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Saturday, March 1, 2014

Pathogenesis and Management of Multiple Sclerosis – An Update for the Multiple Sclerosis Nurse

Bernd Kieseier, Dusseldorf, Germany


The Pathogenesis of Multiple Sclerosis 
Since the clinical presentation of multiple sclerosis (MS) with the typical plaques in the brain was first correlated in 1868,1 much has been learned about this immune-mediated disease, which is characterised by chronic inflammation, demyelination, axonal damage, white matter lesions, brain and spinal cord atrophy and astrocytosis.2 Within white matter lesions that are visible on magnetic resonance imaging (MRI) scans from an early stage,3macrophages strip and engulf the myelin sheath leading to nerve conduction block and neurological deficit.2 A relapse is usually followed by a recovery period, in which remyelination can occur,4 but continued inflammation eventually leads to axonal loss and brain atrophy.5 

Nearly all risk genes identified for MS (currently about 100) are associated with immune function5 and therapies that alter lymphocyte function and migration6 are effective in MS, suggesting an immune aetiology. Some variants of the human leucocyte antigen (HLA) complex and the major histocompatibility complex (MHC) have been associated with MS,7,8 but the risk they confer to a carrier for developing MS is too small to be predictive of disease. These genes, however, are likely to be valuable in determining a clearer understanding of MS pathogenesis. 

In the brains of patients with MS there appears to be an imbalance between the competing pro-inflammatory and anti-inflammatory processes.9 Genetic and environmental factors may assist the movement of autoreactive T cells and antibodies through a damaged blood–brain barrier (BBB) and into the central nervous system (CNS). Once inside brain tissue, pro-inflammatory cytokines, such as interferon gamma(IFNγ), tumour necrosis factor alpha (TNF-α) and interleukin (IL)-2, -15, -17 and -23 are released by activated T-cells. These increase the expression of cell-surface molecules on lymphocytes and antigen-presentingcells (astrocytes, microglia and macrophages), triggering an immune response. In addition, the release of certain anti-inflammatory cytokines (IL-1, -4 and -10) from T-cells stimulates production of antibodies by B cells, which damage host tissue (see Figure 1).10,11 

Disease Course 
MS has an unpredictable and variable course (see Figure 2).12 The disease first manifests with a neurological sign or symptom such as loss of vision, bladder and bowel dysfunction, ataxia or sensory disturbances (e.g. clinically isolated syndrome [CIS]). After this, most patients spend years alternating between periods of relapse and remission (relapsingremitting multiple sclerosis [RRMS]), but approximately 50 % will haveprogressed to a chronic advanced stage within 10 years (secondary progressive MS [SPMS]).12 At this stage there is clear cerebral volume reduction with increased lesion load visible in MRI.10 Most patients show impaired walking within 15 years and are wheelchair bound after 25 years. Up to 65 % of patients show cognitive deficits that may significantly impair work and daily activities.13 

Medications in Current Multiple Sclerosis Management 
In MS, disease-modifying therapies (DMTs), although not a cure, helpmodify and slow down this course and delay progression.12 For almost 20 years the beta interferons (IFNβs) and glatiramer acetate (GA) have been administered to achieve some limitation of damage to the CNS, to delay disease progression and to provide a degree of long-term improvement in symptoms and quality of life (QoL). Regrettably, the latter two goals are only partially achieved with these drugs. Antispastic drugs, analgesics and antidepressants are also used for short-term symptomatic relief and temporarily improve QoL, but have no disease-modifying effect.14,15 

In 1993 the first IFNβ therapy for MS was introduced, followed by GA in 2001, mitoxantrone in 2002 and natalizumab in 2006. Fingolimod,a reversible spingosin-1-phosphate (S1P) receptor antagonist and the first oral DMT in MS treatment, was approved for the treatment of RRMS by the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) in 2010 and 2011, respectively. Teriflunomide wasapproved by the FDA in for RRMS in 2012 and by the EMEA in 2013 and dimethyl fumarate (BG-12) was approved by the FDA for RRMS in 2013; several other agents are in development (e.g. laquinimod, alemtuzumab, daclizumab, ocrelizumab and pegylated IFNβ).16 

The DMTs are associated with various safety and adherence concerns, particularly flu-like symptoms seen with the IFNβs and administrationsite reactions in the treatments given by subcutaneous injection. Therefore, the decision-making process in MS treatment choice should consider two major dimensions: efficacy and burden (see Figure 3).17 The ideal treatment for MS would have a high efficacy and low burden, but the commercially available DMTs fall short of this target. 

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