Multiple sclerosis. c It is seen less frequently in Asians, except offspring of migrants who have settled in the West.

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1 THE BARE ESSENTIALS Multiple slerosis Alasdair Coles Correspondene to: Dr A Coles, Senior Leturer in Neuroimmunology, University of Cambridge, Department of Neurology, Box 165, Addenbrooke s Hospital, Cambridge CB2 0QQ, UK; aj1020@medshl.am.a.uk Multiple slerosis (MS) is aused by inflammatory demyelination and axonal loss in the entral nervous system (CNS) (brain and spinal ord). The key harateristis of the sarring ( slerosis ) and its linial sequelae are dissemination in spae, affeting different anatomial sites, and dissemination in time, appearing episodially over time. EPIDEMIOLOGY Prevalene and inidene In the UK, the prevalene is about 120/ population and the annual inidene is 7/ population. This means the average general pratitioner may never be involved in the diagnosis of MS in their areer but will have 2 4 MS patients on their list, of whih 1 3 will be signifiantly disabled. Depending on how are is organised, up to 20% of a neurologist s general follow-up lini may be made up of people with MS. Gender, age and rae A typial patient, at the time of diagnosis, is a white woman in her 20s. Multiple slerosis is three times more ommon in women than men, a ratio that has inreased over the last entury for unknown reasons. It usually starts in young adults onset before puberty or after the age of 50 is rare. The disease is most ommon in White populations, espeially in Northern ountries. It is seen less frequently in Asians, exept offspring of migrants who have settled in the West. It is oasionally enountered in the British Afro-Caribbean. It is very rare among the indigenous peoples of Afria and Australasia. THE PHASES OF MULTIPLE SCLEROSIS The natural history of three types of MS is shown in fig 1. Relapse is a linially evident attak of demyelination, haraterised by gradual onset of symptoms over days, stabilising over days or weeks, and then gradually resolving, ompletely or partially. Different symptoms of a relapse may appear at different times: by onvention, any appearing within 30 days of the first symptom are said to be part of the same relapse. Stritly speaking, the first episode of demyelination annot be alled a relapse, but is termed an episode. 80% of ases start in this way. The risk of a relapse is doubled after viral infetion or major life events. Clinially isolated syndrome of demyelination is a single linially evident episode of demyelination in the brain or spinal ord without any preeding episodes. This is not (yet) MS beause there has not yet been multiple attaks to give dissemination in time or spae. Conversion from linially isolated syndrome to relapsing-remitting multiple slerosis. Over time, most people with a linially isolated syndrome have a subsequent relapse, so fulfilling the linial riteria for relapsing-remitting MS (see below). The presenting brain MR san helps to prognostiate: if it shows any whitematter lesions, the hane of a relapse is 50% over the subsequent 2 years, inreasing to 80% at 20 years (whih means of ourse that onversely 20% of patients with abnormal sans will not go on to develop MS). If the presenting san is normal, the risk of a relapse over the next 20 years is only 20%. Relapsing-remitting MS is defined as more than one linial attak of demyelination, that is an initial episode followed by at least one relapse, separated by period(s) of omplete or partial reovery, termed remission(s). The initial relapse rate is usually less than 1/year, and subsequently delines. With time, reovery from eah episode is inomplete and fixed disability aumulates. Some 10% of all patients have benign MS, whih is haraterised by lak of signifiant disability even after 20 years of linially evident disease. This is by definition a retrospetive diagnosis and of questionable value as many suh patients do subsequently develop disability. Conversion from relapsing-remitting to seondary progressive MS. The risk of entering the progressive phase inreases with linially evident disease duration (25% at 10 years from onset, 50% within 20 years and 75% after 35 years). It usually starts at around 40 years of age. Seondary progressive MS. Symptoms are ontinuous and gradually worsen, without remission. Superimposed relapses may our, but at muh lower frequeny than in the relapsingremitting phase. In pratie, it is only really possible to diagnose the onset of seondary progression in retrospet and after at least 12 months of observation ;9: doi: /jnnp

2 Figure 1 The natural history of the three types of multiple slerosis. Horizontal axis is time passing, vertial axis is disability. Primary progressive MS. 20% people with MS experiene ontinuous worsening from disease onset with no preeding relapses, although relapses may subsequently our, at low frequeny. ( like hot water trikling down my fae ) rather than numbness or pins and needles. It is important to ask about past symptoms, espeially problems with vision, walking and balane. These may be perfetly straightforward examples of demyelination, whih were passed off as a virus or a mystery illness ( I lost vision in one eye when I was in my twenties I was paralysed for two weeks and then got better ). Alternatively, episodes may have been misdiagnosed as other medial onditions, eg labyrinthitis, repetitive strain injury, Bell s palsy, ystitis. Note urrent level of mobility; it is very hard to judge progression without some baseline statement about disability. Fatigue is the sense of overwhelming diffiulty of doing tasks (physial or ognitive) that are relatively easy at other times of day, or at first exeution. It is more drawn out than the fatigability of myasthenia and does not lead to sleepiness, but to exhaustion and the need for rest. It may our on its own (and ausations of making it up ) early in the disease ourse, or in ombination with other symptoms. Family history and any ontat with people affeted by MS is useful to know early on to help ounselling and antiipate expetations. In MS, there is a 20% hane another family member may be affeted; autosomal dominant or mitohondrial patterns of inheritane are red flags (see differential diagnosis). DIAGNOSING MS The traditional linial diagnosis of MS requires two or more episodes, at least 30 days apart, of symptoms attributable to demyelination at different sites in the CNS, ie dissemination in time and spae. The MDonald riteria (see box) endorse these riteria, but also allow information from MR sans to be inorporated into the diagnosis. These riteria are omplex and designed to standardise researh; their use in everyday linial pratie varies between ountries and entres. In a lassi study by MAlpine in 1972, initial symptoms of MS were weakness in one or more limbs in 35%, opti neuritis 20%, paraesthesiae 20%, diplopia 10%, and disturbane of miturition 5%. History Symptoms harateristi of demyelination are: Lhermitte s symptom ( an eletri shok/tingle runs down my bak/legs when I bend my head forward ), whih may also our with vitamin B12 defiieny, radiation myelopathy or rarely ervial ord ompression, and the Uhthoff phenomenon ( my symptoms reappear/worsen when I have been for a run/had a hot bath/ got ross ). When people with MS desribe their sensory symptoms they often use omplex imagery Examination The most ommon physial signs in unseleted groups of patients with MS are impaired visual auity (more ommon than impaired olour vision) and an extensor plantar response. Almost pathognomoni of MS are an internulear ophthalmologia or a relative afferent pupillary defet. It is very unusual to have had MS for a deade and no impairment of vibration sensation in the feet. A hard sensory level is rare; just like sensory symptoms, sensory signs are usually ompliated and diffiult to delineate (and often not worth bothering with in detail). Absent reflexes and wasting are red flags that the diagnosis of MS may be inorret (although a ord plaque at the dorsal root entry zone may abolish the root level reflex, and disuse atrophy may our in very disabled MS patients). Never hang a diagnosis on a pale dis, espeially temporal pallor whih is a partiularly soft sign. It is very unusual (1% ases) for people with MS to be registered partially sighted. However, women with Leber s hereditary opti neuropathy may develop an MS-like illness. 2009;9: doi: /jnnp

3 The MDonald riteria for diagnosing multiple slerosis The MDonald riteria endorse the linial diagnosis of MS (two or more episodes, at least 30 days apart, of symptoms attributable to demyelination at different sites in the CNS) but also allow the inorporation of MRI evidene into the riteria for dissemination in time and spae. Dissemination in time For those with a linially isolated syndrome of demyelination, MS may be diagnosed in the absene of further linial attaks if (i) an MR brain san, at least 3 months later, shows one or more gadoliniumenhaning lesions or (ii) two sans are done, the first at least 30 days after onset of the linial event and the seond at least 30 days again after that, and one or more new T2 lesions are found on the seond san. Dissemination in spae. If there have been several linial episodes at the same neurologial site, MRI lesions at other loations demonstrate dissemination in spae. The formal riteria, hard to remember and never used in routine pratie, are at least three features from: one gadolinium-enhaning lesion or nine T2 MRI brain lesions one or more infratentorial lesions one or more juxtaortial lesions three or more periventriular lesions (a spinal ord lesion an replae some of these brain lesions). Primary progressive MS may be diagnosed after 1 year of a progressive defiit and two of: plaques on a brain MR san; plaques on a spinal ord MR san; and unmathed CSF oligolonal bands. Opti neuritis First, patients experiene unpleasant gritty eye pain, espeially on eye movement. A day or two later they develop a entral smudge in the vision of one eye, whih progresses variably. The two key things to look for are a relative afferent pupillary defet at presentation, and lear reovery of vision. If there was no afferent pupillary defet, onsider oular auses of impaired vision (glauoma, retinal detahment and entral serous retinopathy). If visual auity remains unimproved or is worsening, then imaging (eg, CT orbits) for a ompressive opti neuropathy is mandatory, followed if normal by sreening for vasulitis (giant ell arteritis in the right age group), viral infetion and neuromyelitis optia. Bilateral opti neuritis or registered visual impairment are very rare in MS and raise other possibilities (see below). Paroxysmal symptoms The ommonest strutural ause of trigeminal neuralgia in young adults is MS. Other paroxysmal symptoms are muh rarer and are pathognomoni of MS: brief (seonds minutes) and very frequent (50 100/day) attaks of dysarthria/ataxia or unilateral dystonia, responding dramatially to arbamazepine. Rubral tremor Patients with advaned disability from MS often have signs of brainstem dysfuntion with a omplex ophthalmoplegia, ataxia, head titubation, dysarthria and a sinuous tremor of the outstrethed arm and hand. The useless hand (eponomously tagged the Oppenheim hand) is loss of proprioeption but not strength or utaneous sensation due to a plaque in the dorsal olumns. Cortial and ognitive syndromes Dementia, epilepsy and foal defiits suh as aphasia do our, but are suffiiently rare to mandate the searh for non-ms auses (see below). Investigations It is possible to diagnose MS without any investigations, but it would be unusual not to request MR imaging whih is useful in various ways: Brain MRI demonstrates the white matter plaques of MS; partiularly harateristi are lesions in the middle erebellar pedunle, oval plaques orientated perpendiular to the lateral ventriles, and mouse bites in the orpus allosum. A single san an demonstrate dissemination of lesions in spae. Serial MR sans an be used to show dissemination of lesions in time whih may substitute for linial episodes under the MDonald riteria (see box). A gadolinium enhaning lesion on MRI represents ative inflammation breaking down the blood-brain-barrier. A plaque is enhaning for about one month. Lesions of MS in the spinal ord are typially oval, less than three vertebral segments in length and affet only part of its axial rosssetion. The ord lesions of neuromyelitis optia (see below) usually streth for many vertebral segments and an affet the whole axial ross-setion. Over the age of 50, non-speifi white-matter lesions beome ommon on MR brain sans and must not be onfused with plaques. Spinal ord lesions retain their signifiane. Visual evoked potentials is the only test that demonstrates demyelination in the opti nerve in patients with no evidene of previous opti neuropathy; the finding of abnormally delayed potentials may demonstrate dissemination in spae. Cerebrospinal fluid (CSF) examination. Oligolonal immunoglobulin bands in the CSF, unmathed or in greater onentration than in serum, are found in 95% of people with MS. However, if the linial history and MR brain san are harateristi there is seldom any need for a lumbar punture. It may be useful when there is diagnosti unertainty suh as in primary progressive MS, or in patients over the age of 50 with ;9: doi: /jnnp

4 Table 1 The differential diagnosis of multiple slerosis Time ourse Clinial features Diagnosis Notes Monophasi illness Cerebrum, opti nerve, ord, meningism, fever + epilepsy, death possible Behaves like a spae-oupying lesion Cerebrum, opti nerve unusual, death possible Aute disseminated enephalomyelitis (ADEM) Tumefative MS Toxi demyelination Follows infetion or vaination This is often assoiated with anti-aquaporin-4 antibodies and so may be onsidered a form of neuromyelitis optia. But tumefative lesions may also be seen in otherwise normal MS Due to toxins in inhaled heroin ( hasing the dragon ) or oaine Relapsingremitting Opti nerve and spinal ord Neuromyelitis optia (Devi s) Anti-aquaporin-4 positive. Long spinal ord lesions illness Foal lesions, stroke like, headahe, fever, skin rash Vasulitis, either as part of a systemi disease or isolated to the CNS (whih is very rare) Cerebral + migraine + dementia CADASIL (erebral autosomal dominant arteriopathy with subortial infarts and leukoenephalopathy) Although imaging mimis MS in that orpus allosum may be involved, white matter lesions of temporal pole are very harateristi of CADASIL and never seen in MS. No oligolonal bands in CSF Bilateral opti atrophy + typial MS syndromes + mitohondrial Leber s hereditary opti neuropathy Women with Leber s mitohondrial mutations may develop an MS-like illness inheritane Multifoal: erebral and brainstem Stroke, espeially due to small vessel disease MRI ord and CSF may disriminate Limbs only Mononeuropathies from hereditary liability to Physial signs and pattern of weakness should give the diagnosis pressure palsies Progressive illness Spinal ord and brainstem Spinoerebellar ataxias Family history. Imaging normal Spinal ord Hereditary spasti paraparesis Family history. Imaging usually normal Early dementia or epilepsy or peripheral neuropathy A leukodystrophy Charateristi imaging abnormities. Look out for Addison s in men (adrenoleukodystrophy) non-speifi MRI white-matter lesions and a linially suggestive history. PREDICTING PROGNOSIS IN MS There is no reliable guide at the onset of MS to the likelihood of it ausing greater or lesser disability. Vague indiators are that fixed disability is reahed quiker by men, older patients, those with primary progressive disease and those who present with brainstem or erebellar symptoms. In pratie, neurologists tend to judge how aggressive the disease is by relapse frequeny and the rate of new MRI lesion formation. However, these are surprisingly unhelpful. For instane, there is a orrelation between the hange in MRI lesion load over 5 years with MS and the disability of that individual 14 years later, but the orrelation oeffiient is only 0.6. THE DIFFERENTIAL DIAGNOSIS OF MS (TABLE 1) Multiple slerosis ontinues to be misdiagnosed. People with MS may first reeive other diagnoses, often orthopaedi in men and psyhiatri in women, before the penny drops. Conversely, non-organi symptoms may be wrongly attributed to MS. Neuromyelitis optia (NMO) is the most ommon form of demyelinating disease in the Far East and Afria. Patients typially have monophasi or reurrent episodes of spinal ord and bilateral opti nerve syndromes, usually muh more severe than in MS. Most, but not all, have serum antibodies to the water hannel, aquaporin-4 and half of patients have other autoantibodies (antiphospholipid and Sjögren s antibodies espeially) whih are probably epiphenomena of B ell dysregulation; this explains demyelination apparently assoiated with systemi lupus erthythematosus ( lupus slerosis ), the antiphospholipid syndrome or other autoimmune disease. These patients have in fat NMO with non-pathogeni antibodies. MRI shows long spinal ord lesions (.3 vertebral segments in length) and symmetrial lesions asending the white matter trats from the brainstem, around the entral anal, into the thalami. Cerebral lesions, if they our, are usually large, oedematous and spae-oupying, often being mistaken for glioma. Roughly 50% of attaks (whih are usually unresponsive to steroids) may improve dramatially with plasma exhange. Long-term therapy is aimed at suppressing B ells and antibody formation (eg, prednisolone, azathioprine, rituximab). Aute disseminated enephalomyelitis (ADEM) is a monophasi demyelinating disease in hildren and adults. As well as foal involvement of brainstem, both opti nerves and ord, patients harateristially have fever, meningism, seizures and redued awareness. Death may our due to gross erebral oedema. ADEM is onsidered to be the onsequene of a rare aberrant immune response to infetions (viruses, myoplasma, borrelia, ampylobater) or vainations. The brain MRI may be indistinguishable from MS but the lesions are said to more often involve the basal ganglia and ortex. CSF oligolonal bands may be present, but less frequently than in MS, and they may not persist over time. There may be striking linial and radiologial improvement over weeks and months. Perhaps as many as 30% of typial episodes of ADEM may be followed by attaks whih lead to the diagnosis of MS. Some laim there is an entity of relapsing ADEM whih is distinguishable from MS. 2009;9: doi: /jnnp

5 THE QUESTIONS PEOPLE WITH MS ASK It has to be remembered that the natural history data ome largely from the era of poor support servies and no disease-modifying drugs. However, there is no evidene yet that these treatments have any long-term effet. How is MS going to affet my life? 50% need a stik to walk 20 years after the first symptoms. Half of all people with MS eventually have ognitive problems. Depression is three times more ommon and the suiide risk is doubled The divore rate is inreased ninefold. At least 2/3 of people with MS are unemployed (or 50% will beome unemployed within 5 years of diagnosis). reommend a healthy/mediterranean diet, not least beause this empowers patients. Can I have surgery? General surgery and all types of anaesthesia are safe. There is histologial evidene that plaques may form in the trats aused by instrumentation of the brain or spinal ord. Myelography, whih is very rarely needed nowadays, is onsidered safe. Should I have a vaination? Vainations do not ause or exaerbate MS. People with persistent disability should be offered influenza vaination. Am I going to die from MS? Life expetany is redued by years. It is very rare to die diretly of MS (for instane respiratory failure from a high ervial plaque). However 2/3 of patients will die of seondary infetions partiularly of skin, hest and bladder due to advaned neurologial disability. Will my hildren (or sibling) get MS? The lifetime risk of MS in white northern Europeans is 0.3%. This inreases to 25% for an idential twin of an MS patient, 5% for other siblings, 2% for a hild, 1% in seond or third-degree relatives. Does stress ause MS or indue relapses? Self-reported stressful life events double the risk of a relapse, but do not ause MS itself. Does smoking affet MS? Smoking (or personality fators assoiated with smoking) inreases the likelihood of onversion from relapsing-remitting MS to seondary progression. Does going on holiday to hot ountries make MS worse? No, this misunderstanding of the Uhthoff phenomenon (see above) is quite ommon. Can I have hildren? MS does not affet fertility or pregnany. During pregnany the relapse rate is redued, to be followed by an inreased rate afterwards (though only 30% will relapse in the postpartum year) leading to no net hange, but the pereption among many women is that they are at risk after delivery. Epidural and spinal anaesthesia is safe. Breast feeding does not affet MS. For some people, an important fator is unertainty over how future disability might affet their ability to look after any hildren. Should I go on a speial diet? Many unpleasant unproven diets have been and still are reommended. The NICE (National Institute for Health and Clinial Exellene) guidelines endorse poor-quality old studies whih suggest that aumulation of disability an be redued by diets rih in linolei aid (sunflower, orn, soya and safflower oils). It is therefore reasonable to MANAGEMENT OF A RELAPSE If there is a question over aute treatment, or relapses are being ounted as part of the riteria for possible disease-modifying therapies and in trials of new therapies, diagnosing a relapse orretly beomes very important. It is not always easy and not every patient an be relied upon to orretly diagnose their own relapses. When patients desribe harateristi symptoms of demyelination (suh as opti neuritis or myelopathy), it is possible for a neurologist or MS speialist nurse to diagnose a relapse over the telephone. If the patients have seen another dotor, who has found new objetive linial signs, the diagnosis of a relapse is reinfored. But it is generally best for the patient to have ready aess to an MS entre providing relapse linis whih have been set up in several parts of the UK. Note: Consider alternative diagnoses if persistent defiits, eg if someone remains ompromised from a myelopathy, onsider spinal ord imaging for strutural lesions (suh as ervial spondylosis). Opti neuritis whih has not reovered is partiularly worrying (see above) ;9: doi: /jnnp

6 Consider an underlying infetion. Pyrexia, typially from a urinary trat infetion may ause a Uhthoff mimi of a relapse ( pseudo-relapse ). Should the patient rest or exerise is an old question whih remains unresolved. The NICE guidelines promote rapid aess for people with a relapse to a dediated rehabilitation unit. is a rare ompliation and partly to prevent this standard pratie is to avoid giving more than three ourses of ortiosteroids in a year. Plasma exhange There is some evidene that plasma exhange may improve 50% of steroid-resistant attaks of CNS demyelination, inluding relapses of MS and neuromyelitis optia. Cortiosteroid treatment Cortiosteroids redue the duration of a relapse by a few weeks but have no effet on the disability arued as a result of the attak eight weeks later, and have no impat on subsequent disease ourse; they should only be given for unpleasant or disabling symptoms and it may be reasonable to wait for a few days to see if there is spontaneous improvement. Oral or iv steroids, at home or in hospital, are probably equally effetive, the standard regime in the UK is oral or iv methylprednisolone, 500 mg 1 g daily, for between 3 and 5 days. Common adverse effets are a metalli taste during the treatment and a few days of inreased energy and insomnia. Asepti nerosis of the hip Table 2 Kurtzke Expanded Disability Severity Sale (EDSS). Despite its name, the EDSS is not a sale of disability alone; but of impairment (sores 0 3.5), disability ( ) and handiap (8.0 10). It is an ordinal sale. Sore Desription 0.0 Normal neurologial examination 1.0 No disability, minimal signs in one funtional system (FS)* 1.5 No disability, minimal signs in more than one FS 2.0 Minimal disability in one FS 2.5 Mild disability in one FS or minimal disability in two FS 3.0 Moderate disability in one FS, or mild disability in three or four FS. Fully ambulatory 3.5 Fully ambulatory but with moderate disability in one FS and more than minimal disability in several others 4.0 Fully ambulatory without aid, self-suffiient, up and about some 12 h/day despite relatively severe disability; able to walk without aid or rest some 500 m 4.5 Fully ambulatory without aid, up and about muh of the day, able to work a full day, may otherwise have some limitation of full ativity or require minimal assistane; haraterised by relatively severe disability; able to walk without aid or rest some 300 m. 5.0 Ambulatory without aid or rest for about 200 m; disability severe enough to impair full daily ativities (work a full day without speial provisions) 5.5 Ambulatory without aid or rest for about 100 m; disability severe enough to prelude full daily ativities 6.0 Intermittent or unilateral onstant assistane (stik, ruth, brae) required to walk about 100 metres with or without resting 6.5 Constant bilateral assistane (stik, ruthes, braes) required to walk about 20 m without resting 7.0 Unable to walk beyond approximately five metres even with aid, essentially restrited to wheelhair; wheels self in standard wheelhair and transfers alone; up and about in wheelhair some 12 h/day 7.5 Unable to take more than a few steps; restrited to wheelhair; may need aid in transfer; wheels self but annot arry on in standard wheelhair a full day; may require motorised wheelhair 8.0 Essentially restrited to bed or hair or perambulated in wheelhair, but may be out of bed itself muh of the day; retains many self-are funtions; generally has effetive use of arms 8.5 Essentially restrited to bed muh of day; has some effetive use of arms, retains some self are funtions 9.0 Confined to bed; an still ommuniate and eat. 9.5 Totally helpless bed patient; unable to ommuniate effetively or eat/swallow 10.0 Death due to MS *Eah system (visual, pyramidal, et) has a separate funtional system sale whih is sored and these sores are ompiled to assist designation of the overall sore. MANAGEMENT OF COMMON SYMPTOMS AND THE ANNUAL ASSESSMENT OF SOMEONE WITH MS At different stages in the disease, various speialities beome important to MS are, inluding urologists, ophthalmologists, speeh and language therapists, physiotherapists, oupational therapists, linial psyhologists, psyhiatrists, rehabilitation physiians and gastroenterologists. Coordination of these servies has been revolutionised by the advent of the MS speialist professional (usually but not neessarily a nurse) who also liaises with soial servies, housing departments, wheelhair linis, as well as providing ontinuity of are and pastoral support. Annual assessment Best pratie is that everyone with MS has the opportunity to see someone with speialist knowledge of their ondition at least one a year. There is onsiderable benefit in doing suh assessments in a multidisiplinary setting, with easy one-stop aess to all the relevant professionals. The tasks during these assessments are to: briefly review the diagnosis define the stage of the disease reord disability in some way, ideally using the Kurtzke sale (table 2) assess how many relapses there have been (for those in the relapsing-remitting phase, this may determine disease-modifying treatments) review persistent symptoms and their treatment (table 3). Patients and their arers and relatives should be routinely asked about embarrassing or diffiult symptoms suh as depression, ognitive impairments, bladder and sexual problems (these are less likely to be volunteered by patients). CARE OF PEOPLE WITH ADVANCED MS See table 3. Two initiatives have transformed the are of people with terminal neurologial disability: greater willingness to use and aept advane diretives greater involvement by palliative are servies. DISEASE-MODIFYING THERAPIES In 1993, the first trial was published of any drug to affet the ourse of MS: interferon-beta-1b redued 2009;9: doi: /jnnp

7 Table 3 Treatment of ommon symptoms of multiple slerosis (MS) listed in order of effiay of treatment (most useful first) Symptom First onsider Non-drug treatment First-line treatment Seond-line treatment Bladder urgeny or urge inontinene Is there a urinary trat infetion? Is the patient deliberately fluid restriting? Measure postmiturition residual bladder volume by ultrasound. Speialist ontinene advie Intermittent selfatheterisation if the post-miturition residual bladder volume.100 ml Bladder noturia Speialist ontinene advie Speialist ontinene advie Bladder reurrent urinary trat infetions (.3 in one year) Neuropathi pain Always hek ulture and sensitivity, avoid long-term antibiotis. Consider bladder stones Carbamazepine speifially for trigeminal neuralgia. Consider musuloskeletal auses of pain, espeially bak pain seondary to spastiity Speialist ontinene advie TENS, ognitive behaviour therapy Oxybutinin (5 mg bd-qds), ommonly auses dry mouth, onstipation. Tolterodine (2 mg bd), rarely auses hest pain and peripheral oedema Desmopressin mg orally or mg intranasally (for noturia). Adverse effets are rare with orret dose: fluid retention, hyponatraemia Amitripylline, gabapentin, pregabalin Hypersomnolene (rare) Obstrutive sleep apnoea Modafanil ( mg bd), adverse effets ommon: abdominal pain and diarrhoea Spastiity Spasti foot drop Constipation Depression Dysphagia Chest infetions Dysarthria Eretile dysfuntion Pressure ulers Faeal inontinene Fatigue Chek for pain and infetions (espeially bladder). Careful hek for ontratures Diet suffiient? Is hydration a problem? Can mobility be improved? Physiotherapy, passive strething, Funtional eletrial stimulator Inrease fluid intake. Change diet Consider soial fators, eg Support servies (linial isolation and loss of status, as psyhology) well as a diret manifestation of the MS. Measure weight, formal swallow assessment, beware reurrent silent hest infetions If reurrent, get formal swallow assessment Speeh therapy Beware depression, diabetes, vasular disease and mediations Chek nutrition and wheelhair fitting Is this overflow from onstipation? May need an abdominal x ray Depression, poor sleep, sedating drugs Swallowing tehniques, hange in diet Speialist ontinene advie Energy-onservation tehniques Poor mobility Is it all due to MS? Aerobi training, rehabilitation, mobility aids Diplopia and osillopsia Poor ognition Emotionalism Ataxia and tremor Assess formally and early. May be due to depression Explain the ondition to family and friends Cognitive fatigue may improve with frequent rests (every 30 min) during high-performane mental tasks Speialist rehabilitation advie Balofen (10 inreasing to 80 mg daily in 2 3 divided doses) Tizanidine (starting at 2 mg, inreasing by 2 mg every 3 days until on 4 mg tds and inrease if still reporting benefit, to maximum of 24 mg daily Adverse effets: drowsiness, dizziness, dry mouth Oral laxatives Antidepressant mediation Sildenafil mg. Adverse effets: flushing, gastrointestinal disturbane, oedema Oxybutinin or tolterodine may help Amantadine 200 mg bd (marginal effiay). Adverse effets: anorexia, anxiety Gabapentin or balofen may help Intravesial botulinum toxin in entres with experiene. Long-term atheterisation only suitable if non-invasive methods do not work, and then suprapubi is better than in-dwelling. Do not use bladder wash-outs Lamotrigine, phenytoin Diazepam, lonazepam, dantrolene Intratheal balofen If limb funtion is already lost, then destrutive surgery or phenol ablation of nerve roots In foal spastiity (eg hip addutors) botulinum toxin to paralyse appropriate musles Suppositories and enemas Adjust position of seating, hest physiotherapy, enteral tube feeding Enteral tube feeding Alprostadil or intra-avernosal papaverine Fluoxetine Triyli antidepressant, seletive serotonin reuptake inhibitor A wide variety of proposed drugs Thalamotomy and/or deep brain stimulation (balofen, isoniazid, arbamazepine, beta-blokers) have little or no effet ;9: doi: /jnnp

8 Table 4 Liensed disease-modifying drugs in the European Union and/or USA Drug Name Administration Adverse effets Interferon-beta 1b Betaferon or Betaseron 250 mg subutaneously on alternate days Interferon-beta 1a Rebif 44 mg subutaneous three times weekly Interferon-beta 1a Avonex 30 mg intramusular one weekly Loal injetion-site reations and flu-like symptoms with pyrexia, whih may be redued by paraetamol and usually subside over months; abnormal liver funtion; bone marrow suppression; 5 30% of patients develop persistent neutralising antibodies (higher with more frequent dosing) whih may redue effiay Glatiramer aetate Copaxone 30 mg subutaneously daily Injetion site reations; rarely a syndrome of severe pain at injetion site +/2 hest pain, whih an our months after starting drug Natalizumab Tysabri 300 mg by intravenous infusion every 4 weeks Mitoxantrone Novantrone Complex and various infusion regimes Progressive multifoal leuoenephalopathy (?1/5000) urrent liene refers to 1:1000 Aute leukaemia (3/1000); ardiotoxiity (1:200) the relapse rate by one third. Sine then, we have learnt that several drugs (table 4) redue the relapse rate and the aumulation of disability over the short term, 2 5 years; and that the outome is better if drugs are given earlier in the ourse of the disease, and before signifiantly fixed disability is established. However, the long-term effiay of these drugs is unlear. In partiular, it is not known whether any influene the onset of the seondary progressive phase of the disease. Treatment of the linially isolated syndrome of demyelination In people with white matter lesions on MR sans at presentation, the interferons and glatiramer aetate redue the onversion to MS over the subsequent 3 years from about 50% to about 30%. It is urrently unlear whether this translates into a signifiant effet on the aumulation of disability. Pratie varies widely aross Europe and the USA. However, in the UK, the onsiderable ost of these drugs, their debated effiay and the unertain prognosis of MS has led to resistane to treating patients at this early stage. Treatment of relapsing-remitting MS The interferons and glatiramer aetate unequivoally redue the relapse rate by about one third in the short term (fig 2). In pivotal trials, they also redued the risk of aquiring fixed disability over 2 years from 38% to 28% although these results were not all statistially signifiant. A meta-analysis suggests that the interferons redue the risk of relapse in the first year of treatment, but may have no effet on relapse rate after that, and they may have no impat on disability at all. The Assoiation of British Neurologists (ABN) guidelines are that all eligible patients should be ambulant (maximum EDSS 6.5) and have one or more indiator of disease ativity out of: two linially signifiant relapses in the last two years; one disabling relapse in the last year; an ative MR san ontaining new or gadolinium enhaning lesions that have developed in the previous year. Treatment of the seondary progressive phase MS The interferons and glatiramer aetate do not affet seondary progression, and there is an inreasing pereption that no immunotherapy, however potent, will. Treatment of primary progressive phase MS There is no effetive disease modifying drug. Stopping interferon-beta or glatiramer aetate It is very diffiult to stop disease-modifying treatment in an individual patient ( But you don t know what my relapse rate would have been without treatment, dotor ). The ABN has suggested these stopping riteria: Figure 2 The annualised relapse rate from the pivotal trials of the interferons and opaxone. There are no error bars for olumns 2 and 3 as not all of the papers summarised ontained the standard deviation of the data. inreased number and severity of relapses or lak of relapse redution ompared with the pre-treatment 1 2 years, espeially if MRI shows new or enhaning lesions development of non-relapsing seondary progressive multiple slerosis, with loss of the ability to walk (EDSS 7 or more). 2009;9: doi: /jnnp

9 Further reading Assoiation of British Neurologists. ABN Guidelines for 2007 (Updated from 2001). Treatment of multiple slerosis with b-interferon and glatiramer aetate. London: Assoiation of British Neurologists, Compston A, MDonald IR, Noseworthy J, et al. MAlpine s multiple slerosis. Fourth edn. Churhill Livingstone, Compston A, Coles A. Multiple slerosis. Lanet 2008;372: Cree B. Neuromyelitis optia: diagnosis, pathogenesis, and treatment. Curr Neurol Neurosi Rep 2008;8: Clerio M, Faggiano F, Palae J, et al. Reombinant interferon beta or glatiramer aetate for delaying onversion of the first demyelinating event to multiple slerosis. Cohrane Database Syst Rev 2008;(2):CD Goodin DS, Cohen BA, O Connor P, et al, Therapeutis and Tehnology Assessment Subommittee of the Amerian Aademy of Neurology. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple slerosis (an evidene-based review): report of the Therapeutis and Tehnology Assessment Subommittee of the Amerian Aademy of Neurology. Neurology 2008;71: Hartung HP, Polman C, Bertolotto A, et al. Neutralising antibodies to interferon beta in multiple slerosis: expert panel report. J Neurol 2007;254: NICE Guidelines. Multiple slerosis. Management of multiple slerosis in primary and seondary are. Clinial Guideline 8 November Developed by the National Collaborating Centre for Chroni Conditions. Polman CH, Reingold SC, Edan G, et al. Diagnosti riteria for multiple slerosis: 2005 revisions to the MDonald Criteria. Ann Neurol 2005;58: Young NP, Weinshenker BG, Luhinetti CF. Aute disseminated enephalomyelitis: urrent understanding and ontroversies. Semin Neurol 2008;28: The role of testing for neutralising antibodies to interferon-beta is unlear. One approah, advoated by European authorities, is to systematially test everyone annually and offer those with high onentration antibodies an alternative treatment suh as glatiramer aetate. Treatment of aggressive relapsing-remitting MS People who ontinue to relapse on interferon-beta or glatiramer aetate, or who present so aggressively that the neurologist has little faith in interferonbeta s ability to ontain the disease, may be onsidered for natalizumab or mitoxantrone. Both should be given in a regional MS entre. Natalizumab, given indefinitely by monthly infusion, is very roughly twie as effiaious as interferon-beta, reduing the relapse rate at 1 year by 68% and the hane of aquiring fixed disability over 2 years by 42% ompared to plaebo. The main onern is a low risk (yet to be established, but perhaps 1/5000) of progressive multifoal leuoenephalopathy. The annual ost is around 20,000, roughly double that of the interferons. Mitoxantrone is liensed for the treatment of worsening relapsing MS (whih means either aggressive relapsing-remitting disease or progressive MS with frequent superimposed relapses) in the USA, but is unliensed in Europe. It is a heap hemotherapy (ytotoxi immunosuppressant) drug, whih may be as effetive, or more, than natalizumab, but also has signifiant adverse effets: total dose exposure is limited by ardiotoxiity and 0.2% risk of aute leukaemia. It is useful as short-term resue treatment for at most 3 years. It may perhaps be better used as indution therapy allowing patients to be maintained long term on less noxious drugs, though the evidene for this approah is limited. Future treatment of MS Over the next few years, neurologists will have to ome to terms with a wide variety of drugs for the treatment of MS, espeially new biologials. Currently under investigation are novel monolonal antibodies; oral immunotherapies; ombination immunotherapies; peptide vaination; neuroprotetive drugs; and reparative strategies using stem ells. Perhaps more signifiantly there is growing evidene that the benefits of aggressive immunotherapy are greatest when given earliest in the ourse of the disease. This raises the diffiult prospet of exposing well non-disabled young adults to potentially toxi treatments, whih would be muh easier if there were good prognosti indiators early in the disease. CONCLUSIONS MS is an inflammatory demyelinating disorder of the CNS in whih there is dissemination of lesions in time and spae. MS is the ommonest ause of neurologial disability in young adults in the West. The diagnosis is usually linial, supported by MRI. New riteria, largely for researh, allow for new asymptomati radiologial lesions to replae the need for a seond linial episode in making the diagnosis of MS. MR sans may also inform prognosis: for instane, abnormalities at the time of a first episode of demyelination inrease the risk of developing MS. An important differential is neuromyelitis optia, haraterised by long spinal ord lesions, bilateral opti neuropathy and sometimes antibodies against aquaporin-4. Useful quality of life improvements ome from speialist nurses o-oordinating multidisiplinary are of MS patients. Cortiosteroids redue the duration, but not the eventual outome, of aute episodes of MS. Current trends in disease-modifying treatments are (i) to treat earlier in the disease ourse and (ii) to use more aggressive immunotherapies with greater toxiity. Aknowledgements: My thanks to Mike Boggild from Liverpool, UK for his insightful and helpful review of this artile. Competing interests: My department has reeived funding from Genzyme for linial trials and experimental work on alemtuzumab as a treatment of multiple slerosis. I have reeived travel expenses for speaking at meetings about alemtuzumab ;9: doi: /jnnp