MS – Now a Treatable Condition?

– Dr. Laura Kennelly (Neurology SHO in St Vincent’s University Hospital) and Professor Niall Tubridy (Consultant Neurologist in St. Vincent’s University Hospital)

60 Second Summary

Multiple sclerosis (MS) is a complex neurodegenerative disease of the central nervous system (CNS), affecting both the brain and spinal cord. For many patients, it may ultimately still result in high levels of functional impairment and disability as the disease progresses. However, fantastic developments have been made in a once untreatable condition. In this article, we offer a background to MS and explore some of the treatment options now available


Multiple sclerosis (MS) is a chronic, likely immune-mediated disease of the central nervous system (CNS), affecting both the brain and spinal cord. It is a complex neurodegenerative disease, characterised by the presence of inflammation, axonal degeneration and multifocal, demyelinating plaques. For many patients it ultimately results in high levels of functional impairment and disability as the disease progresses, with 50% of patients requiring assistance with walking within 15 years.1 Although there is no national register it is estimated that there are 9000 people in Ireland and 2.5 million people worldwide, living with this condition.


Although MS can present at any age, it most typically presents in adults aged 20-40 years. Women are more frequently affected than men by at least a 2:1 ratio. Individuals of Northern European descent have also been found to be more likely to be affected than other ethnicities.3 The clinical presentation of MS is extremely variable. Commonly, patients initially present following a subacute neurological occurrence affecting the CNS, known as a clinically isolated syndrome (CIS). It is the first clinical presentation of a disease that shows characteristics of inflammatory demyelination, that may or may not progress to a diagnosis of MS.4 Clinical presentations are many and varied, depending on the area of the brain affected. They may include upper and lower limb dysfunction, visual disturbances, balance and coordination problems, spasticity, altered sensation, abnormal speech, swallowing disorders, fatigue, bladder and bowel problems, sexual dysfunction, cognitive issues and emotional disturbances. Optic neuritis (inflammation of the optic nerve), Uhthoff’s phenomenon (worsening of MS symptoms with a rise in body temperature, for example, following exercise) and Lhermitte’s phenomenon (an electric-shock like sensation down the spine or limbs on neck flexion) are characteristic of MS. Clinical signs and symptoms may have resolved by the time they are seen by a medical professional, resulting in a normal neurological examination. This highlights the importance of taking a thorough and detailed medical history. However, a CIS (without corresponding radiological or CSF findings) is not enough to make a diagnosis of MS, as per the Revised McDonald Criteria, as it does not fulfil the criteria of lesions disseminated in time (DIT).

Pathology and risk factors:

Inflammatory changes of the CNS are the primary causes of damage in MS. Genetic and environmental factors, including exposure to infectious agents, are thought to influence susceptibility. Environmental factors such as lack of sunlight exposure/vitamin D, cigarette smoking and exposure to infectious agents (EBV, HHV 6) are all thought to be associated with an increased risk of developing MS. Observational studies have suggested that the level of serum vitamin D can influence the risk of developing MS and modify disease activity in MS patients. MS patients who smoke cigarettes have also been shown to have higher rates of disease activity, faster rates of brain atrophy and a greater overall disability burden. Smoking has also been associated with limiting the effectiveness of disease modifying drugs and can increase the risk of developing co-morbidities. As such, smoking cessation and vitamin D supplementation (2000 iu/day) are recommended for all patients with MS.


MS can be classified into four different phenotypes as described by the International Advisory Committee on Clinical Trials of MS – clinically isolated syndrome, relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). The majority (85%) of patients are diagnosed with relapsing remitting multiple sclerosis (RRMS), which is characterised by clearly defined episodes of new or worsened symptoms (relapse), followed by intervals of partial or complete recovery (remission). It can be further classified as being active (with relapses and/or evidence of new findings on MRI) or not active, as well as worsening (increasing disability following a relapse) or not worsening. Secondary progressive multiple sclerosis (SPMS) follows an initial relapsingremitting course in which relapse is not followed by complete recovery and there is gradual accumulation in disability as a result of worsening neurologic function. As with RRMS, it can be classified as either active or inactive as well as ‘with progression’ (disability increased over time, with or without relapses or new MRI activity) or ‘without progression’. Primary progressive MS (PPMS) features worsening neurological function and therefore disability from the onset of symptoms. It does not feature episodes of relapse or remission.

Although not an official classification of MS, radiologically isolated syndrome (RIS) has been used to classify patients with lesions on MRI consistent with MS. These patients may have neurological signs or symptoms not typical of MS and have MRI scans for another reason (e.g. post head trauma). These individuals may or may not go on to develop MS but close monitoring of neurological signs and symptoms is recommended. One third (34%) of patients with an RIS have been found to develop a first acute clinical event consistent with a clinically isolated syndrome of MS within 5 years.


The differential diagnoses to consider include neuromyelitis optica (anti-aquaporin 4), myelin oligodendrocyte glycoprotein related demyelination (anti-MOG), Sjogren’s syndrome (anti-Ro, anti-La), sarcoidosis (serum ACE), systemic lupus erythematous (ANA) and Lyme disease (Borrelia burgdorferi), all of which may present with symptoms similar to MS. The diagnostic criteria for MS are the Revised McDonald Criteria, most recently updated in 2017.13 They consist of a combination of clinical, para-clinical and radiological features, intended to gather evidence data consistent with the disease, while out ruling other potential causes not consistent with MS.3 The criteria support diagnosis on the basis of clinical and radiological evidence (spatial and temporal dispersion of MRI lesions), meaning that many people previously considered to have a first clinical episode (known as clinically isolated syndrome or CIS) can now be diagnosed with MS following an MRI. A diagnosis of MS requires that lesions are ‘disseminated in time and space’. This refers to the occurrence of at least 2 episodes of neurological dysfunction reflecting distinct sites of CNS damage that cannot be explained by any other mechanisms.14 MRI scans show high sensitivity for detection of focal white matter lesions in the CNS and specifically for lesions disseminated in time and space. MS lesions are generally best appreciated on T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) sequences. Dissemination in space is fulfilled by the presence of 1 or more T2 hyper-intense lesions characteristic of MS in 2 of 4 characteristic anatomic locations (periventricular, pericallosal, juxtacortical or infratentorial). Dissemination in time can be demonstrated by a new T2 hyper- intense or gadolinium (Gd) enhancing lesion when compared to an initial baseline MRI scan or simultaneous presence of Gd enhancing and Gd non-enhancing lesions at follow-up MRI examination. Dawson’s fingers are a relatively specific radiological sign for MS. They consist of periventricular demyelinating plaques found perpendicular to the corpus callosum. The diagnosis of MS can be further reinforced by other paraclinical data. This includes the presence of prolonged visual evoked response latency and cerebrospinal fluid (CSF) analysis for the presence of unmatched oligoclonal IgG bands.


The management of MS is complex and evolving and should be approached with a biopsychosocial framework in mind. The principle management strategy is three-fold.

  1. Symptomatic treatment
  2. Acute relapse management
  3. Disease modifying treatment (DMT)

Appropriate management aims to reduce the frequency and severity of relapses, slow the progression of the disease and manage symptoms, in order to maximise a patient’s quality of life. Interventions should aim to alleviate the symptoms while also minimising the risk of side effects from the medical management of MS. A multimodal, interdisciplinary approach is imperative for the most effective management of patients with MS on an inpatient, outpatient and community basis. A major factor to consider when establishing a management plan is the patient’s level of impairment as assessed by the Expanded Disability Status Scale (EDSS). Specialist nurses, occupational therapists, physiotherapists, speech and language therapists, neuropsychologists, pharmacists, dieticians, medical social workers, neurorehabilitation physicians and psychiatrists all imperative for holistic patient care. This is particularly true of patients with advanced MS, who’s need for assistance in many activities of daily living (ADL’s) is greater and increasingly more complex. The main goal is to support patients to control their symptoms, preserve their functional ability and ultimately maximise their independence and quality of life. Symptomatic management can be achieved via pharmacological and non-pharmacological means. This could include management of a patient’s pain, spasticity, bladder and bowel dysfunction, fatigue, swallow, vision, sexual dysfunction, cognition and neuropsychiatric symptoms among others.

The management of an acute relapse of MS most commonly involves the use of high dose corticosteroids (1g methylprednisolone for 3-5 days). High dose steroids have been shown to decrease recovery time from acute attacks but do not alter the progression of the disease. Recent trials have shown noninferiority of oral vs intravenous high dose methylprednisolone. Alternatives, such as IVIG and plasma exchange should be considered for patients who are not suitable candidates for corticosteroid therapy or if the relapse is particularly aggressive.

Disease modifying treatments (DMT’s) are licensed for use in Ireland particularly for people with Relapsing Remitting Multiple Sclerosis. The overall aim of DMT’s is to reduce the number and severity of relapses, and hopefully delay the progression of functional disability and slow the speed at which it happens. Efficacy, route of administration and side effect profile varies among products. The decision to commence a DMT is often guided by the frequency of clinical relapses, MRI radiological activity and disability level. More effective treatments tend to have more serious potential side effects. These side effects can range minor (mild allergic reactions) to major (Progressive Multifocal Leukoencephalopathy [PML]). DMT’s are commonly used in an ‘escalation’ manner, starting with less efficacious but potentially safer therapy, moving up the treatment ladder if there is treatment failure (clinical relapses or new lesions on MRI). Alternatively, an induction method can be used, where drugs with high efficacy are used earlier in the course of the disease, to potentially prevent functional decline. Current advice is to start treatment early, before the development of significant disability, in order to optimise long term outcomes. The decision to switch between agents is dependent on both clinical and radiological criteria.

DMT’s are generally broadly divided into 3 categories, based on their decrease in the annualised relapse rate (ARR). First line DMT’s (beta interferons (Ia/Ib), glatiramer acetate, dimethyl fumarate) are associated with a reduction in ARR of 30-40%, while second line DMT’s (natalizumab, fingolimod, cladribine, ocralizumab and rituximab) are associated with a reduction, on average, of 50- 70%. Third line options such as alemtuzumab are associated with a 60-70% decrease in relapse rate. Data from prospective observational studies suggest that the use of DMT’s is associated with a reduced risk of conversion to secondary progressive MS, particularly with fingolimod, alemtuzumab or natalizumab, compared with no DMT use.18 Careful consideration is necessary when choosing the most appropriate treatment for a patient, balancing efficacy with side effect profile. Interferon beta products (Avonex, Rebif, Betaferon) are the most common first line DMT’s with glatiramer acetate (Copaxone) and dimethylfumarate (Tecfidera) other popular options. Second line options include natalizumab (Tysabari), fingolimod (Gilenya), ocrelizumab (Ocrevus) and rituximab (Rituxan).

Natalizumab is a popular and effective choice for patients with active relapsing and remitting MS. It is a monoclonal antibody directed against α4 integrin and limits the entry of mononuclear cells into the central nervous system. In clinical trials, it has been shown to reduce the progression of the disabling effects of MS by approximately half and decreased the number of MS relapses by two thirds (66%).19 The recommended treatment schedule is 300mg IV infusions at 4-6 week intervals. All patients are screening for JC virus (JCV) antibodies prior to commencing on natalizumab, due to the potential risk of developing natalizumab-associated PML, which can lead to severe disability or death. The estimated incidence of PML in anti-JCV antibody negative patients is 1/10,000. In JCV positive patients, the risk of developing PML is also dependent on immunosuppressant drugs taken in the past, the length of time taking natalizumab (risk increases if patient has been taking Tysabari for >24 months) and the patients JCV antibody titre. Patients who had anti–JCV antibody titres >1.5 units, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk to 11.1/1000.21 To reduce this risk of natalizumab associated PML, retrospective studies have shown that switching to extended interval dosing (EID) from standard interval dosing (SID) is associated with clinically and statistically significantly lower PML risk, without loss of effectiveness. In practice, this means increasing the gap between natalizumab infusions from four to six weeks.22 PML has also been associated with ocrelizumab, rituximab, dimethyl fumarate and fingolimod, but the risk is primarily an issue with natalizumab treatment.23 Such is the efficacy of modern DMT’s, disease remission has become an increasingly attainable target in MS treatment. The phrase No Evidence of Disease Activity (NEDA), has been used to describe same, using both clinical and radiological parameters (without evidence of relapses, disability progression or new T2 lesions on MRI). Guidelines for MRI protocols used to monitor patients in clinical practice have recommended the use of brain T2-weighted MRI, which reveals subclinical active (new and enlarging) lesions.24 Although not currently offered in Ireland, autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option that may be offered to a very select group of patients in certain UK centres. Irish patients may be referred should they fulfil certain strict criteria. These patients often have a very aggressive form of MS or a refractory to at least 2 DMT’s.

Follow up:

Regular MRI scanning (6 months to 1 year) for those on DMT or people with relapsing remitting MS who are not receiving a DMT is advisable. If new MRI activity is seen, then treatment should be escalated or initiated if not already started. Suboptimal responses to treatment should prompt further discussion about changes in treatment regime.


MS is a complex neurodegenerative condition. Remarkable developments have been made in a once untreatable condition. Although there is currently no cure, there are multiple treatment options now available and many more in development for the future.

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