multiple sclerosis

 Multiple sclerosis Straight to the point of care Last updated: Oct 05, 2021 Table of Contents Overview 3 Summary 3 Definition 3 Theory 4 Epidemiology 4 Aetiology 4 Pathophysiology 5 Classification 5 Case history 8 Diagnosis 9 Approach 9 History and exam 10 Risk factors 11 Investigations 13 Differentials 16 Criteria 18 Management 23 Approach 23 Treatment algorithm overview 32 Treatment algorithm 35 Emerging 57 Primary prevention 58 Patient discussions 58 Follow up 59 Monitoring 59 Complications 61 Prognosis 62 Guidelines 63 Diagnostic guidelines 63 Treatment guidelines 64 Online resources 66 Evidence tables 67 References 70 Images 91 Disclaimer 95 Multiple sclerosis Overview Summary Multiple sclerosis (MS) is a demyelinating central nervous system condition clinically defined by two episodes of neurological dysfunction (brain, spinal cord, or optic nerves) that are separated in space and time. Classically presents in white women, aged between 20 and 40 years, with temporary visual or sensory loss. However, it may affect either sex and any age or ethnic group, and may have variable neurological symptom location and/or duration. The patient may have subtle changes in vision, ambulation, and reflexes on examination that provide evidence of previous attacks (which may not have been noticed by the patient). Magnetic resonance imaging (MRI) of both the brain and spinal cord is important in diagnosis. Brain MRI is sensitive, but very susceptible to over-interpretation in the absence of clinical correlation. Spinal cord MRI is abnormal less often, but lends greater specificity when present with brain lesions. Treatment of MS can be divided into three parts: treatment of the acute attack; prevention of future attacks by reducing triggers and use of disease-modifying therapies; and symptomatic treatments of neurological difficulties such as spasticity, pain, fatigue, and bladder dysfunction. Definition Multiple sclerosis (MS) is defined as an inflammatory demyelinating disease characterised by the presence of episodic neurological dysfunction in at least two areas of the central nervous system (brain, spinal cord, and optic nerves) separated in time and space.[1] [BMJ talk medicine: multiple sclerosis] (https://soundcloud.com/bmjpodcasts/multiple-sclerosis? in=bmjpodcasts/sets/bmj-best-practice-clinical) O V E R VIE W This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 3 Multiple sclerosis Theory T H E O R Y Epidemiology There were an estimated 2 million prevalent cases of MS globally in 2016.[11] The estimated prevalence of MS in the US adult population in 2010 was 309.2 per 100,000, representing over 727,000 cases.[12] Both the incidence and the ascertainment (i.e., diagnosis using more sensitive and specific investigations) of MS are felt to be rising globally and in the US.[11] MS is most commonly diagnosed in people between 20 and 40 years old. However, it can occur in children as young as 2 years, where it may be confused for acute disseminated encephalomyelitis. It is occasionally diagnosed in people in their sixth or seventh decade who may have been asymptomatic for years. The estimated 2010 prevalence of MS in the US was highest in people aged 55 to 64 years.[12] There is a significantly skewed sex ratio, with a female to male ratio of around 3:1, and the disparity appears to be increasing.[12] [13] A geographic gradient, with higher incidence at latitudes closer to the poles, has been linked with MS.[12] [14] People of European descent are most commonly affected, but affected black Americans may have more aggressive courses due to a combination of socioeconomic and genetic factors, as well as later diagnosis.[15] The highest prevalence rates are reported in high-income North America, western Europe, and Australasia, with the lowest in eastern sub-Saharan Africa, central sub-Saharan Africa, and Oceania, although accurate data are not available for many parts of the world.[11] Approximately 80% to 85% of people with MS have a relapsing course; in the other 10% to 15% the disease is progressive from onset (primary progressive MS).[16] Aetiology While MS was classically viewed as a disease of central nervous system white matter, there is now substantial evidence supporting both grey and white matter involvement.[17] It appears to have both inflammatory and degenerative components that may be triggered by an environmental factor or factors in people who are genetically susceptible. First-degree family members of patients with MS are 20-40 times more likely to develop MS than the general population.[18] [19] The age-adjusted lifetime risk for children who have one parent with MS is about 2% to 3%.[20] The worldwide prevalence of familial MS has been estimated to be 12.6%.[21] While the genetics of MS are multifactorial, genes in the human leukocyte antigen (HLA) region and the interleukin region are likely to be involved.[22] [23] Genetic testing to predict risk for MS is not currently recommended. Environmental factors that have been postulated to be involved in MS include toxins, viral exposure, and sunlight exposure (and its effect on vitamin D metabolism).[24] [25] While some researchers have proposed that MS is caused by a virus, none of the nearly 20 viruses that have been candidates over the last 20 years have proved to be causative. Epstein-Barr virus is the virus with the greatest link to increased risk of MS.[26] [27] Human herpes virus 6 has also been suggested to be linked to MS but this has not been conclusively demonstrated.[28] Relapses are sometimes triggered by infections or postnatal hormonal changes. Some literature suggests that acute trauma or stressful events may be precipitants, although this is controversial.[29] [30] 4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Theory Pathophysiology The precise pathogenesis of MS is unknown. There is no specific or sensitive antigen or antibody, and there is some debate about whether MS represents a single disease or a syndrome of pathogenically heterogeneous patient subgroups. Conceptualisations of MS immunopathology involve 2 distinct but overlapping and connected phases, inflammatory and degenerative. During the initial stage of the inflammatory phase, lymphocytes with encephalitogenic potential are activated in the periphery by factors such as infection or other metabolic stress. These activated T cells seek entry into the central nervous system (CNS) via attachment to a receptor on endothelial cells. This interaction, mediated by production of matrix metalloproteinases, allows a breach in the blood-brain barrier, leading to further upregulation of endothelial adhesion molecules and additional influx of inflammatory cells. The T cells produce inflammatory cytokines that cause direct toxicity and also attract macrophages that contribute to demyelination. Epitope spread occurs early and contributes to the complexity of the immunopathology. The degenerative component of MS is believed to reflect axonal degeneration and loss. Demyelination disrupts axonal support and leads to destabilisation of axonal membrane potentials, which causes distal and retrograde degeneration over time. There is also a suggestion that inflammatory cells, antibodies, and complement may contribute to axonal injury. Axonal damage has been identified in regions of active inflammation, indicating that it begins early in the disease process.[31] Pathologically, MS is characterised by multifocal areas of demyelination, loss of oligodendrocytes, and astrogliosis with loss of axons primarily in the white matter of the CNS, although cortical lesions may also play a significant role. Clinical heterogeneity and studies of biopsy and autopsy specimens suggest that the mechanisms leading to tissue damage differ from patient to patient. Relapsing-remitting MS shows the most inflammatory activity, followed by early secondary progressive MS. Primary progressive MS is thought to be a primarily degenerative process, although some patients do have relapses and/or enhancing lesions. All currently approved disease-modifying therapies in MS are most active against inflammation. Acute relapses of MS with disturbance of CNS function such as vision or mobility are thought to be periods of increased inflammatory activity of the immune system and treated accordingly. Clinical progression, such as the gradual loss of ability to ambulate over several years, and/or poorer recovery from relapses, is believed to be a manifestation of combined ongoing chronic low-level inflammation with degenerative processes. Brain and spinal cord magnetic resonance imaging (MRI) manifestations of inflammation show contrastenhancing lesions with limited oedema, whereas MRI manifestations of the progressive process show atrophy and T1 hypointensity (or black holes). Management of MS attempts to reduce the potential for triggering the bursts of inflammatory activity known as relapses, as well as limiting the extent of the relapses. Prevention or reduction of inflammation is presumed to reduce cumulative axon loss and long-term disability. Classification T H E O R Y This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 5 Multiple sclerosis Theory T H E O R Y Phenotypic classification[2] [3] MS phenotypes include a consideration of disease activity (based on clinical events and imaging findings) and disease progression. 1. Relapsing disease • Clinically isolated syndrome (CIS) is a clear-cut syndrome such as optic neuritis, brainstem/cerebellar dysfunction, or partial myelitis, that does not fulfill criteria for dissemination in space and time. It is considered to be part of the relapsing MS disease spectrum. CIS may be active or not active. If a subsequent clinical event or radiological activity (gadolinium-enhancing or new/enlarging T2 lesions) follows the initial event in CIS, this becomes relapsing-remitting MS. • Relapsing-remitting MS (RRMS) requires clinical and/or magnetic resonance imaging (MRI) evidence of dissemination in space and time. RRMS is also characterised as active or not active within a specified time frame (e.g., 6 months, 1 year). As a guide, assessments for disease activity should be conducted at least annually. 2. Progressive disease Progressive disease, whether primary progressive (progressive accumulation of disability from onset) or secondary progressive (progressive accumulation of disability after an initial relapsing course), has four possible sub-classifications taking into account the level of disability: • Active and with progression (individual has had an attack and is also gradually worsening) • Active but without progression (e.g., individual has had an attack within a previous specified time frame [i.e., 1 year, 2 years]) • Not active but with progression (e.g., walking speed has decreased) • Not active and without progression (stable disease). MS variants and related conditions Clinically isolated syndrome (CIS) and/or monosymptomatic demyelinating event: • Monophasic demyelinating syndrome, which may or may not develop into MS, has the same demographics as RRMS. • 2017 McDonald criteria state that in patients with a typical CIS and clinical or MRI demonstration of dissemination in space, the presence of cerebrospinal fluid-specific oligoclonal bands allows a diagnosis of MS; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space.[4] • Cerebrospinal fluid (CSF)-specific oligoclonal bands and the presence of T2-weighted MRI lesions at the time of the first clinical event have been identified as independent risk factors for conversion to RRMS. • Various treatment trials have indicated a delay in a second clinical event when CIS cases are treated with disease-modifying therapies used in RRMS. Radiologically isolated syndrome (RIS) • The term RIS is used for patients who have brain abnormalities on MRI suggestive of MS, but who have not had symptoms suggestive of a clinical event. 6 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Theory Neuromyelitis optica spectrum disorders (NMOSD): • NMOSD are no longer considered an MS variant because of distinctive immunopathology, MRI features, and treatment options. • Severe relapses that can be devastating, involving optic nerves and spinal cord only. • Causes loss of vision in one or both eyes, and/or long necrotic cervical and thoracic cord lesions over several segments, resulting in severe paraparesis or quadriparesis that may occur over the course of days or weeks.[5] Cervical spine magnetic resonance imaging scan illustrating neuromyelitis optica spectrum disorder. Extensive multiple levels of cervical spinal cord involvement with oedema and blood-brain barrier breakdown as illustrated by the contrast-enhanced T1-weighted image (left). The T2-weighted image (right) indicates the extent of signal abnormality that may manifest clinically as quadriparesis with severe spasticity and pain From the collection of Dr Lael A. Stone • Demographics of NMOSD are different from typical MS in that there is a non-white predominance. • Treatment also differs, as this is an antibody-mediated disease amenable to immunosuppression and, in severe cases, plasma exchange.[6] [7] • Testing for auto-antibodies associated with NMOSD (anti-aquaporin 4 ([AQP4]) and anti-myelin oligodendrocyte glycoprotein [MOG] antibodies) is required. Cell-based assays are more specific than enzyme-linked immunosorbent assay (ELISA) and should be used if available.[8] [9] Acute disseminated encephalomyelitis (ADEM):[10] • Monophasic illness that is a related, but distinct entity, to MS. • Presents with dramatic post-viral or post-vaccination dysfunction of the central nervous system (CNS) including encephalopathy and multiple brain lesions on MRI that all appear to be roughly simultaneous. • Most common in the paediatric age group, but can occur in adults. • Clinical episode may last 3 to 6 months. • No signs, symptoms, or radiographic evidence of prior or subsequent damage to the CNS. T H E O R Y This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 7 Multiple sclerosis Theory T H E O R Y Case history Case history #1 A 28-year-old white woman who has smoked 1 pack per day for the last 10 years presents with subacute onset of cloudy vision in one eye, with pain on movement of that eye. She also notes difficulty with colour discrimination, particularly of reds. She was treated for a sinus infection 2 weeks ago and, on further history, recalls that she had a 3-week history of unilateral hemibody paraesthesias during examination week in university 6 years ago. She occasionally has some tingling on that side if she is overly tired, stressed, or hot. Case history #2 A 31-year-old woman with strong family history of autoimmune disease is 6 months postnatal and develops ascending numbness and weakness in both feet, slightly asymmetrically, over a period of 2 weeks. She gradually develops difficulty walking to the point where she presents to an emergency department and is also found to have a urinary tract infection. Other presentations MS can present in a myriad of ways in individuals from disparate demographic backgrounds. The most common presentations for MS are optic neuritis and transverse myelitis, but other presentations include brainstem syndromes, cerebellar syndromes (ataxia), and sensory syndromes. Patients may also present with a progressive course, often with foot drop or spastic paraplegias in the later years. Incidental findings of changes on brain magnetic resonance imaging consistent with MS are also reported in asymptomatic patients. MS may present with depression, cognitive decline, or even psychosis, and should be considered in the differential of these disorders, particularly if there are associated physical symptoms or signs. 8 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Diagnosis Approach The diagnosis of MS is made by careful neurological history and examination and is confirmed by ancillary testing, such as magnetic resonance imaging (MRI) of the brain and spinal cord and evaluation of cerebrospinal fluid (CSF), in the absence of an alternative explanation for symptoms and signs. Neurological history A history of transient motor, cerebellar, sensory, gait, or visual dysfunction lasting over 48 hours and not accompanied by fever or other intercurrent illness is suggestive of a demyelinating episode of MS. Symptoms are often asymmetric and involve only one side of the body or one limb, although bilateral involvement can occur. Patches of odd sensation such as wetness or tingling may occur, and band-like or hemiband-like sensations are pathognomonic for spinal cord lesions. Neurological examination Funduscopy should be performed to view the optic disc, and the 'swinging flashlight' test can be used to evaluate for an afferent pupillary defect. Colour vision should be assessed to look for red desaturation (a more subtle sign of optic neuritis). Eye movements may also be particularly revealing as patients may develop internuclear ophthalmoplegia (INO) or other abnormalities in the absence of symptoms. The presence of nystagmus or abnormal saccades may suggest a cerebellar lesion. Testing of tone and reflexes in the upper and lower extremities to look for upper motor neuron signs, such as spasticity and hyperreflexia, is important. The gait must be carefully assessed, preferably by walking the patient at least 7.6 metres (25 feet). Signs may include mild dragging of the foot as well as spasticity and balance problems. Imaging MRI is the definitive imaging test for MS. The images must be interpreted by specialists who are very familiar with typical MS findings on MRI, and in the context of the patient's history and examination. Recommendations on standardised MRI protocols were published in 2021.[3] Brain imaging Sagittal three-dimensional (3D) fluid-attenuated inversion recovery (FLAIR) with multiplanar reconstruction acquisition is recommended as the core sequence for diagnosis and monitoring of MS, due to its high sensitivity.[3] High quality two-dimensional (2D) pulse-sequences (i.e., ≤3 mm slice thickness and no gap between slices) are an acceptable alternative if it is not possible to acquire sufficiently high quality 3D FLAIR images. Pre-contrast T1-weighted sequences are not required. A 3 T scanner is preferred, but a 1.5 T system is acceptable; 7 T systems are not recommended except in a research setting. Intravenous gadolinium-based contrast agents are invaluable during initial investigations to show dissemination in time and to exclude alternative diagnoses, but only single doses should be used owing to the potential risk of gadolinium accumulation in the brain. Diffusion-weighted imaging may be useful for differential diagnosis or in patients for whom gadolinium is contraindicated, but should not be used as an alternative to gadolinium-enhanced T1-weighted imaging to show acute demyelinating lesions.[3] Spinal cord imaging DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 9 Multiple sclerosis Diagnosis DIA G N O SIS MRI of the spinal cord is recommended for all patients. It is an extremely valuable, and often underused, non-invasive test that is helpful both for identifying MS lesions and for excluding alternative diagnoses. The cervical and thoracolumbar spinal cord, including conus, should be imaged. A 1.5 T or 3 T scanner is acceptable, but there is no evidence that 3 T results in greater detection of spinal cord lesions than scanning at lower field strengths. Axial sequences are helpful in characterising cord lesions, but these sequences are considered to be optional. The use of sagittal gadolinium-enhanced sequences for diagnostic purposes is recommended; these should be done immediately after the gadoliniumenhanced brain MRI if possible.[3] Laboratory evaluation Laboratory evaluations in MS are recommended to exclude MS mimics or diseases that may contribute to MS symptoms, such as thyroid disease, vitamin B12 deficiency, and diabetes mellitus. People with large spinal cord lesions over several segments of spinal cord, poor recovery from optic neuritis, or atypical lesions on MRI brain should undergo antibody testing (anti-aquaporin 4 [AQP4] and anti-myelin oligodendrocyte glycoprotein [MOG] antibodies) to evaluate for neuromyelitis optica spectrum disorders.[5] [8] [9] Lumbar puncture with CSF examination for oligoclonal bands, and CSF immunoglobulin G (IgG) index may be done. Due to the invasive nature of lumbar puncture, all other non-invasive tests should be pursued first. Note that the CSF is normal in 10% to 20% of MS cases. Evoked potentials, particularly visual evoked potentials, should be performed to assist in establishing the diagnosis in patients for whom MRI is contraindicated (e.g., presence of a pacemaker or claustrophobia). These studies are not helpful in monitoring response to treatment. History and exam Key diagnostic factors visual disturbance in one eye (common) • Graying or blurring of vision in one eye (can be described as looking through petroleum jelly). May have pain in moving that eye and describe loss of colour discrimination, particularly reds. peculiar sensory phenomena (common) • Patients often describe odd sensations of a patch of wetness or burning, or hemibody sensory loss or tingling. In particular, banding or hemibanding is associated with spinal cord lesions. Lhermitte’s sign (electric shock-like sensations extending down the cervical spine radiating to the limbs) and trigeminal neuropathy or neuralgia are other possible sensory findings in MS. Other diagnostic factors female sex (common) • Female to male sex ratio is approximately 3:1.[12] [13] age 20-40 years (common) 10 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Diagnosis • Most commonly diagnosed between age 20 and 40 years. foot dragging or slapping (common) • Patient will often describe gradual onset of weakness after walking several streets or several miles such that the foot slaps the ground. This weakness resolves with rest. leg cramping (common) • Patient describes involuntary movement in the lower leg with cramping or jerking in the calves, particularly at night or while driving. fatigue (common) • May be related to MS primarily, but often worsened dramatically by multifactorial causes such as poor sleep hygiene, depression, restless legs, urinary frequency, or underlying sleep apnoea. urinary frequency (common) • Multifactorial causes including damage to the central nervous system resulting in urinary retention and detrusor instability. • Urinary tract infections are more frequent in patients with urinary retention. bowel dysfunction (common) • Constipation is commonly seen in MS. • Bowel urgency and incontinence are almost always symptoms of constipation and should be managed as such. spasticity/increased muscle tone (common) • Damage to the central nervous system may result in increased muscle tone. Commonly affects the legs and can be very unpleasant and painful, disturbing sleep as well as ambulation. increased deep tendon reflexes (common) • Particularly clonus at the ankles and often asymmetrical. imbalance/incoordination (common) • Wide-based gait and/or limb ataxia indicate cerebellar dysfunction, which occurs frequently in MS. pale optic disc or non-correctable visual loss (uncommon) • Suggestive of optic neuritis. incorrect responses to Ishihara colour blindness test plates (uncommon) • Damage to optic nerve may be accompanied by decrease in ability to see reds, which are seen as less intense or orange. abnormal eye movements (uncommon) • Internuclear ophthalmoplegia (nystagmus of the abducting eye with absent adduction of the other eye) or isolated nystagmus may be present. Risk factors DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 11 Multiple sclerosis Diagnosis DIA G N O SIS Strong female sex • Long described, but poorly understood, risk factor felt to be related to hormonal influences on autoimmunity, as well as on differences in recognition of self/non-self. family history of MS • First-degree family members of patients with MS are 20-40 times more likely to develop MS than the general population.[18] [19] • The age-adjusted lifetime risk for children who have one parent with MS is about 2% to 3%.[20] • The worldwide prevalence of familial MS has been estimated to be 12.6%.[21] northern latitude • Described in epidemiological studies and variously ascribed to genetic, environmental, and viral causes, including vitamin D deficiency related to inadequate sunlight exposure.[12] [25] Weak genetic factors • Multiple genes are felt to contribute.[23] While the HLA region is known to be a major factor in genetic susceptibility, the primary gene within the complex has not been identified and remains under study. • The interleukin receptor genes IL7 receptor alpha (IL7RA) and IL2 receptor alpha (IL2RA) have been found to be associated with increased risk of MS. These candidate genes relate to the immune system, as well as recognition of self/non-self.[22] smoking • Cigarette smoking is associated with both increased risk for the development of MS and increased disability in people with MS.[32] [33] vitamin D deficiency • Increasing evidence suggests that low childhood sunlight exposure as well as low vitamin D levels at diagnosis are risk factors for MS.[25] There is evidence for the role of vitamin D metabolism as part of normal immune function and its disturbance in other autoimmune diseases.[34] autoimmune disease • Patients with MS often have family members with autoimmune diseases and are more prone to developing autoimmune diseases themselves.[35] Epstein-Barr virus • Epstein-Barr virus is the virus with the greatest link to increased risk of MS.[26] [27] overweight/obesity in children and adolescents • There appears to be a link between overweight/obesity in children and adolescents and the later occurrence of MS, particularly for girls.[36] 12 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Diagnosis Investigations 1st test to order Test Result MRI - brain • Should be performed on high field magnet (3 T is preferred, but 1.5 T is acceptable), with intravenous ganodolinium-based contrast. Representative axial magnetic resonance images using fluidattenuated inversion recovery (FLAIR) showing typical lesions seen in MS in the periventricular regions. Comparable slices using the contrast agent gadolinium illustrate blood-brain barrier breakdown/active inflammation in 2 of the lesions. The FLAIR lesions that do not enhance are likely to be older, with a combination of gliosis and low-level chronic inflammation and degeneration From the collection of Dr Lael A. Stone • Sagittal three-dimensional (3D) fluid-attenuated inversion recovery (FLAIR) with multiplanar reconstruction acquisition is recommended. Axial T2-weighted FLAIR should be obtained if this sequence is not available.[3] • Almost all patients with MS will have abnormal cranial MRI, but the interpretation of the MRI may be difficult. Images must be interpreted by specialists who are very familiar with typical MS findings on MRI. • Sagittal fluid-attenuated inversion recovery (FLAIR) images can help distinguish between MS lesions and non-specific white matter changes, such as seen in association with hypertension, diabetes, age >50, smoking, migraine, high cholesterol, and toxin exposures. hyperintensities in the periventricular white matter; most sensitive images are sagittal FLAIR DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 13 Multiple sclerosis Diagnosis DIA G N O SIS Test Result Sagittal fluid-attenuated inversion recovery (FLAIR) images with typical MS lesions involve the corpus callosum either as discrete lesions or as finger-like projections perpendicular to the corpus callosum. Note also the enlargement of the ventricles and diffuse atrophy of more advanced MS From the collection of Dr Lael A. Stone • MRI is also used for assessment of disease activity and monitoring of treatment effectiveness.[3] MRI - spinal cord • MRI of the spinal cord is recommended for all patients. Many patients with MS will have cervical spinal cord lesions and the specificity of this finding is very high. Magnetic resonance imaging scan of the cervical spine at high (≥1 Tesla) magnetic field strength illustrating a lesion that may cause myelopathic symptoms of bowel and bladder dysfunction as well as spastic paraparesis From the collection of Dr Lael A. Stone demyelinating lesions in the spinal cord, particularly the cervical spinal cord; detection of alternate diagnosis, such as cervical spondylosis 14 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Diagnosis Test Result • The cervical and thoracolumbar spinal cord, including conus, should be imaged. A 1.5 T or 3 T scanner can be used. The use of sagittal gadolinium-enhanced sequences is recommended.[3] MRI is also used for assessment of disease activity and monitoring of treatment effectiveness.[3] FBC • Indicated to exclude alternative diagnoses or concomitant illnesses. should be normal comprehensive metabolic panel • Indicated to exclude alternative diagnoses or concomitant illnesses. should be normal thyroid-stimulating hormone • Indicated to exclude alternative diagnoses or concomitant illnesses. should be normal vitamin B12 • Indicated to exclude alternative diagnoses or concomitant illnesses. should be normal Other tests to consider Test Result antibody testing for neuromyelitis optica spectrum disorders (NMOSD) • Testing for antibodies characteristic of NMOSD (anti-aquaporin 4 [AQP4] and anti-myelin oligodendrocyte glycoprotein [MOG] antibodies) is recommended in patients with long segments of spinal cord demyelination with or without optic neuritis, and in patients with recurrent optic neuritis with normal brain imaging.[8] [9] • Cell-based assays are more specific than enzyme-linked immunosorbent assay (ELISA) and should be used if available. positive in NMOSD cerebrospinal fluid evaluation • Due to the invasive nature of the testing, all other non-invasive tests should be pursued first.[4] • Note that the cerebrospinal fluid (CSF) is normal in 10% to 20% of MS cases. glucose and protein should be normal; cell count may be slightly elevated but never above 50/microlitre; oligoclonal bands and elevated CSF IgG and IgG synthesis rates are present in 80% of MS cases evoked potentials • Performed in patients for whom MRI is contraindicated. • Visual evoked potentials are most commonly abnormal, with somatosensory and auditory evoked potentials less so. • Somatosensory evoked potentials can be painful for the patient, as well as technically difficult. • These studies are useful to assist in establishing the diagnosis but they are not helpful for monitoring response to treatment. prolongation of conduction, particularly asymmetrical prolongation in the visual evoked potentials DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 15 Multiple sclerosis Diagnosis DIA G N O SIS Differentials Condition Differentiating signs / symptoms Differentiating tests Myelopathy due to cervical spondylosis • The patient's symptoms and signs are all below the neck (although they may have dizziness and headache). • MRI of the cervical spine shows compression of the spinal cord. Fibromyalgia • Generalised weakness and non-specific fatigue are common. • Neurological examination is normal apart from possible functional overlay. • MRI brain may show non-specific white matter changes, but not the characteristic MS findings. Postural orthostatic tachycardia syndrome with or without cervicogenic migraine • History is significant for headaches and dizziness, particularly with change of head position or standing. Examination is normal. • MRI of the cervical spine may show cervical spondylosis. • Tilt table testing may be abnormal. Sleep disorders • Patient describes non-restful sleep with variable features of snoring, restless legs, and apnoea. Memory changes and mood disturbances may be prominent. Neurological examination is normal. • Abnormal sleep study. Sjogren syndrome • Symptoms of dry eyes and dry mouth as well as joint stiffness and pain. Neurological examination is usually normal. • Elevated autoantibodies (anti-Ro/SSA and anti-La/ SSB). • MRI brain and spinal cord are normal. Vitamin B12 deficiency • Numbness, fatigue, and possible memory loss. Posterior column loss of sensation (vibration and proprioception) in the presence of increased reflexes on examination. • Low vitamin B12 level, high methylmalonic acid level. • MRI does not show characteristic lesions of MS. Ischaemic stroke • History indicates sudden onset of symptoms. Signs and symptoms usually explainable on the basis of a single neurological lesion, rather than multiple lesions. • CT head shows ischaemic changes. • Diffusion-weighted MRI will be abnormal in the acute setting. Peripheral neuropathy • Loss of sensation and reflexes in the feet and hands if large nerve fibre, severe pain if small nerve fibre. • Abnormal electromyogram if large nerve fibre, abnormal skin biopsy for number of nerve fibres if small fibre. • Blood tests for specific cause (e.g., haemoglobin 16 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Diagnosis Condition Differentiating signs / symptoms Differentiating tests A1c [HbA1c] or thyroidstimulating hormone) are abnormal. Lymphoma • Patient has gradual onset of severe disability. • MRI shows persistent enhancing lesion over time, which may worsen despite treatment. • Neoplastic cells seen on cerebrospinal fluid cytology. Inherited disorders such as mitochondrial diseases and leukodystrophies • Patient has gradual onset of memory or cognitive problems, sometimes in the setting of neuropathy. • MRI appearance is quite distinct and includes prominent symmetrical white matter changes and normal spinal cord MRI. • Some blood tests are available for specific disorders. Sarcoidosis • Patient may have prior history of pulmonary sarcoid and shortness of breath. • Highly elevated serum ACE level. • Abnormal chest x-ray and gallium scans. • MRI brain non-specific white matter changes; MRI brain or spinal cord may show meningeal enhancement. Guillain-Barre syndrome • Loss of reflexes with predominantly motor symptoms. Dangerous respiratory complications are more common. • MRI is normal. • Cerebrospinal fluid shows characteristic cytoalbumin dissociation, and the classical MS findings of oligoclonal bands and elevated IgG and IgG synthesis are absent. Amyotrophic lateral sclerosis (ALS) • Mixed upper and lower motor neuron signs are present: increased reflexes (upper motor neuron) with atrophy and fasciculations (lower motor neuron). • Visual changes are absent. • ALS may involve dysphagia and pulmonary function abnormalities, but the dysphagia, unlike in MS, is usually accompanied by tongue fasciculations and dysphonia. • Electromyogram is diagnostic of ALS. It is normal in MS unless there is a comorbidity such as diabetes or B12 deficiency. • Compressive lesions may resemble ALS and MRI of the spinal cord is recommended to exclude compressive syndromes; if MS is present, characteristic lesions are usually seen on MRI. • Muscle biopsies are useful to exclude primary muscle pathology. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 17 Multiple sclerosis Diagnosis DIA G N O SIS Condition Differentiating signs / symptoms Differentiating tests Systemic lupus erythematosus • Patient may have fevers, joint pain and swelling, muscle tenderness, (malar) rash. • Elevated anti-nuclear antibodies (however, it is common to have mild elevation in MS), positive anti-DS DNA. Criteria McDonald criteria (2017 revision) - diagnostic criteria for MS[4] • In a patient with a typical clinically isolated syndrome and fulfilment of clinical or magnetic resonance imaging (MRI) criteria for dissemination in space, and no better explanation for the clinical presentation, demonstration of cerebrospinal fluid (CSF)-specific oligoclonal bands in the absence of other CSF findings atypical of MS allows a diagnosis of this disease to be made. This recommendation is an addition to the 2010 McDonald criteria. • Symptomatic and asymptomatic MRI lesions can be considered in the determination of dissemination in space or time. MRI lesions in the optic nerve in a patient presenting with optic neuritis remain an exception and, owing to insufficient evidence, cannot be used in fulfilling the McDonald criteria. In the 2010 McDonald criteria, the symptomatic lesion in a patient presenting with brainstem or spinal cord syndrome could not be included as MRI evidence of dissemination in space or time. • Cortical and juxtacortical lesions can be used in fulfilling MRI criteria for dissemination in space. Cortical lesions could not be used in fulfilling MRI criteria for dissemination in space in the 2010 McDonald criteria. • The diagnostic criteria for primary progressive MS in the 2017 McDonald criteria remain the same as those outlined in the 2010 McDonald criteria, aside from removal of the distinction between symptomatic and asymptomatic MRI lesions and that cortical lesions can be used. • At the time of diagnosis, a provisional disease course should be specified (relapsing-remitting, primary progressive, or secondary progressive) and whether the course is active or not, and progressive or not, based on the previous year’s history. The phenotype should be periodically re-evaluated based on accumulated information. This recommendation is an addition to the 2010 McDonald criteria. McDonald criteria (2010 revision) - diagnostic criteria for MS[44] Two or more attacks; objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of prior attack. • No further data needed. Two or more attacks; objective clinical evidence of 1 lesion • Dissemination in space (DIS) demonstrated by MRI, or await further clinical attack implicating a different site. One attack, objective clinical evidence of 2 or more lesions • Dissemination in time (DIT) demonstrated by MRI or second clinical attack. 18 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Diagnosis One attack, objective clinical evidence of 1 lesion (monosymptomatic presentation, clinically isolated syndrome) • DIS demonstrated by MRI or second clinical attack at a different central nervous system (CNS) site, and • DIT demonstrated by MRI or second clinical attack. Insidious neurological progression suggestive of MS • One year of disease progression (retrospectively or prospectively determined) and 2 of the following: • DIS in brain (1 or more T2 lesions in periventricular, juxtacortical, or infratentorial regions) • DIS in spinal cord (2 or more T2 lesions in cord) • Positive CSF (oligoclonal bands or elevated immunoglobulin G [IgG] index). McDonald criteria (2017 revision) - MRI findings[4] Dissemination in space (DIS): • One or more T2-hyperintense lesions in 2 or more of 4 areas of the CNS: periventricular, cortical or juxtacortical, infratentorial brain regions, and the spinal cord. Dissemination in time (DIT): • Simultaneous presence of asymptomatic gadolinium (Gd)-enhancing and non-enhancing lesions at any time, or • New T2 and/or Gd-enhancing lesion on follow-up MRI, irrespective of timing with reference to baseline scan. Functional systems (FS) criteria[45] 1. Pyramidal function • 0 - Normal • 1 - Abnormal signs without disability • 2 - Minimal disability • 3 - Mild/moderate paraparesis or hemiparesis; severe monoparesis • 4 - Marked paraparesis or hemiparesis; moderate quadriparesis or monoparesis • 5 - Paraplegia, hemiplegia, or marked paraparesis • 6 - Quadriplegia • V - Unknown . 2. Cerebellar function • 0 - Normal • 1 - Abnormal signs without disability • 2 - Mild ataxia • 3 - Moderate truncal or limb ataxia • 4 - Severe ataxia • 5 - Unable to perform coordinated movements DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 19 Multiple sclerosis Diagnosis DIA G N O SIS • V - Unknown • X - Weakness. 3. Brainstem function • 0 - Normal • 1 - Signs only • 2 - Moderate nystagmus or other mild disability • 3 - Severe nystagmus, marked extra-ocular weakness or moderate disability of other cranial nerves • 4 - Marked dysarthria or other marked disability • 5 - Inability to speak or swallow • V - Unknown. 4. Sensory function • 0 - Normal • 1 - Vibration or figure-writing decrease only, in 1 or 2 limbs • 2 - Mild decrease in touch or pain or proprioception, and/or moderate decrease in vibration in 1 or 2 limb, or vibration in 3 or 4 limbs • 3 - Moderate decrease in touch or pain or proprioception, and/or essentially lost vibration in 1 or 2 limbs; or mild decrease in touch or pain and/or moderate decrease in all proprioceptive tests in 3 or 4 limbs • 4 - Marked decrease in touch or pain or loss of proprioception, alone or combined in 1 or 2 limbs; or moderate decrease in touch or pain and/or severe proprioceptive decrease in more than 2 limbs • 5 - Loss of sensation in 1 or 2 limbs; or moderate decrease in touch or pain and/or loss of proprioception for most of the body below the head • 6 - Sensation essentially lost below the head • V - Unknown. 5. Bowel and bladder function • 0 - Normal • 1 - Mild urinary hesitancy, urgency, or retention • 2 - Moderate hesitancy, urgency, or retention of bowel or bladder, or rare urinary incontinence • 3 - Frequent urinary incontinence • 4 - Almost constant catheterisation • 5 - Loss of bladder function • 6 - Loss of bowel function • V - Unknown. 6. Visual function • 0 - Normal • 1 - Scotoma with visual acuity >20/30 (corrected) • 2 - Worse eye with scotoma with maximal acuity 20/30 to 20/59 • 3 - Worse eye with large scotoma or decrease in fields, acuity 20/60 to 20/99 • 4 - Marked decrease in fields, acuity 20/100 to 20/200; grade 3 plus maximal acuity of better eye <20/60 • 5 - Worse eye acuity <20/200; grade 4 plus better eye acuity <20/60 • V - Unknown. 20 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Diagnosis 7. Cerebral function • 0 - Normal • 1 - Mood alteration • 2 - Mild decrease in mentation • 3 - Moderate decrease in mentation • 4 - Marked decrease in mentation • 5 - Dementia • V - Unknown. 8. Other function • 0 - Normal • 1 - Other neurological finding. The expanded disability status scale (EDSS)[45] 0.0 - Normal neurological exam. 1.0 - No disability, minimal signs on 1 functional system (FS). 1.5 - No disability, minimal signs on 2 of 7 FS. 2.0 - Minimal disability in 1 of 7 FS. 2.5 - Minimal disability in 2 FS. 3.0 - Moderate disability in 1 FS or mild disability in 3 to 4 FS, though fully ambulatory. 3.5 - Fully ambulatory but with moderate disability in 1 FS and mild disability in 1 or 2 FS, or moderate disability in 2 FS, or mild disability in 5 FS. 4.0 - Fully ambulatory without aid; up and about 12 hours a day despite relatively severe disability; able to walk without aid 500 metres. 4.5 - Fully ambulatory without aid, up and about much of day, able to work a full day, may otherwise have some limitations of full activity or require minimal assistance; relatively severe disability; able to walk without aid 300 metres. 5.0 - Ambulatory without aid for about 200 metres; disability impairs full daily activities. 5.5 - Ambulatory for 100 metres; disability precludes full daily activities. 6.0 - Intermittent or unilateral constant assistance (walking stick, crutch, or brace) required to walk 100 metres with or without resting. 6.5 - Constant bilateral support (walking stick, crutch, or braces) required to walk 20 metres without resting. 7.0 - Unable to walk beyond 5 metres even with aid, essentially restricted to wheelchair, wheels self, transfers alone, active in wheelchair about 12 hours a day. 7.5 - Unable to take more than a few steps, restricted to wheelchair, may need aid to transfer; wheels self, but may require motorised chair for full day's activities. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 21 Multiple sclerosis Diagnosis DIA G N O SIS 8.0 - Essentially restricted to bed, chair, or wheelchair but may be out of bed much of day, retains self care functions, generally effective use of arms. 8.5 - Essentially restricted to bed much of day, some effective use of arms, retains some self-care functions 9.0 - Helpless bed-patient, can communicate and eat. 9.5 - Unable to communicate effectively or eat/swallow. 10.0 - Death. 22 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Approach For updates on diagnosis and management of coexisting conditions during the pandemic, see our topic 'Management of coexisting conditions in the context of COVID-19'. The main goals of treatment are prevention of disability and improvement of quality of life. Treatment is generally divided into three main categories: management of acute worsening/relapses; disease-modifying therapy; and symptomatic management. Disease-modifying treatment should be managed by a neurologist. Non-pharmacological interventions, such as cognitive training and psychological interventions, may offer some benefit to patients with MS, particularly regarding quality of life outcomes.[46] [47] Results should be interpreted cautiously; further studies, with improved design, are required to assess the effectiveness of nonpharmacological interventions.[48] [49] Acute management of relapses The first step in management of acute worsening and/or relapse is to be certain that there is no concomitant illness or infection. Patients with MS commonly experience worsening of their condition during urinary tract infections (which may be asymptomatic), sinusitis, viral infection, cellulitis and other skin infections, or fevers from any cause. Underlying infections should be appropriately treated.[50] If the relapse affects function (e.g., decreased or double vision, difficulty walking, or difficulty using a hand due to coordination or weakness problems), treatment with high-dose methylprednisolone and oral taper can be offered if not contraindicated by infection or poorly controlled diabetes or hypertension.[51] [52] Whether this treatment has any long-term effect on disability is unknown, but symptomatic improvement is often observed. Intravenous administration is the standard route; however, if this is not possible, highdose oral administration may be considered and is non-inferior to intravenous administration.[53] Various oral regimens exist; a specialist should be consulted when selecting an oral regimen. In cases of neuromyelitis optica spectrum disorders (NMOSD), high-dose intravenous corticosteroid treatment is first-line treatment. A longer oral taper may be required to prevent relapse, especially for patients who are seropositive for myelin oligodendrocyte glycoprotein auto-antibodies. For more information, see our topic on Transverse myelitis. Patients with severe acute relapse or rapidly progressing disability may benefit from plasma exchange or plasma exchange plus intravenous corticosteroids.[7] [54] Disease-modifying therapy - clinically isolated syndrome (CIS) There is evidence supporting reduced risk of progression to clinically definite MS with immunomodulatory treatment of CIS.[55] Disease-modifying therapies for patients with a first clinical episode and magnetic resonance imaging (MRI) features consistent with MS include glatiramer, interferon beta-1b, interferon beta-1a, teriflunomide, dimethyl fumarate, and diroximel fumarate. In the US, fingolimod and siponimod may also be used. Disease-modifying therapy - relapsing-remitting MS (RRMS) Disease-modifying therapy should be considered for all patients with relapsing-remitting MS (RRMS).[16] [56] However, some patients may have a benign course, or be in an age group (generally, >55 years) where the benefits of disease-modifying therapy may be less clear. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 23 Multiple sclerosis Management M A N A G E M E N T Interferon beta preparations, glatiramer, dimethyl fumarate, diroximel fumarate, and teriflunomide are generally considered to be first-line agents.[57] [58] [59] [60] [61] [Evidence B] In some countries, fingolimod and siponimod may also be used as first-line agents. However, fingolimod, siponimod, natalizumab, ocrelizumab, cladribine, and alemtuzumab are more commonly reserved for patients who have more aggressive disease and/or have not tolerated or responded to previous disease-modifying agents.[57] [58] [62] [63] [64] [65] [66] In patients with RRMS, further investigation is required to determine whether long-term outcomes are more favourable when treatment is initiated with: moderately effective, safer medications, with escalation as needed; or with higher efficacy disease-modifying therapies from the outset.[67] [68] [69] Interferon beta and glatiramer Interferon beta preparations and glatiramer are believed to interfere with the formation of new demyelinating plaques in the central nervous system. Systematic reviews and meta-analyses indicate that they reduce relapse rates by approximately 30%.[70] [71] One network meta-analysis concluded that interferon beta and glatiramer both reduce relapse rates and delay progression, with comparable effectiveness, although there was a high risk of bias across studies.[72] Long-term observational data (median 21 years from randomised controlled trial enrolment) suggest that early treatment with interferon beta-1b is associated with prolonged survival in initially treatment-naive patients with RRMS.[73] Interferon beta preparations are metabolised in the liver and require periodic monitoring of full blood count and hepatic function. Glatiramer does not have the flu-like side effects of the interferons, but may take 6-9 months for clinical effect.[74] [75] Tolerability and adherence to interferon beta preparations and glatiramer do not appear to differ markedly.[76] Local injection-site reactions and a wide spectrum of generalised cutaneous adverse events are frequently reported with these disease-modifying therapies, particularly the subcutaneous formulations.[77] However, most are mild and do not require cessation of therapy. Glatiramer is available as different subcutaneous formulations that can be given either once daily or three times weekly.[78] Peginterferon beta-1a is also available as a subcutaneous formulation and is given every 2 weeks.[79] [80] Dimethyl fumarate An oral disease-modifying therapy that reduces annual relapse rates by around 40% to 50% when compared with placebo.[81] [82] Monitoring of blood counts is required during dimethyl fumarate therapy. Possible adverse effects include full-body flushing, gastrointestinal (GI) events, and headache. Full-body flushing may continue throughout treatment, although it can be controlled with the use of aspirin. GI-related adverse effects are usually transient, lasting for approximately 8 weeks following initiation of dimethyl fumarate; they are reduced by taking the medication with food, particularly foods containing some type of fat or oil. Over-the-counter treatments for heartburn and indigestion can be used to help to alleviate GI adverse effects. Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving dimethyl fumarate; persistent lymphopenia appears to be a risk factor.[83] Monitoring of lymphocyte counts every 6 months while on therapy is advised. 24 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Clinically significant cases of liver injury in patients treated with dimethyl fumarate have been reported.[84] The onset ranged from a few days to several months after initiation of treatment. Liver function tests should be obtained at baseline and considered at 6- to 12-month intervals. Diroximel fumarate Diroximel fumarate, an orally administered agent, is similar to dimethyl fumarate with comparable efficacy. Both drugs have the same active metabolite (monomethyl fumarate).[85] In one open-label phase 3 study, diroximel fumarate was associated with lower rates of GI adverse events than dimethyl fumarate.[86] Risk of clinically significant cases of liver injury should be considered in patients on diroximel fumarate; liver function tests should be monitored during treatment. Teriflunomide Teriflunomide is a selective oral immunosuppressant with anti-inflammatory properties. It has been shown to reduce annual relapse rates by around 31% when compared with placebo.[87] Monitoring of blood work is required during therapy, specifically liver function (every month for 6 months) and baseline tuberculosis testing. Patients taking teriflunomide may experience GI events such as nausea and diarrhoea, and elevated blood pressure, as well as hair thinning/loss, in the initial 8 months of treatment. Teriflunomide is a potential teratogen; pregnancy should be excluded before starting treatment, and contraception must be used during treatment. A drug elimination procedure must be undertaken before trying to conceive. Fingolimod An oral sphingosine 1-phosphate (S1P)-receptor modulator whose mechanism of action involves preventing egress of lymphocytes from lymph nodes.[88] Fingolimod has been shown to significantly reduce annual relapse rates compared with placebo, to improve other MRI outcomes, to improve quality of life, and to have an acceptable safety profile.[89] Fingolimod is a non-selective S1P agonist and is associated with potential off-target adverse effects, including persistent bradycardia, bronchoconstriction, and macular oedema. The UK Medicines and Healthcare products Regulatory Agency (MHRA) stipulates a number of contraindications relating to fingolimod use in patients with pre-existing cardiac disorders.[90] Patients require an ECG and ophthalmological examination, preferably including optical coherence tomography, prior to initiating fingolimod. ECG is repeated 6 hours after the initial dose of fingolimod. Exact protocols regarding first dose-monitoring vary, but must involve heart rate monitoring for bradycardia. The initial dose should be administered in a setting with resources available to manage symptomatic bradycardia. Patients require periodic full blood count and hepatic function monitoring. Repeat optical coherence tomography occurs 3-4 months after initiation of the medication. Patients should be monitored for the development of severe headaches, which may be due to vasospasm, and pulmonary issues such as shortness of breath and reduction in vital capacity.[88] [91] Severe worsening of MS has been reported after stopping fingolimod; the disease can become much worse than before the medication was started M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 25 Multiple sclerosis Management M A N A G E M E N T or while it was being taken. Although this is rare, it can result in permanent disability. Patients should be monitored closely for evidence of exacerbation of their condition after stopping treatment.[92] The potential exists for fatal reactivation of herpes virus infections in patients receiving fingolimod.[88] [91] PML has been reported in patients taking fingolimod. A baseline MRI, as well as routine MRIs during treatment, should be performed.[3] Cases of basal cell carcinoma have been reported in patients taking fingolimod, and the drug is contraindicated in patients with basal cell carcinoma. Siponimod An S1P receptor modulator for oral use with a similar mechanism of action to fingolimod. Siponimod is approved by the US Food and Drug Administration (FDA) for the treatment of adults with relapsing forms of MS, including RRMS (and clinically isolated syndrome and active secondary progressive disease). One randomised extension of a phase 2 study reported that disease activity was low in patients with RRMS during 24 months of siponimod treatment.[93] Potential adverse effects of siponimod therapy include increased risk of infection, macular oedema, lymphopenia, and transient decreases in heart rate. Siponimod selectively modulates S1P receptor type 1 and type 5, so may be associated with a reduced risk of adverse effects induced by S1P3 receptor activation.[94] Cladribine Works by gradually depleting T and B lymphocytes. One placebo-controlled phase 3 trial reported significantly reduced relapse rates at 2 years in patients with RRMS who were randomised to treatment with oral cladribine.[95] Adverse effects include lymphopenia and increased risk of infection (specific concern for herpes infections). Cladribine may increase the risk of malignancy and of fetal harm; it must not be used by patients with current malignancy, or by women and men of reproductive age who do not plan to use effective contraception. Oral cladribine is approved by the FDA in the US for the treatment of relapsing forms of MS in adults, including RRMS. It is licensed by the European Medicines Agency (EMA) for the treatment of adult patients with highly active relapsing MS. Natalizumab A monoclonal antibody given by intravenous infusion every 4 weeks. It reduces annual relapse rates by over 60% in patients with RRMS or secondary progressive MS.[96] Natalizumab is associated with an increased risk of PML. Factors associated with this increased risk are believed to include John Cunningham virus (JCV) antibody positivity, particularly with higher titres of the antibody, length of time on natalizumab, and prior exposure to chemotherapy or immunosuppressive agents (not including corticosteroids).[97] [98] Expert panel recommendations regarding the stratification and ongoing monitoring of natalizumab-associated PML risk have been published.[99] There is evidence that the incidence of PML among MS patients taking natalizumab has decreased since the introduction of JCV testing and risk-stratification recommendations.[100] A baseline MRI should be performed, as well as routine MRI during treatment.[3] 26 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ocrelizumab A humanised anti-CD20 monoclonal antibody approved by the FDA and the EMA for the treatment of relapsing forms of MS.[101] [102] Network meta-analyses indicate that ocrelizumab is at least as effective as other currently approved disease-modifying therapies for relapsing MS, with a similar safety profile.[103] [104] Ocrelizumab can cause infusion-related reactions, which can be severe, and increase risk of infection. It may also increase the risk for malignancies, particularly breast cancer. Rituximab A chimeric anti‐human CD20 monoclonal antibody used off-label for the management of MS in some countries.[105] There is evidence for the efficacy and safety of rituximab in patients with RRMS.[106] [107] Alemtuzumab A monoclonal antibody directed against the CD52 antigen, alemtuzumab is approved for use in adult patients with RRMS.[108] [109] [110] It is given by intravenous infusion for two treatment courses separated by 12 months. One Cochrane review found that, compared with interferon beta-1a, alemtuzumab reduced the proportion of patients with RRMS who experienced relapse, disease progression, change of expanded disability status scale score, and development of new T2 lesions on MRI over 24-36 months.[111] Rare, serious adverse effects, some fatal, reported within 3 days of alemtuzumab infusion include myocardial ischaemia, myocardial infarction, cerebral haemorrhage, cervicocephalic arterial dissection, pulmonary alveolar haemorrhage, and thrombocytopenia.[112] Immune-mediated conditions can occur many months after treatment. A risk of serious and life-threatening infusion reactions, infections, and an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders, have also been reported.[111] Serious cases of stroke and tears in the lining of arteries in the head and neck (cervicocephalic arterial dissection) have been reported in patients soon after alemtuzumab treatment (usually within 1 day). These can result in permanent disability and even death.[113] Healthcare professionals should consider stopping alemtuzumab in patients who develop signs of any of these conditions. Alemtuzumab should be given in a hospital with ready access to intensive care facilities and specialists who can manage serious adverse reactions. Vital signs should be monitored before and during each infusion, liver function tests should be performed before and during treatment, and patients should be monitored for signs of pathological immune activation. Patients should be informed of the signs and symptoms of these conditions at each infusion, and advised to seek immediate medical attention if they experience symptoms.[114] Because of its safety profile, alemtuzumab is approved by the FDA for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. In Europe, the use of alemtuzumab is restricted to patients with RRMS that is highly active despite adequate treatment with at least one disease-modifying therapy or if the disease is worsening rapidly, with a minimum of two disabling relapses in 1 year and brain imaging showing new damage. Alemtuzumab must not be used in patients with certain heart, circulation, or bleeding disorders.[114] M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 27 Multiple sclerosis Management M A N A G E M E N T Pregnancy and the postpartum period: disease-modifying therapy It is important to discuss family planning and pregnancy with women and girls of childbearing age, starting at or soon after diagnosis of MS.[115] MS does not affect fertility, and contraception should be used when pregnancy is not wanted. There is uncertainty regarding the potential harms to neonates from the use of disease-modifying drugs pre-conception and during pregnancy. For all drugs, the risk of potential harm to the neonate must be weighed against the risk of relapse in individual patients.[56] Guidelines from the Association of British Neurologists outline considerations with specific medications and circumstances.[115] Prospective data indicate that among pregnant women with MS (who were only allowed short courses of glucocorticoids for treatment of MS during pregnancy), risk for relapse is lower during pregnancy than at baseline.[116] However, approximately 1 in 4 women had a relapse in the first 3 months post partum.[116] It has been postulated that breastfeeding during the postnatal period may reduce relapse in patients with MS, but this requires further investigation.[117] Recommendations regarding specific agents The EMA recommends that, because of the risk of major congenital malformations, fingolimod must not be used in pregnant women or in women of childbearing age who are not using effective contraception. If a woman becomes pregnant while using fingolimod, the medicine must be stopped and the pregnancy should be closely monitored.[118] Cladribine may increase the risk of fetal harm, so it must not be used by women of childbearing age who are not using effective contraception. Teriflunomide is a potential teratogen. A drug elimination procedure must be undertaken before trying to conceive. Disease-modifying therapy - progressive MS Patients with rapid disease progression or who have a mixture of progression and relapses may be treated with many of the same medications used for RRMS. Secondary progressive MS The following medications are FDA-approved for relapsing forms of MS, including active secondary progressive disease: siponimod, cladribine, interferon beta-1a, interferon beta-1b, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, diroximel fumarate, and alemtuzumab. Siponimod is the only therapy with demonstrated efficacy in a large randomised controlled trial of patients with secondary progressive MS.[119] Siponimod reduced the risk of disability progression compared with placebo (statistically significant lower percentage of patients with confirmed progression of disability in 3 months in the siponimod group) in a large double-blind, randomised controlled trial of patients with secondary progressive MS.[119] Intravenous methylprednisolone (FDA-approved for the treatment of acute exacerbations of MS) administered using a pulse-dose protocol has been used regularly with some benefit in patients with secondary progressive MS. However, there is no consensus on optimal dosing. It may be considered in patients who do not have other treatment options, but the benefit must be weighed against potential adverse effects. 28 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Cladribine reduced relapses and MRI lesion activity in a 96-week phase 2 randomised study of patients with active relapsing MS for whom interferon was not effective.[120] However, patients with secondary progressive MS made up only a small percentage of the trial population. Interferon beta preparations do not appear to prevent the development of permanent physical disability in secondary progressive disease.[121] [122] Natalizumab did not reduce disability progression on the primary composite endpoint of a phase 3, randomised, double-blind, placebo-controlled trial of patients with secondary progressive MS.[123] However, it did reduce upper limb worsening.[123] Mitoxantrone has been shown to reduce annualised relapse rate by about one half in both RRMS and secondary progressive MS patients. However, it may be poorly tolerated due to GI and fatigue-related side effects. Mitoxantrone has the potential for serious adverse effects including cardiotoxicity (requiring regular monitoring of left ventricular ejection fraction) and acute myelogenous leukaemia, and so it is rarely used.[124] [125] Close monitoring of liver function and blood count should be undertaken in patients receiving mitoxantrone; neither mitoxantrone nor other systemic immunosuppressants should be used in patients who have frequent urinary tract infections or concomitant illness.[126] Primary progressive MS Ocrelizumab, approved by the FDA for the treatment of primary progressive MS, was associated with lower rates of clinical and MRI progression than placebo in a phase 3 trial of patients with primary progressive MS.[102] However, ocrelizumab has not been studied in patients older than age 55 years or in those with severe disability (expanded disability status scale >6.5). Thus, in Europe it is approved in early-stage primary progressive MS only.[127] Other medications that have been used include cyclophosphamide, methotrexate, and azathioprine, but there is no consensus regarding their benefits in primary progressive MS.[128] These medications may be used in locations where ocrelizumab is not available. Symptomatic management - fatigue Non-pharmacological management • Practitioners should obtain full blood count with differential, thyroid-stimulating hormone, vitamin B12, and vitamin D levels, as well as a brief sleep history, before assuming that the patient has MSrelated fatigue. • Some patients with MS who report fatigue simply are not getting enough sleep or have poor sleep habits and sleep hygiene, or excessive caffeine intake. Other patients have disturbed sleep due to depression, restless legs, spasticity, pain, or bladder frequency, and these conditions should be treated appropriately. Caffeine and alcohol use can have effects on the bladder and cause disruption. Some patients have concomitant sleep disorders, such as sleep apnoea. • Most patients with MS benefit from regular exercise programmes, which promote restful sleep and reduce fatigue.[129] [130] Progressive resistance training is a rehabilitation tool that may help to reduce fatigue.[131] • Some patients with fatigue may benefit from mind-body therapies, such as yoga and relaxation, or from cognitive behavioural therapy. Although the evidence supporting the use of these therapies in patients with MS is limited, they are relatively safe and can be used in conjunction with pharmacological management.[132] [133] [134] M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 29 Multiple sclerosis Management M A N A G E M E N T Pharmacological management • If the patient continues to report fatigue following non-pharmacological approaches, amantadine can be trialled. Side effects include livedo reticularis and occasional disturbances of thought processes. • An alternative medication are modafinil or armodafinil.[135] [136] • Although methylphenidate and amfetamine and/or dextroamphetamine have not been shown to be effective in trials, some patients respond favourably to them in practice. Symptomatic management - gait impairment Non-pharmacological management Various physiotherapy regimens improve gait and balance in patients with MS, particularly those with mild to moderate levels of disability.[137] [138] [139] Progressive resistance training may help to improve balance.[131] One systematic review found that virtual reality training is at least as effective as conventional training in improving balance and gait in people with MS.[140] Pharmacological management Fampridine can be used to improve gait endurance, and may increase gait speed.[141] [142] Clinical trials and post-marketing surveillance indicate a dose-related increased risk of seizures with fampridine.[142] Doses should be administered 12 hours apart. Patients must have normal creatinine levels and no history of seizures before starting fampridine.[143] Healthcare providers should monitor for seizures in patients taking fampridine, and provide adequate patient education. Symptomatic management - sensory symptoms Patients with MS often report paraesthesias and other unpleasant sensations. These do not have to be treated with medications, but can be if they are bothersome to the patient or interfere with functioning.[144] Exacerbations or relapses that involve solely sensory symptoms, such as paraesthesias, do not require intravenous corticosteroids and may be treated with low doses of anticonvulsants such as gabapentin or the newer carbamazepine derivatives.[145] Various types of pain can occur in patients with MS: trigeminal neuralgia, painful dysaesthesias, painful tonic spasms and other spasticity-related pain, and musculoskeletal pain. Central or neuropathic pain can be treated with anticonvulsant and antidepressant medication.[146] Symptomatic management - spasticity Patients with MS often experience increased muscle tone, particularly in their legs. This can be very unpleasant and painful, disturbing sleep with leg cramps in the calves, and affecting ambulation. The first line of management is gentle stretching exercises, which are best provided by a knowledgeable physiotherapist. Treatment of constipation and bladder dysfunction can also be helpful. 30 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Baclofen can be used to treat spasticity. Side effects include fatigue, clouding of mental functioning, and unmasking of underlying muscle weakness, resulting in patients reporting increased weakness. Intrathecal pumps that deliver either a constant or a variable rate of baclofen are options for: • wheelchair- or bed-bound patients, in whom spasticity limits their ability to sit in a chair or perform personal hygiene, and • select ambulatory patients, who are affected by the side effects of high-dose oral antispasticity medications. Tizanidine is helpful for spasticity, but is more sedating than baclofen.[147] It may therefore be useful at bedtime. Tizanidine may affect liver function and lower blood pressure. It should not be used with ciprofloxacin, which potentiates its action.[148] Clonazepam or gabapentin can be very helpful for bedtime spasms and restless legs. Localised botulinum toxin injections have been demonstrated to be effective in the management of spasticity associated with MS; maximum benefit is generally obtained with concomitant physiotherapy. The treatment of spasticity with localised botulinum toxin injections must balance potential symptom benefit with possible decrease in functional strength.[149] [150] [151] Cannabinoids may be effective for treating symptoms of spasticity in MS.[152] [153] [154] [155] The College of Family Physicians of Canada recommends that clinicians may consider medical cannabinoids for refractory spasticity in MS, and specifies delta-9-tetrahydrocannabinol/cannabidiol oromucosal spray (also known as nabiximols) as the medical cannabinoid of choice.[156] The National Institute of Health and Care Excellence in England recommends a trial of delta-9-tetrahydrocannabinol/cannabidiol oromucosal spray to treat moderate to severe spasticity in adults with MS in whom other pharmacological treatments for spasticity are not effective.[157] Symptomatic management - urinary dysfunction There is currently no agreed consensus on the management of urinary dysfunction ('neurogenic bladder') in patients with MS, and this topic remains controversial.[158] Furthermore, the progressive nature of MS can make the management of symptoms such as urinary dysfunction difficult and complex. Optimisation of bladder management may require consultation with a urologist, neurourologist, or urogynaecologist for testing and management, but some simple measures can be very helpful. Patients with MS should limit intake of caffeine and 'vitamin waters', as these are significant sources of bladder irritation leading to frequency. Bladder function can be improved by management of constipation and simple timed voiding. Some MS patients with urinary dysfunction may benefit from mind-body therapies, such as yoga and relaxation.[159] They are relatively safe, albeit with limited supporting evidence, and can be used in conjunction with pharmacological management.[132] [133] Asymptomatic bladder infections are a major problem in MS, particularly if patients have urinary retention, and preventative measures, such as increasing fluid intake and prophylactic antibiotics, may be needed. Although there are little supporting data in the medical literature, some patients have found that consuming cranberry capsules has reduced their incidence of urinary tract infections substantially. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 31 Multiple sclerosis Management M A N A G E M E N T Oxybutynin and other agents such as solifenacin, darifenacin, tolterodine, fesoterodine, and trospium can be used to reduce urinary frequency, but patients should be assessed for post-void residual volume before prescribing these agents. Botulinum toxin injections have been effectively used to treat detrusor muscle over-reactivity and decrease patients’ urinary frequency, urgency, and incontinence.[149] [160] [161] Intermittent self-catheterisation is often required after this treatment. Symptomatic management - tremor Patients with MS may exhibit tremors of many types. It is important to distinguish true tremors from clonus (either ankle or knee), which would be managed as spasticity; paroxysmal symptoms, which would respond best to anti-seizure medications; or tremulousness from a variety of causes such as anxiety or hyperthyroidism. The most disabling and difficult tremor to manage in MS is cerebellar tremor, which may involve the head, trunk, and extremities, as well as the voice. In severe cases, tremor alone prevents ambulation and often inhibits performance of activities of daily living such as dressing, toileting, and eating. The most common pharmacological interventions are propranolol, primidone, and clonazepam. Care must be taken with each of these therapies because of potential adverse effects. Propranolol can produce hypotension and depression. Primidone can be very sedating, and is therefore often initiated with single dose given at night, which can be increased to a 3-times-daily dosing regimen, depending on the clinical response. Clonazepam is also sedating and may be habit-forming. It is usually initiated at a low dose, which can be titrated to higher doses depending on the clinical response.[162] [163] Treatment algorithm overview Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer Acute ( summary ) acute relapse affecting function 1st methylprednisolone adjunct plasma exchange 32 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing ( summary ) relapsing-remitting MS 1st immunomodulators with fatigue plus lifestyle modification and/or nonpharmacological therapies adjunct pharmacotherapy with urinary frequency plus lifestyle modification ± mind-body therapies ± pharmacotherapy with sensory symptoms (pain and paraesthesia) adjunct low-dose anticonvulsant or antidepressant with increased muscle tone (with or without spasms) plus physiotherapy ± antispasticity pharmacotherapy with tremor plus pharmacotherapy with gait impairment plus physiotherapy and/or progressive resistance training (PRT) adjunct fampridine secondary progressive MS 1st siponimod or methylprednisolone 2nd cladribine with fatigue plus lifestyle modification ± pharmacotherapy with urinary frequency plus lifestyle modification ± pharmacotherapy with sensory symptoms (pain and paraesthesia) adjunct low-dose anticonvulsant or antidepressant with increased muscle tone (with or without spasms) plus physiotherapy ± antispasticity pharmacotherapy with tremor plus pharmacotherapy with gait impairment plus physiotherapy ± fampridine primary progressive MS 1st consideration for pharmacotherapy with fatigue plus lifestyle modification ± pharmacotherapy with urinary frequency plus lifestyle modification ± pharmacotherapy with sensory symptoms (pain and paresthaesia) adjunct low-dose anticonvulsant or antidepressant with increased muscle tone (with or without spasms) plus physiotherapy ± antispasticity pharmacotherapy M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 33 Multiple sclerosis Management M A N A G E M E N T Ongoing ( summary ) with tremor plus pharmacotherapy with gait impairment plus physiotherapy ± fampridine 34 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Treatment algorithm Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer Acute acute relapse affecting function 1st methylprednisolone Primary options » methylprednisolone: 1000 mg intravenously once daily for 3 days; various oral regimens have been reported, consult specialist for guidance on oral dosing » Patients with MS who are in an acute relapse with symptoms affecting functioning (e.g., walking, vision) may benefit from methylprednisolone in high doses.[52] Intravenous administration is the standard route; however, if this is not possible, high-dose oral administration may be considered and is noninferior to intravenous administration.[53] Various oral regimens exist; therefore, a specialist should be consulted when selecting an oral regimen. » Patient should be screened for infection, and serum glucose should be monitored in patients with diabetes. » Generally high-dose treatment is given for 3 days, but in severe relapse treatment can be given for 5 days. » In cases of neuromyelitis optica spectrum disorders, a longer oral taper may be required to prevent relapse, especially for patients who are seropositive for myelin oligodendrocyte glycoprotein auto-antibodies. adjunct plasma exchange Treatment recommended for SOME patients in selected patient group » Patients with severe acute relapse or rapidly progressing disability may benefit from plasma exchange or plasma exchange plus intravenous corticosteroids.[7] [54] M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 35 Multiple sclerosis Management M A N A G E M E N T Ongoing relapsing-remitting MS relapsing-remitting MS 1st immunomodulators Primary options » interferon beta 1a: 30 micrograms intramuscularly once weekly; or 44 micrograms subcutaneously three times weekly Dose depends on brand and formulation used. OR » interferon beta 1b: 250 micrograms subcutaneously once daily on alternate days OR » peginterferon beta 1a: 63 micrograms subcutaneously once daily initially on day 1, increase to 94 micrograms once daily on day 15, then 125 micrograms every 2 weeks thereafter OR » glatiramer: (20 mg/ml solution) 20 mg subcutaneously once daily; (40 mg/ml solution): 40 mg subcutaneously three times weekly OR » teriflunomide: 7-14 mg orally once daily OR » dimethyl fumarate: 120-240 mg orally twice daily OR » diroximel fumarate: 231 mg orally twice daily initially for 7 days, then increase to 462 mg twice daily; may temporarily decrease dose to initial dose if patient does not tolerate maintenance dose and then increase again within 4 weeks Secondary options » fingolimod: 0.5 mg orally once daily 36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing OR » siponimod: consult specialist for guidance on dose; dose depends on CYP2C9 genotype OR » natalizumab: 300 mg intravenously once every 4 weeks OR » ocrelizumab: 300 mg intravenously as a single dose initially, followed by 300 mg as a single dose 2 weeks later, then 600 mg every 6 months OR » rituximab: consult specialist for guidance on dose Tertiary options » cladribine: consult specialist for guidance on oral dose OR » alemtuzumab: 12 mg intravenously daily for 5 consecutive days for the first treatment course, then 12 mg intravenously daily for 3 consecutive days given 12 months later » Disease-modifying therapy should be offered to all patients with relapsing-remitting MS (RRMS).[16] [56] However, some patients may have a benign course or be in an age group where the benefits of disease-modifying therapy may be less clear. » Interferon beta preparations, glatiramer, dimethyl fumarate, diroximel fumarate, and teriflunomide are generally considered to be first-line agents.[57] [58] [59] [60] [61] [Evidence B] In some countries, fingolimod and siponimod may also be used as first-line agents. However, fingolimod, siponimod, natalizumab, ocrelizumab, cladribine, and alemtuzumab are more commonly reserved for patients who have more aggressive disease and/or have not tolerated or responded to previous diseasemodifying agents.[57] [58] [62] [63] [64] [65] [66] M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 37 Multiple sclerosis Management M A N A G E M E N T Ongoing » Clinically significant cases of liver injury in patients treated with dimethyl fumarate have been reported.[84] The onset ranged from a few days to several months after initiation of treatment. Liver function tests should be obtained at baseline and considered at 6- to 12- month intervals. Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients on dimethyl fumarate; persistent lymphopenia appears to be a risk factor.[83] Monitoring of lymphocyte counts every 6 months while on therapy is advised. » Diroximel fumarate is similar to dimethyl fumarate (both drugs have the same active metabolite, monomethyl fumarate). It has comparable efficacy but lower rates of gastrointestinal adverse events.[85] [86] Risk of clinically significant cases of liver injury should be considered in patients on diroximel fumarate; liver function tests should be monitored during treatment. » Teriflunomide is a potential teratogen; pregnancy should be excluded before starting treatment, and contraception must be used during treatment. A drug elimination procedure must be undertaken before trying to conceive. » Fingolimod can cause persistent bradycardia, which can increase the risk of serious cardiac arrhythmias. The UK Medicines and Healthcare products Regulatory Agency (MHRA) stipulates a number of contraindications relating to fingolimod use in patients with pre-existing cardiac disorders.[90] Severe worsening of MS after stopping fingolimod has been reported, which, although rare, can result in permanent disability.[92] Cases of PML and cases of basal cell carcinoma have also been reported in patients taking fingolimod. The European Medicines Agency (EMA) recommends that, because of the risk of major congenital malformations, fingolimod must not be used in pregnant women or in women of childbearing age who are not using effective contraception. If a woman becomes pregnant while using fingolimod, the medicine must be stopped and the pregnancy should be closely monitored.[118] » Siponimod is associated with a lower risk of adverse events than fingolimod. » Natalizumab is associated with an increased risk of PML. John Cunningham virus (JCV) testing should be carried out for risk stratification, and natalizumab should be continued only if benefits outweigh the risks in 38 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing patients at higher risk for PML.[97] [98] [165] Expert panel recommendations regarding the stratification and ongoing monitoring of natalizumab-associated PML risk have been published.[99] » Ocrelizumab is approved by the EMA and the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS.[101] [102] Ocrelizumab can cause infusion-related reactions, which can be severe, and increase risk of infection. It may also increase the risk for malignancies, particularly breast cancer. » Rituximab is used off-label for the management of MS in some countries.[105] There is evidence for the efficacy and safety of rituximab in patients with RRMS.[106] [107] » Oral cladribine is approved by the FDA for the treatment of relapsing forms of MS in adults, including RRMS. It is licensed by the EMA for the treatment of adult patients with highly active relapsing MS. Cladribine may increase the risk of malignancy and of fetal harm; it must not be used by patients with current malignancy, or by women and men of reproductive potential who do not plan to use effective contraception. » Alemtuzumab has been associated with rare, serious adverse effects, some fatal, within 3 days of infusion, including myocardial ischaemia, myocardial infarction, cerebral haemorrhage, cervicocephalic arterial dissection, pulmonary alveolar haemorrhage, and thrombocytopenia.[112] Immune-mediated conditions can occur many months after treatment. A risk of serious and life-threatening infusion reactions, infections, and an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders, have also been reported.[111] Serious cases of stroke and tears in the lining of arteries in the head and neck (cervicocephalic arterial dissection) in patients soon after alemtuzumab treatment (usually within 1 day). These can result in permanent disability and even death.[113] Healthcare professionals should consider stopping alemtuzumab in patients who develop signs of any of these conditions. » Alemtuzumab should be given in a hospital with ready access to intensive care facilities and specialists who can manage serious adverse reactions. Vital signs should be monitored before and during each infusion, liver function tests should be performed before and during treatment, and patients should be monitored for M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 39 Multiple sclerosis Management M A N A G E M E N T Ongoing signs of pathological immune activation. Patients should be informed of the signs and symptoms of these conditions at each infusion, and advised to seek immediate medical attention if they experience symptoms.[114] Because of its safety profile, alemtuzumab is approved by the FDA for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. In Europe, the use of alemtuzumab is restricted to patients with RRMS that is highly active despite adequate treatment with at least one disease-modifying therapy or if the disease is worsening rapidly, with a minimum of two disabling relapses in 1 year and brain imaging showing new damage. Alemtuzumab must not be used in patients with certain heart, circulation, or bleeding disorders.[114] » There is uncertainty regarding the potential harms to neonates from the use of diseasemodifying drugs pre-conception and during pregnancy. For all drugs, the risk of potential harm to the neonate must be weighed against the risk of relapse in individual patients.[56] Guidelines from the Association of British Neurologists outline considerations with specific medications and circumstances.[115] with fatigue plus lifestyle modification and/or nonpharmacological therapies Treatment recommended for ALL patients in selected patient group » Most patients with MS benefit from regular exercise programmes.[129] [130] Good sleep hygiene practices should be encouraged. » Progressive resistance training is a rehabilitation tool that may also help to reduce fatigue.[131] » Some patients may benefit from mind-body therapies, such as yoga and relaxation, or from cognitive behavioural therapy. Although the evidence supporting the use of these therapies in patients with MS is limited, they are relatively safe and can be used in conjunction with pharmacological management.[132] [133] [134] adjunct pharmacotherapy Treatment recommended for SOME patients in selected patient group Primary options » amantadine: 100 mg orally in the morning and 100 mg in the afternoon no later than 2-3 pm 40 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing OR » modafinil: 100-200 mg orally in the morning, repeat when required in the afternoon OR » armodafinil: 150-250 mg orally in the morning » If the patient continues to report fatigue after non-pharmacological approaches, amantadine, modafinil, or armodafinil can be trialled.[135] [136] with urinary frequency plus lifestyle modification ± mind-body therapies ± pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » oxybutynin: 5 mg orally (immediate-release) two to three times daily OR » tolterodine: 1-2 mg orally (immediaterelease) twice daily; 2-4 mg (extendedrelease) once daily OR » solifenacin: 5-10 mg orally once daily OR » darifenacin: 7.5 to 15 mg orally (extendedrelease) once daily OR » fesoterodine: 4-8 mg orally (extendedrelease) once daily OR » botulinum toxin type A: consult specialist for guidance on dose » Caffeine and 'vitamin waters' should be avoided. » Presence of urinary tract infection should be excluded. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 41 Multiple sclerosis Management M A N A G E M E N T Ongoing » Full assessment by a urologist may be required and urinary retention excluded. There is currently no agreed consensus on the management of urinary dysfunction ('neurogenic bladder') in patients with MS, and this topic remains controversial.[158] » Oxybutynin and other agents such as solifenacin, darifenacin, fesoterodine, and tolterodine may be used for symptoms of urinary frequency if retention is not present. » Botulinum toxin injections and intermittent selfcatheterisation are additional treatment options. » Some patients may benefit from mind-body therapies, such as yoga and relaxation.[159] They are relatively safe, albeit with limited supporting evidence, and can be used in conjunction with pharmacological management.[132] [133] with sensory symptoms (pain and paraesthesia) adjunct low-dose anticonvulsant or antidepressant Treatment recommended for SOME patients in selected patient group Primary options » gabapentin: 100 mg orally once daily at bedtime initially, increase by 100 mg/day increments to 300 mg once daily at bedtime; or 100-300 mg three times daily OR » pregabalin: 150 mg/day orally given in 3 divided doses initially, increase after 2-3 days to 300 mg/day given in 3 divided doses OR » carbamazepine: 200-400 mg orally twice daily OR » oxcarbazepine: 150-300 mg orally twice daily OR » duloxetine: 60 mg orally once daily OR 42 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing » amitriptyline: 25-100 mg orally once daily » These symptoms do not always require treatment. However, if they are bothersome to the patient or interfere with functioning, low-dose anticonvulsants and antidepressants can be used. » Various types of pain can occur in patients with MS: trigeminal neuralgia, painful dysaesthesias, painful tonic spasms and other spasticityrelated pain, and musculoskeletal pain. Central or neuropathic pain can be treated with anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine, oxcarbazepine) and antidepressants (e.g., duloxetine, amitriptyline).[146] with increased muscle tone (with or without spasms) plus physiotherapy ± antispasticity pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » baclofen: 5 mg orally three times daily initially, increase by 5 mg/dose increments every 3 days, maximum 80 mg/day OR » tizanidine: 2-4 mg orally three times daily OR » clonazepam: 0.5 to 1 mg orally once daily at bedtime OR » gabapentin: 100-300 mg orally once daily at bedtime OR » botulinum toxin type A: consult specialist for guidance on dose Secondary options » baclofen intrathecal: consult specialist for guidance on dose Tertiary options M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 43 Multiple sclerosis Management M A N A G E M E N T Ongoing » delta-9-tetrahydrocannabinol/cannabidiol: (2.7 mg/2.5 mg oromucosal spray) consult specialist for guidance on buccal dose » The first line of management is gentle stretching exercises, which are best provided by a physiotherapist. » Side effects of baclofen include fatigue, clouding of mental functioning, and unmasking of underlying muscle weakness, resulting in patients reporting increased weakness. » Tizanidine is more sedating than baclofen. It should not be used with ciprofloxacin, which potentiates its action. » The treatment of spasticity with botulinum toxin must weigh the balance of the potential symptom benefit with possible decrease in functional strength.[149] [150] [151] » Cannabinoids may be effective for treating symptoms of spasticity in MS.[152] [153] [154] [155] The College of Family Physicians of Canada recommends that clinicians may consider medical cannabinoids for refractory spasticity in MS, and specifies delta-9- tetrahydrocannabinol/cannabidiol oromucosal spray (also known as nabiximols) as the medical cannabinoid of choice.[156] The National Institute of Health and Care Excellence in England recommends a trial of delta-9- tetrahydrocannabinol/cannabidiol oromucosal spray to treat moderate to severe spasticity in adults with MS in whom other pharmacological treatments for spasticity are not effective.[157] with tremor plus pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » propranolol: 5 mg twice daily initially, increase by 5 mg/dose increments up to 20 mg twice daily OR » primidone: 50 mg once daily at bedtime initially, increase by 12.5 mg/day increments up to 50 mg three times daily OR 44 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing » clonazepam: 0.25 mg three times daily initially, increase by 0.25 mg/dose increments up to 1 mg three times daily » Care must be taken with each of the therapies. Propranolol may produce adverse effects of hypotension and depression. Primidone and clonazepam can be sedating, and clonazepam can also be habit forming. » Medications are always started at a low dose, which can be increased according to the clinical response. with gait impairment plus physiotherapy and/or progressive resistance training (PRT) Treatment recommended for ALL patients in selected patient group » Various physiotherapy regimens improve gait and balance in patients with MS, particularly in those with mild to moderate levels of disability.[137] [138] [139] » PRT may help to improve balance.[131] » Virtual reality training is an alternative to conventional training.[140] adjunct fampridine Treatment recommended for SOME patients in selected patient group Primary options » fampridine: 10 mg orally every 12 hours » Fampridine can be used to improve gait endurance and may increase gait speed.[141] [143] Clinical trials and post-marketing surveillance indicate a dose-related increased risk of seizures with fampridine.[142] Doses should be administered 12 hours apart. Patients must have normal creatinine levels and no history of seizures before starting fampridine.[143] Healthcare providers should monitor for seizures, and provide adequate patient education. secondary progressive MS 1st siponimod or methylprednisolone Primary options » siponimod: consult specialist for guidance on dose; dose depends on CYP2C9 genotype Secondary options M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 45 Multiple sclerosis Management M A N A G E M E N T Ongoing » methylprednisolone: consult specialist for guidance on dose » Siponimod is approved in some countries for active secondary progressive MS. Siponimod reduced the risk of disability progression compared with placebo (statistically significant lower percentage of patients with confirmed progression of disability in 3 months in the siponimod group) in a large double-blind, randomised controlled trial of patients with secondary progressive MS.[119] » Intravenous methylprednisolone (approved by the US Food and Drug Administration for the treatment of acute exacerbations of MS) administered using a pulse-dose protocol has been used regularly with some benefit in patients with secondary progressive MS. However, there is no consensus on optimal dosing. It may be considered in patients who do not have other treatment options, but the benefit must be weighed against potential adverse effects. 2nd cladribine Primary options » cladribine: consult specialist for guidance on oral dose » Oral cladribine is approved in some countries for active secondary progressive MS. Cladribine reduced relapses and magnetic resonance imaging (MRI) lesion activity in a 96-week phase 2 randomised study of patients with active relapsing MS for whom interferon was not effective.[120] However, patients with secondary progressive MS made up only a small percentage of the trial population. » Cladribine may increase the risk of malignancy and of fetal harm; it must not be used by patients with current malignancy, or by women and men of reproductive potential who do not plan to use effective contraception. with fatigue plus lifestyle modification ± pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » amantadine: 100 mg orally in the morning and 100 mg in the afternoon no later than 2-3 pm OR 46 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing » modafinil: 100-200 mg orally in the morning, repeat when required in the afternoon OR » armodafinil: 150-250 mg orally in the morning » Most patients with MS benefit from regular exercise programmes.[129] [130] Good sleep hygiene practices should also be encouraged. » If the patient continues to report fatigue after non-pharmacological approaches, amantadine, modafinil, or armodafinil can be trialled.[135] [136] with urinary frequency plus lifestyle modification ± pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » oxybutynin: 5 mg orally (immediate-release) two to three times daily OR » tolterodine: 1-2 mg orally (immediaterelease) twice daily; 2-4 mg (extendedrelease) once daily OR » solifenacin: 5-10 mg orally once daily OR » darifenacin: 7.5 to 15 mg orally (extendedrelease) once daily OR » fesoterodine: 4-8 mg orally (extendedrelease) once daily OR » botulinum toxin type A: consult specialist for guidance on dose » Caffeine and 'vitamin waters' should be avoided. » Presence of urinary tract infection should be excluded. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 47 Multiple sclerosis Management M A N A G E M E N T Ongoing » Full assessment by a urologist may be required and urinary retention excluded. » Oxybutynin and other agents such as solifenacin, darifenacin, fesoterodine, and tolterodine may be used for symptoms of urinary frequency if retention is not present. » Botulinum toxin injections and intermittent selfcatheterisation are additional treatment options. with sensory symptoms (pain and paraesthesia) adjunct low-dose anticonvulsant or antidepressant Treatment recommended for SOME patients in selected patient group Primary options » gabapentin: 100 mg orally once daily at bedtime initially, increase by 100 mg/day increments to 300 mg once daily at bedtime; or 100-300 mg three times daily OR » pregabalin: 150 mg/day orally given in 3 divided doses initially, increase after 2-3 days to 300 mg/day given in 3 divided doses OR » carbamazepine: 200-400 mg orally twice daily OR » oxcarbazepine: 150-300 mg orally twice daily OR » duloxetine: 60 mg orally once daily OR » amitriptyline: 25-100 mg orally once daily » These symptoms do not always require treatment. However, if they are bothersome to the patient or interfere with functioning, low-dose anticonvulsants and antidepressants can be used. » Various types of pain can occur in patients with MS: trigeminal neuralgia, painful dysaesthesias, painful tonic spasms and other spasticity48 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing related pain, and musculoskeletal pain. Central or neuropathic pain can be treated with anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine, oxcarbazepine) and antidepressants (e.g., duloxetine, amitriptyline).[146] with increased muscle tone (with or without spasms) plus physiotherapy ± antispasticity pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » baclofen: 5 mg orally three times daily initially, increase by 5 mg/dose increments every 3 days, maximum 80 mg/day OR » tizanidine: 2-4 mg orally three times daily OR » clonazepam: 0.5 to 1 mg orally once daily at bedtime OR » gabapentin: 100 mg orally once daily at bedtime initially, increase by 100 mg/day increments to 300 mg once daily at bedtime; or 100-300 mg three times daily OR » botulinum toxin type A: consult specialist for guidance on dose Secondary options » baclofen intrathecal: consult specialist for guidance on dose Tertiary options » delta-9-tetrahydrocannabinol/cannabidiol: (2.7 mg/2.5 mg oromucosal spray) consult specialist for guidance on buccal dose » The first line of management is gentle stretching exercises, which are best provided by a physiotherapist. » Side effects of baclofen include fatigue, clouding of mental functioning, and unmasking M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 49 Multiple sclerosis Management M A N A G E M E N T Ongoing of underlying muscle weakness, resulting in patients reporting increased weakness. » Tizanidine is more sedating than baclofen. It should not be used with ciprofloxacin, which potentiates its action. » The treatment of spasticity with botulinum toxin must weigh the balance of the potential symptom benefit with possible decrease in functional strength.[149] [150] [151] » Cannabinoids may be effective for treating symptoms of spasticity in MS.[152] [153] [154] [155] The College of Family Physicians of Canada recommends that clinicians may consider medical cannabinoids for refractory spasticity in MS, and specifies delta-9- tetrahydrocannabinol/cannabidiol oromucosal spray (also known as nabiximols) as the medical cannabinoid of choice.[156] The National Institute of Health and Care Excellence in England recommends a trial of delta-9- tetrahydrocannabinol/cannabidiol oromucosal spray to treat moderate to severe spasticity in adults with MS in whom other pharmacological treatments for spasticity are not effective.[157] with tremor plus pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » propranolol: 5 mg twice daily initially, increase by 5 mg/dose increments up to 20 mg twice daily OR » primidone: 50 mg once daily at bedtime initially, increase by 12.5 mg/day increments up to 50 mg three times daily OR » clonazepam: 0.25 mg three times daily initially, increase by 0.25 mg/dose increments up to 1 mg three times daily » Care must be taken with each of the therapies. Propranolol may produce adverse effects of hypotension and depression. Primidone and clonazepam can be sedating, and clonazepam can also be habit forming. 50 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing » Medications are always started at a low dose, which can be increased according to the clinical response. with gait impairment plus physiotherapy ± fampridine Treatment recommended for ALL patients in selected patient group Primary options » fampridine: 10 mg orally every 12 hours » Various physiotherapy regimens improve gait and balance in patients with MS, particularly those with mild to moderate levels of disability.[131] [137] [138] [139] [140] » Fampridine can be used to improve gait endurance and may increase gait speed.[141] [143] » Clinical trials and post-marketing surveillance indicate a dose-related increased risk of seizures with fampridine.[142] Doses should be administered 12 hours apart. Patients must have normal creatinine levels and no history of seizures before starting fampridine.[143] Healthcare providers should monitor for seizures, and provide adequate patient education. primary progressive MS primary progressive MS 1st consideration for pharmacotherapy Primary options » ocrelizumab: 300 mg intravenously as a single dose initially, followed by 300 mg as a single dose 2 weeks later, then 600 mg every 6 months » Ocrelizumab, approved by the US Food and Drug Administration (FDA) for the treatment of primary progressive MS, was associated with lower rates of clinical and magnetic resonance imaging (MRI) progression than placebo in a phase 3 trial of patients with primary progressive MS.[102] However, ocrelizumab has not been studied in patients older than 55 years of age or in those with severe disability (expanded disability status scale >6.5). Thus, in Europe, it is approved for early-stage primary progressive MS only.[127] » Other medications that have been used include cyclophosphamide, methotrexate, and azathioprine, but there is no consensus regarding the benefits in primary progressive M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 51 Multiple sclerosis Management M A N A G E M E N T Ongoing MS. These medications may be used in locations where ocrelizumab is not available. with fatigue plus lifestyle modification ± pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » amantadine: 100 mg orally in the morning and 100 mg in the afternoon no later than 2-3 pm OR » modafinil: 100-200 mg orally in the morning, repeat when required in the afternoon OR » armodafinil: 150-250 mg orally in the morning » Most patients with MS benefit from regular exercise programmes.[129] [130] Good sleep hygiene practices should be encouraged. » If the patient continues to report fatigue after non-pharmacological approaches, amantadine, modafinil, or armodafinil can be trialled.[135] [136] with urinary frequency plus lifestyle modification ± pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » oxybutynin: 5 mg orally (immediate-release) two to three times daily OR » tolterodine: 1-2 mg orally (immediaterelease) twice daily; 2-4 mg (extendedrelease) once daily OR » solifenacin: 5-10 mg orally once daily OR » darifenacin: 7.5 to 15 mg orally (extendedrelease) once daily OR 52 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing » fesoterodine: 4-8 mg orally (extendedrelease) once daily OR » botulinum toxin type A: consult specialist for guidance on dose » Caffeine and 'vitamin waters' should be avoided. » Presence of urinary tract infection should be excluded. » Full assessment by a urologist may be required and urinary retention excluded. » Oxybutynin and other agents such as solifenacin, darifenacin, fesoterodine, and tolterodine may be used for symptoms of urinary frequency if retention is not present. » Botulinum toxin injections and intermittent selfcatheterisation are additional treatment options. with sensory symptoms (pain and paresthaesia) adjunct low-dose anticonvulsant or antidepressant Treatment recommended for SOME patients in selected patient group Primary options » gabapentin: 100 mg orally once daily at bedtime initially, increase by 100 mg/day increments to 300 mg once daily at bedtime; or 100-300 mg three times daily OR » pregabalin: 150 mg/day orally given in 3 divided doses initially, increase after 2-3 days to 300 mg/day given in 3 divided doses OR » carbamazepine: 200-400 mg orally twice daily OR » oxcarbazepine: 150-300 mg orally twice daily OR M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 53 Multiple sclerosis Management M A N A G E M E N T Ongoing » duloxetine: 60 mg orally once daily OR » amitriptyline: 25-100 mg orally once daily » These symptoms do not always require treatment. However, if they are bothersome to the patient or interfere with functioning, low-dose anticonvulsants and antidepressants can be used. » Various types of pain can occur in patients with MS: trigeminal neuralgia, painful dysaesthesias, painful tonic spasms and other spasticityrelated pain, and musculoskeletal pain. Central or neuropathic pain can be treated with anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine, oxcarbazepine) and antidepressants (e.g., duloxetine, amitriptyline).[146] with increased muscle tone (with or without spasms) plus physiotherapy ± antispasticity pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » baclofen: 5 mg orally three times daily initially, increase by 5 mg/dose increments every 3 days, maximum 80 mg/day OR » tizanidine: 2-4 mg orally three times daily OR » clonazepam: 0.5 to 1 mg orally once daily at bedtime OR » gabapentin: 100 mg orally once daily at bedtime initially, increase by 100 mg/day increments to 300 mg once daily at bedtime; or 100-300 mg three times daily OR » botulinum toxin type A: consult specialist for guidance on dose Secondary options 54 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Ongoing » baclofen intrathecal: consult specialist for guidance on dose Tertiary options » delta-9-tetrahydrocannabinol/cannabidiol: (2.7 mg/2.5 mg oromucosal spray) consult specialist for guidance on buccal dose » The first line of therapy is gentle stretching exercises, which are best provided by a physiotherapist. » Side effects of baclofen include fatigue, clouding of mental functioning, and unmasking of underlying muscle weakness, resulting in patients reporting increased weakness. » Tizanidine is more sedating than baclofen. It should not be used with ciprofloxacin, which potentiates its action. » The treatment of spasticity with botulinum toxin must weigh the balance of the potential symptom benefit with possible decrease in functional strength.[149] [150] [151] » Cannabinoids may be effective for treating symptoms of spasticity in MS.[152] [153] [154] [155] The College of Family Physicians of Canada recommends that clinicians may consider medical cannabinoids for refractory spasticity in MS, and specifies delta-9- tetrahydrocannabinol/cannabidiol oromucosal spray (also known as nabiximols) as the medical cannabinoid of choice.[156] The National Institute of Health and Care Excellence in England recommends a trial of delta-9- tetrahydrocannabinol/cannabidiol oromucosal spray to treat moderate to severe spasticity in adults with MS in whom other pharmacological treatments for spasticity are not effective.[157] with tremor plus pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » propranolol: 5 mg twice daily initially, increase by 5 mg/dose increments up to 20 mg twice daily OR » primidone: 50 mg once daily at bedtime initially, increase by 12.5 mg/day increments up to 50 mg three times daily M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 55 Multiple sclerosis Management M A N A G E M E N T Ongoing OR » clonazepam: 0.25 mg three times daily initially, increase by 0.25 mg/dose increments up to 1 mg three times daily » Care must be taken with each of the therapies. Propranolol may produce adverse effects of hypotension and depression. Primidone and clonazepam can be sedating and clonazepam can also be habit forming. » Medications are always started at a low dose, which can be increased according to the clinical response. with gait impairment plus physiotherapy ± fampridine Treatment recommended for ALL patients in selected patient group Primary options » fampridine: 10 mg orally every 12 hours » Various physiotherapy regimens improve gait and balance in patients with MS, particularly those with mild to moderate levels of disability.[131] [137] [138] [139] [140] » Fampridine can be used to improve gait endurance and may increase gait speed.[141] [143] » Clinical trials and post-marketing surveillance indicate a dose-related increased risk of seizures with fampridine.[142] Doses should be administered 12 hours apart. Patients must have normal creatinine levels and no history of seizures before starting fampridine.[143] Healthcare providers should monitor for seizures, and provide adequate patient education. Patients must have normal creatinine levels and no history of seizures before starting this medication. 56 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Management Emerging Ofatumumab In a phase 2b double-blind study of patients with relapsing-remitting MS, the anti-CD20 monoclonal antibody ofatumumab decreased the number of new magnetic resonance imaging (MRI) gadoliniumenhancing lesions 12 weeks after treatment initiation.[166] In two double-blind, double-dummy, phase 3 trials, ofatumumab was associated with lower annualised relapse rates than teriflunomide in patients with relapsing MS.[167] In August 2020, the US Food and Drug Administration (FDA) approved ofatumumab injection for the treatment of adults with relapsing forms of MS, including relapsing-remitting MS, active secondary progressive MS, and clinically isolated syndrome. Other sphingosine 1-phosphate (S1P) receptor modulators Ozanimod is approved by the FDA for adult patients with relapsing forms of MS, and by the European Medicines Agency (EMA) for treatment of adult patients with relapsing-remitting MS with active disease. One randomised, double-blind phase 3 trial reported that ozanimod was well tolerated, and associated with a significantly lower relapse rate compared with interferon beta-1a, in patients with relapsing MS treated for at least 12 months.[168] Ponesimod is approved by the FDA and the EMA to treat adults with relapsing forms of MS. One randomised, double-blind phase 3 study reported that ponesimod significantly reduced annual relapses compared with teriflunomide in patients with relapsing MS.[169] Other agents at different stages of development include ceralifimod, GSK2018682, and MT-1303.[85] [170] Stem cell therapy The premise of haematopoietic stem cell transplantation (HSCT) is that the dysregulated, autoreactive immune system of patients with MS could be eradicated and replaced by a new, tolerant one.[171] One meta-analysis concluded that autologous HSCT can induce long-term remission for patients with MS with a high degree of safety; greatest benefit was observed with low- and intermediate-intensity regimens, and for patients with relapsing-remitting MS with the presence of gadolinium-enhancing lesions at baseline MRI.[172] In a preliminary study in patients with relapsing-remitting MS, non-myeloablative HSCT resulted in prolonged time to disease progression compared with continued disease-modifying therapy.[173] The American Society for Blood and Marrow Transplantation recommends that treatment-refractory relapsing MS with high risk of future disability is considered as a 'standard of care, clinical evidence available' indication for autologous HSCT.[174] Other stem cell approaches under investigation include the use of mesenchymal stem cells, placental stem cells, and intrathecal administration.[175] [176] [177] Evobrutinib Evobrutinib is a selective oral inhibitor of Bruton's tyrosine kinase that blocks B-cell activation. One doubleblind, randomised, phase 2 trial reported that patients with relapsing MS who received evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 to 24 than those who received placebo. There were no significant differences in annualised relapse rate or disability progression.[178] Ibudilast Ibudilast inhibits some cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and Toll-like receptor 4, and can cross the blood–brain barrier. In a phase 2 trial involving patients with primary or secondary progressive MS, ibudilast was associated with slower progression of brain atrophy than placebo.[179] Adverse events reported in patients receiving ibudilast included gastrointestinal symptoms, headache, and depression. Alpha-lipoic acid In a single-centre, 2-year, double-blind, randomised trial, oral alpha-lipoic acid was associated with a 68% reduction in annualised percent change brain volume, with some suggestion of clinical benefit, in patients with secondary progressive MS. Safety, tolerability, and compliance were favourable.[180] M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 57 Multiple sclerosis Management M A N A G E M E N T Deep brain stimulation (DBS) DBS has been evaluated in MS patients with tremor. Results have been variable, and patients should be selected carefully for consideration of DBS.[181] [182] Dietary approaches The influence of modifiable lifestyle factors such as diet and exercise on the development and course of MS, and on the quality of life of people with MS, is increasingly recognised.[183] [184] Many patients with MS and those who care for them are interested in the effects of diet on MS activity and/or symptoms. Various dietary approaches such as paleolithic, gluten-free, Swank, Wahls, or the Mediterranean diet have been promoted for people with MS. There are currently no high-quality studies to provide sufficient evidence to recommend one approach over another. This is a key area of ongoing research.[185] [186] Primary prevention There are no clear strategies for primary prevention other than encouraging at-risk individuals not to smoke and possibly taking a multivitamin containing vitamin D.[37] Patient discussions Discuss the benefits and risks of disease-modifying therapies with the patient, and take their preferences into account when deciding on treatment. Ensure that this discussion continues throughout the disease course. The influence of modifiable lifestyle factors such as diet and exercise on the development and course of MS are increasingly recognised. Encourage patients to stay as active as possible with some form of regular exercise. Research on specific dietary interventions is ongoing. Generally, patients should be encouraged to follow a healthy diet with adequate fruits and vegetables. Offer patients regular follow-ups with primary care physicians as well as their neurologist; data indicate that the presence and worsening of such conditions as obesity, hypertension, diabetes mellitus, and high cholesterol are associated with increased disability in MS.[207] Patients who have been diagnosed with MS will find a great deal of information available to them, much of it conflicting and confusing. Useful information is available from the many worldwide MS societies and organisations. [Multiple Sclerosis International Federation] (https://www.msif.org) 58 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Follow up Monitoring Monitoring The frequency of monitoring for patients with MS depends on the status of the patient. Patients who are experiencing a relapse should be seen by their healthcare provider at the time of the relapse or soon after to determine if there is any need for acute management, and to assess the impact of the relapse on their choice of ongoing therapy. Most patients need to be seen only every 6 to 12 months if they are relatively stable and not requiring medication changes in either their symptomatic or disease-modifying therapy. Some practitioners obtain timed 25-foot walk (T25FW) and 9-hole peg tests as quantitative measures of functioning that allows for comparison from visit to visit.[202] The minimally important clinical difference for improvements in the T25FW test is estimated to be 20% for patients with MS.[203] MS-specific patient-reported outcomes Patient-reported outcomes (PRO) specific to MS have been identified. The evaluation of more than 80 PRO tools specific for MS supports the use of the Multiple Sclerosis Impact Scale (MSIS-29; measures the physical and psychological impact of MS) and the Leeds Multiple Sclerosis Quality of Life scale (LMSQOL). However, one systematic review concluded that new MS instruments specific to primary progressive MS and secondary progressive MS populations are needed.[204] Ongoing laboratory evaluation Patients with MS have a higher incidence of diabetes and of vitamin B12, vitamin D, and thyroid deficiencies than the general population, and should have appropriate blood work performed to screen for those conditions on occasion, particularly in patients with fatigue. The need for further monitoring blood work depends on the disease-modifying agent used. No monitoring is required for glatiramer. Patients on interferons, fingolimod, and natalizumab should have full blood count and liver function tests checked every 3 to 6 months. John Cunningham virus (JCV) antibody titre testing should also be undertaken at baseline for patients on natalizumab. Expert panel recommendations regarding the stratification and ongoing monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk have been published.[99] Immunosuppressive agents such as methotrexate and azathioprine require frequent monitoring of liver function and blood counts. For patients on fingolimod, monitoring should include repeat ophthalmological examination 3 to 4 months after initiating treatment. Patients should also be monitored closely for evidence of exacerbation of MS after stopping fingolimod treatment.[92] Alemtuzumab requires monthly blood and urine monitoring for 48 months after the last infusion through a stringent risk evaluation and mitigation strategy. The clinical and radiographical impact of neutralising antibodies to interferon beta-1b is still unclear.[205] Magnetic resonance imaging (MRI) surveillance An MRI brain should be obtained 3 to 6 months after initiation or switching of disease-modifying therapy; a longer interval may be considered for patients treated with slow-acting disease-modifying therapy. The same protocol should be used as for the baseline MRI.[3] An annual MRI is recommended in clinically stable patients to monitor for new disease activity; imaging should be performed more frequently if there are concerns.[206] [3] F O L L O W U P This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 59 Multiple sclerosis Follow up F O L L O W U P MRI is also used to monitor for complications of treatment, such as progressive multifocal leukoencephalopathy.[3] Spinal imaging for monitoring should be considered in patients with a spinal cord phenotype (few brain lesions), repeated spinal cord relapse, or progressive disability that cannot be explained by MRI brain findings.[3] Spinal cord MRI is not recommended for routine follow-up monitoring of disease activity in other patients with MS. The need for MRI for monitoring during pregnancy should be assessed on a case-by-case basis; e.g., it may be appropriate for a patient with unexpected disease activity. Gadolinium-based contrast agents are contraindicated during pregnancy.[3] 60 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Follow up Complications Complications Timeframe Likelihood urinary tract infections variable high Patients with urinary tract infections may present only with neurological worsening. Therefore, the threshold for screening for urinary tract infection should be low. Urinary tract infections should be treated appropriately and preventive measures considered, such as increased hydration, control of constipation, and prophylactic antibiotics. osteopenia and osteoporosis variable high Multifactorial causes include inactivity, smoking, low intake of calcium and vitamin D, and use of corticosteroids. There may also be an underlying process in the pathophysiology of MS that increases the likelihood of osteopenia and osteoporosis. Patients should be screened for osteoporosis and treated appropriately. Prophylaxis with calcium and vitamin D should be considered in all patients. depression variable high Multifactorial causes such as sleep disturbance and situational response. The incidence of depression is quite high in MS and may cause difficulty with sleep as well as exacerbating fatigue. Treatment of MS-related depression is similar to that for other types of depression, including pharmacotherapy and psychological therapy, although further research on the management of depression in MS is needed.[192] A proprietary formulation containing a mixture of dextromethorphan and quinidine can be used for pseudobulbar affect. It may also be used as an adjunct treatment for depression in patients with MS. The evidence for improvement in quality of life and functional and cognitive outcomes is inconclusive.[193] Exercise has been reported to significantly improve depressive symptoms among people with MS, with a greater effect noted when exercise reduced fatigue.[194] Consultation with a mental healthcare provider may be helpful. visual impairment variable high Visual complications of MS are protean and are a primary manifestation of the disease. Disease-modifying therapy is directed at preventing recurrence or occurrence of these manifestations, which include optic neuritis, intranuclear ophthalmoplegia, nystagmus, and diplopia caused by various types of extra-ocular movement abnormalities. Patients should be seen by an experienced ophthalmologist, preferably a neuro-ophthalmologist, to make sure that symptoms are truly MS related, and not related to difficulties from medications (e.g., cystic macular oedema caused by fingolimod, corneal difficulties caused by amantadine, or glaucoma or F O L L O W U P This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 61 Multiple sclerosis Follow up F O L L O W U P Complications Timeframe Likelihood cataract formation as a result of corticosteroid use). Most ocular manifestations of MS do not have specific treatments apart from primary prevention of the disease, although some clinicians use gabapentin to reduce motility disturbance from nystagmus. erectile dysfunction (ED) variable high Common in MS. ED is characterised by the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. The exact cause of ED after MS is still unclear. Sildenafil citrate is an effective treatment for ED, but there is limited evidence to support its use in patients with MS.[201] cognitive impairment variable medium Cognitive training and psychological interventions may offer some benefit, particularly regarding quality of life outcomes; however, the evidence for these interventions is inconclusive.[46] [48] [195] Low-certainty evidence suggests that memory rehabilitation may be effective in improving memory function in patients with MS.[196] [197] Some patients will benefit from improving sleep and/or increasing their level of general physical activity.[198] [199] Treatment of depression may also be of benefit. Although full cognitive assessment is costly and resource intensive, a brief cognitive assessment (involving the Symbol Digit Modalities Test and California Verbal Learning Test) has been recommended for MS.[200] impaired mobility variable medium Disease-modifying therapy is directed at preventing progression, with variable effectiveness. Patients should be seen by an experienced physiotherapist who can assist with the prescription of appropriate devices including ankle foot orthosis (AFO) and 4-wheeled walkers with hand brakes, which are preferred for patients with MS due to stability issues. Progressive resistance training (PRT) is a rehabilitation tool that has been shown to improve muscle strength in patients with MS.[131] However, there is uncertainty as to whether it can improve functional capacity. Prognosis It is very difficult to prognosticate effectively for patients with MS. Some patients have a very benign course and/or respond well to treatment, whereas others become rapidly disabled within several years of diagnosis. One long-term follow-up study of a pivotal interferon beta-1b trial in patients with MS suggested that longterm physical and cognitive outcomes may be largely determined early in the disease course.[187] Various factors favouring better prognosis have been reported in demographic studies conducted in the pretreatment era, and include include female sex, sensory symptoms, or optic neuritis at onset.[188] Poorer prognostic factors include frequent relapses and motor or cerebellar onset.[189] [190] Magnetic resonance imaging (MRI) is a useful tool to assist in prognosis; e.g., to predict MS development, disability, and disability progression.[3] Higher MRI lesion burden at onset may portend a poorer prognosis, particularly for cognitive outcomes.[187] [191] 62 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Guidelines Diagnostic guidelines Europe Use of imaging in multiple sclerosis (https://www.ean.org/research/eanguidelines/guideline-reference-center) Published by: European Academy of Neurology (European Federation of Neurological Societies) Last published: 2011 International Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria (https://www.sciencedirect.com/science/article/pii/S1474442217304702?via %3Dihub) Published by: International Panel on Diagnosis of MS Last published: 2018 International validation protocol: recommendations for a brief international cognitive assessment for multiple sclerosis (BICAMS) (https:// www.bicams.net/scientific-background/publications.aspx) Published by: BICAMS Committee Last published: 2012 North America Consensus recommendations on the use of MRI in patients with multiple sclerosis (https://www.thelancet.com/journals/laneur/article/ PIIS1474-4422(21)00095-8/fulltext) Published by: Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS); Consortium of Multiple Sclerosis Centres (CMSC); North American Imaging in Multiple Sclerosis Cooperative (NAIMS) Last published: 2021 G UID E LIN E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 63 Multiple sclerosis Guidelines G UID E LIN E S Treatment guidelines United Kingdom Cannabis-based medicinal products (https://www.nice.org.uk/guidance/ ng144) Published by: National Institute for Health and Care Excellence (UK) Last published: 2021 Neuropathic pain in adults: pharmacological management in non-specialist settings (https://www.nice.org.uk/guidance/cg173) Published by: National Institute for Health and Care Excellence Last published: 2020 Multiple sclerosis in adults: management (https://www.nice.org.uk/guidance/ cg186) Published by: National Institute for Health and Care Excellence Last published: 2019 Cladribine tablets for treating relapsing-remitting multiple sclerosis (https:// www.nice.org.uk/guidance/ta493) Published by: National Institute for Health and Care Excellence Last published: 2017 Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis (https://pn.bmj.com/ content/15/4/273) Published by: Association of British Neurologists Last published: 2015 Europe ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis (https://www.ectrims.eu/guidelines) Published by: European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)/European Academy of Neurology (EAN) Last published: 2018 EFNS guideline on the use of anti-interferon beta antibody measurements in multiple sclerosis (https://www.ean.org/research/ean-guidelines/guidelinereference-center) Published by: European Academy of Neurology Last published: 2011 International International consensus on quality standards for brain healthfocused care in multiple sclerosis (https://journals.sagepub.com/ doi/10.1177/1352458518809326) Published by: Multiple Sclerosis Journal Last published: 2018 64 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Guidelines North America Consensus recommendations on the use of MRI in patients with multiple sclerosis (https://www.thelancet.com/journals/laneur/article/ PIIS1474-4422(21)00095-8/fulltext) Published by: Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS); Consortium of Multiple Sclerosis Centres (CMSC); North American Imaging in Multiple Sclerosis Cooperative (NAIMS) Last published: 2021 The use of disease-modifying therapies in multiple sclerosis: principles and current evidence (https://ms-coalition.org/resources) Published by: MS Coalition Last published: 2019 Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis (https://www.aan.com/Guidelines/Home/ ByTopic?topicId=18) Published by: American Academy of Neurology Last published: 2018 Clinical practice guideline: multiple sclerosis and management of urinary tract infection (https://actt.albertadoctors.org/CPGs/Pages/Multiple-Sclerosisand-Urinary-Tract-Infection.aspx) Published by: Toward Optimized Practice, Alberta Last published: 2017 Evidence-based guideline: assessment and management of psychiatric disorders in individuals with multiple sclerosis (https://www.aan.com/ Guidelines/Home/ByTopic?topicId=18) Published by: American Academy of Neurology Last published: 2014 (reaffirmed 2016) Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis (https://www.aan.com/Guidelines/Home/ ByTopic?topicId=18) Published by: American Academy of Neurology Last published: 2014 (reaffirmed 2020) G UID E LIN E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 65 Multiple sclerosis Online resources O N LIN E R E S O U R C E S Online resources 1. BMJ talk medicine: multiple sclerosis (https://soundcloud.com/bmjpodcasts/multiple-sclerosis? in=bmjpodcasts/sets/bmj-best-practice-clinical) (external link) 2. Multiple Sclerosis International Federation (https://www.msif.org) (external link) 66 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Evidence tables Evidence tables How does interferon beta compare with glatiramer in people with relapsing‐ remitting multiple sclerosis? This table is a summary of the analysis reported in a Cochrane Clinical Answer that focuses on the above important clinical question. View the full source Cochrane Clinical Answer (https://www.cochranelibrary.com/cca/ doi/10.1002/cca.1612/full) Evidence B * Confidence in the evidence is moderate or low to moderate where GRADE has been performed and there may be no difference in effectiveness between the intervention and comparison for key outcomes. Population: Adults with relapsing‐remitting multiple sclerosis Intervention: Interferon beta (1a or 1b) Comparison: Glatiramer Outcome Effectiveness (BMJ rating) † Confidence in evidence (GRADE) ‡ Number of participants with relapse: at 24 months ᵃ No statistically significant difference Moderate Number of participants with confirmed progression: at 24 months ᵃ No statistically significant difference Moderate Withdrawal due to adverse events (follow‐up 24 months) No statistically significant difference Low Withdrawal due to serious adverse events No statistically significant difference GRADE assessment not performed for this outcome Relapse frequency: at 24 months No statistically significant difference GRADE assessment not performed for this outcome Relapse frequency: at 36 months Favours comparison GRADE assessment not performed for this outcome Mean number of active (new or enlarged) T2‐hyperintense lesions: at 24 months ᵇ ᶜ No statistically significant difference Low E VID E N C E TA B L E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 67 Multiple sclerosis Evidence tables E VID E N C E TA B L E S Outcome Effectiveness (BMJ rating) † Confidence in evidence (GRADE) ‡ Mean change in total T2‐ hyperintense lesion load: at 24 months ᶜ ᵈ Favours intervention Moderate Quality of life - None of the studies identified by the review assessed this outcome Note ᵃ There was also no statistically significant difference between treatment groups for this outcome at 36 months (GRADE assessment not performed). ᵇ There was a statistically significant difference favouring interferon beta at 6 months, but no statistically significant difference between treatment groups at 12 months. A GRADE assessment was not performed for these subgroups. ᶜ The Cochrane review which underpins this Cochrane Clinical Answer found similar results for T1 lesions. See the Cochrane systematic review for more details. ᵈ There was a statistically significant difference favouring interferon beta at 12 months, but no statistically significant difference between treatment groups at 36 months. A GRADE assessment was not performed for these subgroups. * Evidence levels The Evidence level is an internal rating applied by BMJ Best Practice. See the EBM Toolkit (https:// bestpractice.bmj.com/info/evidence-tables/) for details. Confidence in evidence A - High or moderate to high B - Moderate or low to moderate C - Very low or low † Effectiveness (BMJ rating) Based on statistical significance, which demonstrates that the results are unlikely to be due to chance, but which does not necessarily translate to a clinical significance. 68 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Evidence tables ‡ Grade certainty ratings High The authors are very confident that the true effect is similar to the estimated effect. Moderate The authors are moderately confident that the true effect is likely to be close to the estimated effect. Low The authors have limited confidence in the effect estimate and the true effect may be substantially different. Very Low The authors have very little confidence in the effect estimate and the true effect is likely to be substantially different. BMJ Best Practice EBM Toolkit: What is GRADE? (https://bestpractice.bmj.com/info/toolkit/learn-ebm/whatis-grade/) E VID E N C E TA B L E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 69 Multiple sclerosis References R E F E R E N C E S Key articles • Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86. Full text (https://n.neurology.org/ content/83/3/278.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/24871874? tool=bestpractice.bmj.com) • Wattjes MP, Ciccarelli O, Reich DS, et al. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 2021 Aug;20(8):653-670. Full text (https://www.doi.org/10.1016/S1474-4422(21)00095-8) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/34139157?tool=bestpractice.bmj.com) • Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-73. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29275977?tool=bestpractice.bmj.com) • Kantarci O, Wingerchuk D. Epidemiology and natural history of multiple sclerosis: new insights. Curr Opin Neurol. 2006 Jun;19(3):248-54. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16702830? tool=bestpractice.bmj.com) • Tramacere I, Del Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015 Sep 18;(9):CD011381. Full text (https://www.cochranelibrary.com/cdsr/ doi/10.1002/14651858.CD011381.pub2/full) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/26384035?tool=bestpractice.bmj.com) • Scolding N, Barnes D, Cader S, et al. Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. Pract Neurol. 2015 Aug;15(4):273-9. Full text (https://pn.bmj.com/content/15/4/273.long) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/26101071?tool=bestpractice.bmj.com) References 1. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005 Dec;58(6):840-6. Full text (https://onlinelibrary.wiley.com/ doi/full/10.1002/ana.20703) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16283615? tool=bestpractice.bmj.com) 2. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86. Full text (https://n.neurology.org/ content/83/3/278.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/24871874? tool=bestpractice.bmj.com) 3. Wattjes MP, Ciccarelli O, Reich DS, et al. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 2021 70 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis References Aug;20(8):653-670. Full text (https://www.doi.org/10.1016/S1474-4422(21)00095-8) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/34139157?tool=bestpractice.bmj.com) 4. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-73. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29275977?tool=bestpractice.bmj.com) 5. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177-89. Full text (https:// n.neurology.org/content/85/2/177.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/26092914? tool=bestpractice.bmj.com) 6. Wingerchuk DM. Immune-mediated myelopathies. Continuum (Minneap Minn). 2018 Apr;24(2, Spinal Cord Disorders):497-522. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29613897? tool=bestpractice.bmj.com) 7. Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011 Jan 18;76(3):294-300. Full text (https:// n.neurology.org/content/76/3/294.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21242498? tool=bestpractice.bmj.com) 8. Sechi E, Shosha E, Williams JP, et al. Aquaporin-4 and MOG autoantibody discovery in idiopathic transverse myelitis epidemiology. Neurology. 2019 Jul 23;93(4):e414-20. Full text (https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC7508328) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/31235660?tool=bestpractice.bmj.com) 9. Salama S, Pardo S, Levy M. Clinical characteristics of myelin oligodendrocyte glycoprotein antibody neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2019 May;30:231-5. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467709) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/30825703?tool=bestpractice.bmj.com) 10. Wingerchuk DM, Lucchinetti CF. Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol. 2007 Jun;20(3):343-50. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17495631? tool=bestpractice.bmj.com) 11. GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 Mar;18(3):269-85. Full text (https://www.thelancet.com/journals/laneur/article/ PIIS1474-4422(18)30443-5/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30679040? tool=bestpractice.bmj.com) 12. Wallin MT, Culpepper WJ, Campbell JD, et al. The prevalence of MS in the United States: a population-based estimate using health claims data. Neurology. 2019 Mar 5;92(10):e1029-40. Full text (https://n.neurology.org/content/92/10/e1029.long) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/30770430?tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 71 Multiple sclerosis References R E F E R E N C E S 13. Orton SM, Herrera BM, Yee IM, et al. Canadian Collaborative Study Group. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006 Nov;5(11):932-6. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/17052660?tool=bestpractice.bmj.com) 14. Giovannoni G, Ebers G. Multiple sclerosis: the environment and causation. Curr Opin Neurol. 2007 Jun;20(3):261-8. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17495618?tool=bestpractice.bmj.com) 15. Marrie RA, Cutter G, Tyry T, et al. Does multiple sclerosis-associated disability differ between races? Neurology. 2006 Apr 25;66(8):1235-40. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16636241? tool=bestpractice.bmj.com) 16. De Angelis F, John NA, Brownlee WJ. Disease-modifying therapies for multiple sclerosis. BMJ. 2018 Nov 27;363:k4674. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30482751? tool=bestpractice.bmj.com) 17. Calabrese M, Filippi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol. 2010 Aug;6(8):438-44. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20625376?tool=bestpractice.bmj.com) 18. Kantarci O, Wingerchuk D. Epidemiology and natural history of multiple sclerosis: new insights. Curr Opin Neurol. 2006 Jun;19(3):248-54. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16702830? tool=bestpractice.bmj.com) 19. Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17. Full text (https://core.ac.uk/reader/38368654?utm_source=linkout) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/18970977?tool=bestpractice.bmj.com) 20. Compston A, Coles A. Multiple sclerosis. Lancet. 2002 Apr 6;359(9313):1221-31. [Erratum in: Lancet. 2002 Aug 24;360(9333):648.] Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11955556? tool=bestpractice.bmj.com) 21. Harirchian MH, Fatehi F, Sarraf P, et al. Worldwide prevalence of familial multiple sclerosis: a systematic review and meta-analysis. Mult Scler Relat Disord. 2018 Feb;20:43-7. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/29291483?tool=bestpractice.bmj.com) 22. Yeo TW, De Jager PL, Gregory SG, et al. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol. 2007 Mar;61(3):228-36. 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Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17560172?tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 73 Multiple sclerosis References R E F E R E N C E S 36. Rasul T, Frederiksen JL. Link between overweight/obese in children and youngsters and occurrence of multiple sclerosis. J Neurol. 2018 Dec;265(12):2755-63. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29700643?tool=bestpractice.bmj.com) 37. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1678-88S. 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BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis References 47. Sesel AL, Sharpe L, Naismith SL. Efficacy of psychosocial interventions for people with multiple sclerosis: a meta-analysis of specific treatment effects. Psychother Psychosom. 2018;87(2):105-11. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29518781?tool=bestpractice.bmj.com) 48. Rosti-Otajärvi EM, Hämäläinen PI. Neuropsychological rehabilitation for multiple sclerosis. Cochrane Database Syst Rev. 2014 Feb 11;(2):CD009131. Full text (https://www.cochranelibrary.com/ cdsr/doi/10.1002/14651858.CD009131.pub3/full) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/24515630?tool=bestpractice.bmj.com) 49. Amatya B, Khan F, Galea M. 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Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1819-28. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/23122652? tool=bestpractice.bmj.com) 80 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis References 111. Zhang J, Shi S, Zhang Y, et al. Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev. 2017 Nov 27;(11):CD010968. 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Cochrane Database Syst Rev. 2012 Jan 18;(1):CD005181. Full text R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 81 Multiple sclerosis References R E F E R E N C E S (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005181.pub3/full) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/22258960?tool=bestpractice.bmj.com) 122. La Mantia L, Vacchi L, Rovaris M, et al. Interferon beta for secondary progressive multiple sclerosis: a systematic review. J Neurol Neurosurg Psychiatry. 2013 Apr;84(4):420-6. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/22952326?tool=bestpractice.bmj.com) 123. Kapoor R, Ho PR, Campbell N, et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018 May;17(5):405-15. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/29545067?tool=bestpractice.bmj.com) 124. Wundes A, Kraft GH, Bowen JD, et al. Mitoxantrone for worsening multiple sclerosis: tolerability, toxicity, adherence and efficacy in the clinical setting. Clin Neurol Neurosurg. 2010 Dec;112(10):876-82. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20727669? tool=bestpractice.bmj.com) 125. Martinelli Boneschi F, Vacchi L, Rovaris M, et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013 May 31;(5):CD002127. Full text (https://www.cochranelibrary.com/ cdsr/doi/10.1002/14651858.CD002127.pub3/full) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/23728638?tool=bestpractice.bmj.com) 126. Cohen JA, Confavreux C. Combination therapy in multiple sclerosis. 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Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. Arch Phys Med Rehabil. 2013 Sep;94(9):1800-28.e3. Full text (https:// www.archives-pmr.org/article/S0003-9993(13)00361-4/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/23669008?tool=bestpractice.bmj.com) 131. Kjølhede T, Vissing K, Dalgas U. Multiple sclerosis and progressive resistance training: a systematic review. Mult Scler. 2012 Sep;18(9):1215-28. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/22760230? tool=bestpractice.bmj.com) 82 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. 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BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis References 195. Dardiotis E, Nousia A, Siokas V, et al. Efficacy of computer-based cognitive training in neuropsychological performance of patients with multiple sclerosis: a systematic review and metaanalysis. Mult Scler Relat Disord. 2018 Feb;20:58-66. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29306740?tool=bestpractice.bmj.com) 196. Chiaravalloti ND, Moore NB, Nikelshpur OM, et al. An RCT to treat learning impairment in multiple sclerosis: The MEMREHAB trial. Neurology. 2013 Dec 10;81(24):2066-72. Full text (https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3863346) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/24212393?tool=bestpractice.bmj.com) 197. das Nair R, Martin KJ, Lincoln NB, et al. 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All rights reserved. 89 Multiple sclerosis References R E F E R E N C E S 27;68(13):977-84. Full text (http://n.neurology.org/content/68/13/977.full) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/17389300?tool=bestpractice.bmj.com) 206. Bermel RA, Naismith RT. Using MRI to make informed clinical decisions in multiple sclerosis care. Curr Opin Neurol. 2015 Jun;28(3):244-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/25887772? tool=bestpractice.bmj.com) 207. Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat Rev Neurol. 2017 Jun;13(6):375-82. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28303911? tool=bestpractice.bmj.com) 90 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Images Images Figure 1: Cervical spine magnetic resonance imaging scan illustrating neuromyelitis optica spectrum disorder. Extensive multiple levels of cervical spinal cord involvement with oedema and blood-brain barrier breakdown as illustrated by the contrast-enhanced T1-weighted image (left). The T2-weighted image (right) indicates the extent of signal abnormality that may manifest clinically as quadriparesis with severe spasticity and pain From the collection of Dr Lael A. Stone IM A G E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 91 Multiple sclerosis Images IM A G E S Figure 2: Representative axial magnetic resonance images using fluid-attenuated inversion recovery (FLAIR) showing typical lesions seen in MS in the periventricular regions. Comparable slices using the contrast agent gadolinium illustrate blood-brain barrier breakdown/active inflammation in 2 of the lesions. The FLAIR lesions that do not enhance are likely to be older, with a combination of gliosis and low-level chronic inflammation and degeneration From the collection of Dr Lael A. Stone 92 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Images Figure 3: Sagittal fluid-attenuated inversion recovery (FLAIR) images with typical MS lesions involve the corpus callosum either as discrete lesions or as finger-like projections perpendicular to the corpus callosum. Note also the enlargement of the ventricles and diffuse atrophy of more advanced MS From the collection of Dr Lael A. Stone IM A G E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 93 Multiple sclerosis Images IM A G E S Figure 4: Magnetic resonance imaging scan of the cervical spine at high (≥1 Tesla) magnetic field strength illustrating a lesion that may cause myelopathic symptoms of bowel and bladder dysfunction as well as spastic paraparesis From the collection of Dr Lael A. Stone 94 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Multiple sclerosis Disclaimer Disclaimer BMJ Best Practice is intended for licensed medical professionals. BMJ Publishing Group Ltd (BMJ) does not advocate or endorse the use of any drug or therapy contained within this publication nor does it diagnose patients. 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Contact us + 44 (0) 207 111 1105 support@bmj.com BMJ BMA House Tavistock Square London WC1H 9JR UK 96 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 05, 2021. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Contributors: // Authors: Mary Alissa Willis, MD Associate Professor and Chair Department of Neurology, University of Mississippi Medical Center, Jackson, MS DISCLOSURES: MAW has received payment for participating on the speakers' bureaus of Biogen, Genzyme, Novartis, and Genentech for speaking about multiple sclerosis. MAW also serves on the editorial board for the International Journal of MS Care. // Acknowledgements: Dr Mary Alissa Willis would like to gratefully acknowledge Dr Lael A. Stone, a previous contributor to this topic. We have since been made aware that Dr Stone is deceased. // Peer Reviewers: Alex Rae-Grant, MD Project Leader for Neurology Neurological Institute, Cleveland Clinic, Cleveland, OH DISCLOSURES: ARG declares that he has no competing interests. Sarah A. Morrow, MD, FRCPC, MS Associate Professor of Neurology Department of Clinical Neurological Sciences, London Health Sciences Centre, University Hospital, Ontario, Canada DISCLOSURES: SAM declares that she has no competing interests. Marcelo Kremenchutzky, MD Director The London Multiple Sclerosis Clinic, Associate Professor, Schulich School of Medicine, University of Western Ontario, Neurologist, Clinical Neurological Sciences Department, University Hospital, London Health Sciences Centre, Ontario, Canada DISCLOSURES: MK declares that he has no competing interests. Abhijit Chaudhuri, DM, MD, PhD, FACP, FRCPGlasg, FRCPLond Consultant Neurologist Department of Neurology, Queen’s Hospital, Romford, UK DISCLOSURES: AC declares that he has no competing interests.