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Diagnosis of Multiple Sclerosis
Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating, degenerative disease of the central nervous system (CNS). During the early phases of the disease, the integrity of the blood-brain barrier (BBB) is compromised, permitting the invasion of monocytes and T cells into the brain parenchyma, resulting in the demyelination characteristic of MS lesions.1,2
The revised McDonald Criteria for the diagnosis of MS, which include both clinical criteria and specific magnetic resonance imaging (MRI) findings, has resulted in the earlier diagnosis of MS with a high degree of both specificity and sensitivity. This allows for better counselling of patients and earlier treatment.3
The typical clinical course of MS is relapsing-remitting, characterised by an initial event of acute or subacute neurological disturbance, generally indicated as clinically isolated syndrome (CIS) followed by recurrence of symptoms over time. CIS is the type of onset in around 85% of MS cases, while the remaining 15% of patients have a progressive disease from onset (primary progressive (PP) MS). CIS is distinguished from radiologically isolated syndrome (RIS), in which patients have incidentally detected MRI T2 bright foci suggestive of demyelination in the absence of clinical symptoms.2,4
One of the primary motivations for early diagnosis of MS is the potential for early treatment to delay the onset of additional clinical relapses and to possibly delay long-term disability. The first opportunity to initiate disease-modifying treatment (DMT) in patients with MS is often when they are in the CIS stage. Clinical trials have demonstrated the benefit of DMTs in delaying or preventing patients with high-risk CIS from converting to clinically definite MS. For patients with a CIS when the diagnosis of MS cannot yet be established according to the revised McDonald criteria, only beta interferons and glatiramer acetate are approved by the regulatory agencies.2,5
The results of numerous studies assessing the risk of conversion from CIS to clinically definite MS, suggest that patients who have asymptomatic brain MRI lesions at the time of presentation of CIS have a 60 to 80% chance of developing clinically definite MS by 10 years, whereas those without brain lesions have approximately a 20% risk of clinically definite MS by 10 years.2
Classification of Multiple Sclerosis6
Relapsing-Remitting MS (RRMS)
- 85% of patients who develop MS have RRMS
- Severity varies greatly in from individual to individual.
- Initial average annual relapse rate of about 2-2.5, dropping to approximately one per year.
- Frequent relapses, especially at disease onset, considered as poor prognostic sign.
- At 10 years after disease onset 50% of patients will enter the SPMS phase, at 20 years this will rise to 80%.
Progressive-Relapsing MS (PRMS)
- Can be identified as worsening Relapsing-Remitting MS (progressive disease with obvious relapses).
- Important to identify in terms of treatment. Whether the patient with PRMS is already on disease modifying therapies or not, switching to other treatments such as Tysabri or Mitoxantrone may be crucial in prevention of further disease activity and slowing down the evolution from PRMS to SPMS.
Secondary-Progressive MS (SPMS)
- Defined as progression of clinical disability (with or without relapses and minor fluctuations) after a relapsing-remitting onset.
- Disability progresses even in between relapses.
- Establishing when patients are converting from RRMS to SPMS can be difficult and only become apparent over a significant length of time.
Primary-Progressive MS (PPMS)
- Approximately 10%-15% of the MS population and, as opposed to other forms of MS, with no female propensity.
- Progressive from onset without discernible relapses or remissions.
- Usually later age of onset (40’s onwards), though in rare cases can occur at an earlier age.
- Typically presents with an increasing spastic gait already affecting quality of walking.
- Poorer prognosis; it takes approximately 6 years to reach the Expanded Disability Status Scale (EDSS) of 6.
Benign MS
- Isolated attacks with complete recovery, with little or no accumulation of disability.
- The attacks may be separated by 10 years or more.
- Often goes undiagnosed for several years and in many instances, is diagnosed post-mortem.
Currently Available Treatments7,8
DMTs can reduce the rate and frequency of relapses, and slow progression to disability. However, their long-term effect on clinical outcome is not yet fully known. There are a number of different DMTs currently available in Ireland, which allows for individualised treatment. Treatment decisions must balance the benefits of individual drugs with their risks and side-effects (see table 1 and 2).
Beta interferons (IFN-β)
IFN-β is a type I interferon with anti-viral and anti- inflammatory characteristics. Potential mechanisms of action include decreased IFN-γ production and inhibition of antigen presentation leading to reduced activation of T cells, and reduction of T cell adhesion and proteases important for T cell entry across the BBB.
Glatiramer acetate
GA is a random combination of four amino acids which has a structural similarity to myelin basic protein. It is thought to modulate immunity by shifting the T helper (Th)1 lymphocytes in MS patients towards a predominance of Th2 phenotype, which may contribute to disease amelioration.
Natalizumab
Natalizumab is a monoclonal antibody to the αα4 subunit of αα4ββ1 integrin, a protein found on the surface of lymphocytes. αα4ββ1 integrins interact with the vascular-cell adhesion molecule 1 enabling adhesion of lymphocytes to the vascular endothelium. It prevents the transmigration of inflammatory lymphocytes across the BBB into the CNS.
Alemtuzumab
Alemtuzumab is a humanised IgG1 monoclonal antibody directed against CD52, a small glycoprotein expressed on the surface of many types of white blood cells including T and B lymphocytes. Alemtuzumab lyses cells expressing CD52 by antibody-dependent cellular cytolysis. The reduction in the level of circulating B and T cells and subsequent repopulation, may reduce the potential for relapse, which ultimately delays disease progression.
Fingolimod
Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. S1P binds to S1P receptors predominantly on lymphocytes, signalling for them to exit lymph nodes and enter the circulation. Fingolimod binds to S1P receptors on naïve and activated lymphocytes, thus retaining them in lymph nodes, away from the CNS where they incite inflammation and tissue damage.
Teriflunomide
Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits dihydroorotate dehydrogenase (DHODH), a mitochondrial membrane protein essential for de novo pyrimidine synthesis. Inhibiting DHODH blocks high levels of lymphocyte proliferation. Teriflunomide does not kill resting lymphocytes – thus, previously acquired cellular immunity is not lost with treatment.
Dimethyl fumarate
The exact mechanism of action by which DMF exerts its effect in MS is still unclear, but is thought to involve enhancement of endogenous mechanisms to counteract oxidative stress, via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway.
Established vs Novel Treatments in MS7,8
The beta interferons and glatiramer acetate are established, effective treatments for which there is long-term clinical experience. Major advantages of the injectable DMTs include a known and favourable safety profile, long-term efficacy and established patient support services. They are also generally well tolerated despite the route of administration.
More recently, monoclonal antibodies have been developed which act through specific mechanisms, e.g. blocking α-4 integrin interactions (natalizumab), or lysing cells expressing CD52 (alemtuzumab). These agents can be highly effective, but sometimes have serious potential complications. Natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (although anti-JCV antibody testing provides supportive information for risk stratification of treatment in individual patients), while alemtuzumab is associated with the development of new autoimmune disorders. Both of these agents are administered via intravenous infusion.
Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate) provide efficacy, tolerability and convenience. However, there are currently no long-term post-marketing efficacy and safety data in a general MS population.
Current data support the gradual introduction of orals as an option for patients with RRMS if there is any indication of a suboptimal response or intolerance or lack of adherence to the injectable treatments. Appropriate programs for monitoring adverse events are warranted.
Treatment Selection and Adherence
Determinants in DMT selection include disease type and activity (see table 2 for indications of individual agents), the benefit to risk assessment, and contraindications in the individual patient. However, patient preferences play an increasingly major role in treatment decision making.
A major issue with therapies in MS is that it is not clear to date whether they benefit subjects in the longer term and whether they fulfil the patients’ perception of benefit. In CIS they will need to be used for much longer in essentially asymptomatic subjects, and thus one might expect higher rates of dropout. Some of these issues will arise as a result of long-term administration of any therapy.
The prerequisites for a well-informed treatment decision by the patient are knowledge of the disease, treatment options and efficacy, potential side-effects and risks. Obtaining information regarding the patient’s knowledge of the disease is therefore important for counselling. A shared decision-making process is increasingly advocated as an ideal model of treatment decisions. It is important that patients are encouraged to establish their preference and are involved in the decision of choosing which treatment most suitable to them.
Good adherence to therapy is important in achieving the full beneficial effects of long-term treatments. It has been reported that 13 to 72% of patients do not adhere to disease-modifying MS treatments, and poor adherence or treatment gaps are associated with a higher rate of relapse.5
A simple starting point to promote adherence is educating patients about the necessity for therapy, while setting realistic expectations. Properly counselling patients before therapy is initiated can prevent problems with adherence further along the treatment course, e.g. although DMTs do not cure MS, through relapse reduction and delay in progression, they can help patients maintain function and quality of life. Patients who are in remission must understand that although they may not be experiencing relapses or signs of progression, the disease may be active at a subclinical level and thus, continuation of therapy is necessary to help reduce disease burden.9
Poor adherence is often caused by side-effects resulting in a negative impact on quality of life. It is therefore important that patients have realistic expectations of potential side-effects and that strategies to monitor and manage them are discussed in detail.
With injectable DMTs, only one-third of the reasons found to be responsible for poor adherence are dependent on the application form. This means that non-injection related factors of nonadherence play a major role, as is known from chronic disorders like epilepsy or hypertension.5
Other barriers to maintaining treatment adherence in patients with MS include forgetting the medication, and issues with complacency and treatment fatigue.9
The use of electronic devices with recording dose history provides useful data on forgetfulness and helps identify non-adherent patients using injectable DMTs.
In the currently growing field of MS therapeutics, patient counselling and perceiving patients’ attitudes will be of huge importance for treatment selection and adherence aiming at clinical stability and optimal quality of life. Proper management of treatment expectations should be used to promote adherence, reinforce perceived effectiveness, and minimise adverse events.9,10
Table 1. Disease-Modifying Treatments in Multiple Sclerosis – Efficacy and Main Side-Effects7,8
![Table 1 DMTs in MS - Efficacy and Main Side-Effects]()
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Table 2. Disease-Modifying Treatments in Multiple Sclerosis – List of Agents Available in Ireland
![Table 2 DMTs in MS - List of Agents Available in Ireland]()
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Abbreviations:
MS: multiple sclerosis; CNS: central nervous system; MRI: magnetic resonance image; CIS: clinically isolated syndrome; RIS: radiologically isolated syndrome; DMT: disease-modifying treatment; RRMS: Relapsing-Remitting MS; PRMS: Progressive-Relapsing MS; SPMS: Secondary-Progressive MS; PPMS: Primary-Progressive MS; EDSS: Expanded Disability Status Scale; S1P: sphingosine 1-phosphate; DHODH: dihydroorotate dehydrogenase; Nrf2: nuclear factor (erythroid-derived 2)-like 2; PML: progressive multifocal leukoencephalopathy; ARR: annualised relapse rate; WBCs: white blood cells; RTIs: respiratory tract infections; BP: blood pressure; GI: gastrointestinal; CBCs: complete blood counts; SC: subcutaneous; IM: intramuscular; IV: intravenous; BBB: blood-brain barrier; CDMS: clinically definite MS; admin: administration.
References:
1. Larochelle C et al. FEBS Lett 2011;585:3770–3780. 2. Marcus JF and Waubant EL. Neurohospitalist 2012;3(2):65-80. 3. Polman CH et al. Ann Neurol. 2011 Feb; 69(2):292–302. 4. Gajofatto A et al. Dis Markers 2013;35( 6):687–699. 5. Bayas A and Mäurer M. Patient Prefer Adherence 2015;9:265–274. 6. HSE (September 2012). Handbook for nurses and midwives caring for people with Multiple Sclerosis. A guide to support practice. 7. Cross AH and Naismith RT. J Intern Med 2014;275(4):350-63. 8. Nicholas R et al. Drug Des Devel Ther 2011;5:255–274. 9. Costello K et al. Medscape J Med. 2008;10(9): 225. 10. Di Battista et al. Mult Scler Int 2014. Article ID 752318.
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Caroline McDermott
