radial shock wave therapy (rswt), were beneficial for limiting spasticity, helping limit excitability, or increasing range of motion. alternative treatments over 50% of people with ms may use complementary and alternative medicine, although percentages vary depending on how alternative medicine is defined. regarding the characteristics of users, they are more frequently women, have had ms for a longer time, tend to be more disabled and have lower levels of satisfaction with conventional healthcare. the evidence for the effectiveness for such treatments in most cases is weak or absent. treatments of unproven benefit used by people with ms include dietary supplementation and regimens, vitamin d, relaxation techniques such as yoga, herbal medicine (including medical cannabis), hyperbaric oxygen therapy, self-infection with hookworms, reflexology, acupuncture, and mindfulness. evidence suggests vitamin d supplementation, irrespective of the form and dose, provides no benefit for people with ms; this includes for measures such as relapse recurrence, disability, and mri lesions while effects on health‐related quality of life and fatigue are unclear. there is insufficient evidence supporting high-dose biotin and some evidence for increased disease activity and higher risk of relapse with its use. prognosis the availability of treatments that modify the course of multiple sclerosis beginning in the 1990s, known as disease-modifying therapies (dmts), has improved prognosis. these treatments can reduce relapses and slow progression, but as of 2022 there is no cure. the prognosis of ms depends on the subtype of the disease, and there is considerable individual variation in the progression of the disease. in relapsing ms, the most common subtype, a 2016 cohort study found that after a median of 16.8 years from onset, one in ten needed a walking aid, and almost two in ten transitioned to secondary progressive ms, a form characterized by more progressive decline. with treatments available in the 2020s, relapses can be eliminated or substantially reduced. however, "silent progression" of the disease still occurs. in addition to secondary progressive ms (spms), a small proportion of people with ms (10–15%) experience progressive decline from the onset, known as primary progressive ms (ppms). most treatments have been approved for use in relapsing ms; there are fewer treatments with lower efficacy for progressive forms of ms. the prognosis for progressive ms is worse, with faster accumulation of disability, though with considerable individual variation. in untreated ppms, the median time from onset to requiring a walking aid is estimated as seven years. in spms, a 2014 cohort study reported that people required a walking aid after an average of five years from onset of spms, and were chair or bed-bound after an average of fifteen years. after diagnosis of ms, characteristics that predict a worse course are male sex, older age, and greater disability at the time of diagnosis; female sex is associated with a higher relapse rate. as of 2018, no biomarker can accurately predict disease progression in every patient. spinal cord lesions, abnormalities on mri, and more brain atrophy are predictive of a worse course, though brain atrophy as a predictor of disease course is experimental and not used in clinical practice as of 2018. early treatment leads to a better prognosis, but a higher relapse frequency when treated with dmts is associated with a poorer prognosis. a 60-year longitudinal population study conducted in norway found a 7-year shorter life expectancy in ms compared with the general population and a rise in survival in ms during the observation period. median life expectancy for rrms patients was 77.8 years and 71.4 years for ppms, compared to 81.8 years for the general population. life expectancy for men was 5 years shorter than for women. epidemiology deaths from multiple sclerosis per million persons in 2012 0 1 2 3–5 6–12 13–25 ms is the most common autoimmune disorder of the central nervous system. the latest estimation of the total number of people with ms was 2.8 million globally, with a prevalence of 36 per 100,000 people. moreover, prevalence varies widely in different regions around the world. in africa, there are 5 people per 100,000 diagnosed with ms, compared to south east asia where the prevalence is 9 per 100,000, 112 per 100,000 in the americas, and 133 per 100,000 in europe. increasing rates of ms may be explained simply by better diagnosis. studies on populational and geographical patterns have been common and have led to a number of theories about the cause. ms usually appears in adults in their late twenties or early thirties but it can rarely start in childhood and after 50 years of age. the primary progressive subtype is more common in people in their fifties. similarly to many autoimmune disorders, the disease is more common in women, and the trend may be increasing. as of 2020, globally it is about two times more common in women than in men, and the ratio of women to men with ms is as high as 4:1 in some countries. in children, it is even more common in females than males, while in people over fifty, it affects males and females almost equally. history medical discovery detail of carswell's drawing of ms lesions in the brain stem and spinal cord (1838) robert carswell (1793–1857), a british professor of pathology, and jean cruveilhier (1791–1873), a french professor of pathologic anatomy, described and illustrated many of the disease's clinical details, but did not identify it as a separate disease. specifically, carswell described the injuries he found as "a remarkable lesion of the spinal cord accompanied with atrophy". under the microscope, swiss pathologist georg eduard rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels. the french neurologist jean-martin charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868. summarizing previous reports and adding his own clinical and pathological observations, charcot called the disease sclerose en plaques. diagnosis history the first attempt to establish a set of diagnostic criteria was also due to charcot in 1868. he published what now is known as the "charcot triad", consisting in nystagmus, intention tremor, and telegraphic speech (scanning speech). charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly". diagnosis was based on charcot triad and clinical observation until schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: dissemination of the lesions in time (dit) and space (dis), and that "signs and symptoms cannot be explained better by another disease process". the dit and dis requirement was later inherited by the poser and mcdonald criteria, whose 2017 revision is in use. during the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s. since the beginning of the 21st century, refinements of the concepts have taken place. the 2010 revision of the mcdonald criteria allowed for the diagnosis of ms with only one proved lesion (cis). in 1996, the us national multiple sclerosis society (nmss) (advisory committee on clinical trials) defined the first version of the clinical phenotypes that is in use. in this first version they provided standardized definitions for four ms clinical courses: relapsing-remitting (rr), secondary progressive (sp), primary progressive (pp), and progressive relapsing (pr). in 2010, pr was dropped and cis was incorporated. three years later, the 2013 revision of the "phenotypes for the disease course" were forced to consider cis as one of the phenotypes of ms, making obsolete some expressions like "conversion from cis to ms". other organizations have proposed later new clinical phenotypes, like hams (highly active ms). historical cases photographic study of locomotion of a woman with ms with walking difficulties created in 1887 by muybridge there are several historical accounts of people who probably had ms and lived before or shortly after the disease was described by charcot. a young woman called halldora who lived in iceland around 1200 suddenly lost her vision and mobility but recovered them seven days after. saint lidwina of schiedam (1380–1433), a dutch nun, may be one of the first clearly identifiable people with ms. from the age of 16 until her death at 53, she had intermittent pain, weakness of the legs and vision loss: symptoms typical of ms. both