Fast Facts: Multiple Sclerosis

A new era of disease modification and treatment

S.E. Hughes, G. Macaron

• Publisher: S. Karger
• Year: 2021
• ISBN:
  9783318067996
• Edition: 5
• Topic: Medicine
• Subtopic: Neurology

Multiple sclerosis (MS) is a leading cause of disability in young adults, carrying a considerable individual and societal economic burden. The development of disease-modifying therapies and updates to diagnostic criteria are leading us into a new era for MS management, both in the earliest disease phases and progressive MS. In this completely revised/fully updated edition of Fast Facts: Multiple Sclerosis, we present the most recent evidence on disease pathogenesis and all clinical aspects of the condition, as well as the latest on disease-modifying therapies and other potential treatments. Given the need for multidisciplinary management of MS, we have written this resource for the benefit of all health professionals involved in MS care. Table of Contents: • Epidemiology and genetics • Pathology • The clinical picture • Treatment of relapses and symptoms • Disease-modifying treatment • Emerging therapies • Special MS populations • Lifestyle considerations and the multidisciplinary team • Advanced MS

3The clinical picture

A brief history

Historically, the earliest personal account of MS was recorded in the diaries of Frederick D’Este, grandson of King George III. Although his condition was not diagnosed in his lifetime, from 1822 to 1846 he kept a detailed log of his symptoms, which included transient loss of vision, clumsiness of the hands, weakness of the legs, incontinence and dizziness. MS became recognized as a clinicopathological entity around 1870, when Charcot noted a link between the symptoms of MS and nerve damage. Over the next 50 years, various hypotheses were promulgated, including an infectious cause, and oligoclonal bands were discovered in the cerebrospinal fluid (CSF). By 1950, it was clear that MS was a disease of the CNS and by 1960, the beneficial effect of steroids in the management of acute relapses had been identified. By the 1990s, the first injectable disease-modifying therapies (DMTs) were in use. In 2001, the McDonald criteria for the diagnosis of MS were revolutionized by the incorporation of MRI to demonstrate dissemination of lesions in space and time.¹

We now know that MS is an inflammatory, demyelinating and neurodegenerative disease that affects multiple sites across the CNS. The clinical phenotype of MS depends largely on the location of inflammatory lesions, resulting in a broad spectrum of symptoms and signs. While the majority of individual lesions, particularly within the cerebral hemispheres, are asymptomatic, pathology in ‘eloquent’ areas such as the optic nerve, spinal cord and brainstem is usually accompanied by a relevant clinical syndrome.

Definitions

Clinically isolated syndrome. The term ‘clinically isolated syndrome’ (CIS) has previously been used to describe the first presentation of demyelination. However, following revisions to the McDonald criteria in 2010, a diagnosis of MS can now be made following the very first attack if the initial MRI shows evidence of dissemination in time (both enhancing and non-enhancing lesions) and space.² The term ‘clinically isolated syndrome’ is no longer in favor as it suggests diagnostic uncertainty for the patient and the physician.

Multiple sclerosis. A person has clinically definite MS when there is objective clinical evidence of lesion dissemination in time (DIT) and space (DIS). The second clinical episode must occur in a different site from the original lesion at least 1 month later. When reviewing a patient with CIS or MS, a detailed neurological history and examination must be taken to search for evidence of new symptoms or signs of CNS demyelination. Importantly, the incorporation of MRI and CSF features into modern diagnostic criteria permits a diagnosis of MS to be made in some patients at the time of the CIS.

Radiologically isolated syndrome. Increasing use of MRI to investigate neurological symptoms has resulted in an increase in incidental findings. A person has a radiologically isolated syndrome (RIS) if MRI is suggestive of MS but they have had no clinical episodes and the neurological examination is normal. In one study of people with RIS, one-third had developed a clinical episode at 5 years.³

Types of multiple sclerosis

It is important to define the subtype (or phenotype) of MS, as this can guide prognosis and choice of DMT. For example, therapies that reduce the frequency and severity of relapses may not be helpful to people with progressive disease. As all the available treatments have potential side effects, all patients should be provided with a risk–benefit analysis appropriate to their MS subtype. The traditionally recognized patterns of MS are:

•relapsing remitting (RRMS)

•secondary progressive (SPMS)

•primary progressive (PPMS)

•progressive relapsing (PRMS).

Figure 3.1 The two patterns of RRMS: (a) relapses with return to normal neurological function; (b) relapsing disease with stepwise, accumulated disability.

Relapsing remitting disease is the most common form of MS, accounting for 65–70% of patients. RRMS is characterized by periods of acute neurological disturbance (relapses), which last for at least 24 hours and are not attributable to other causes such as infection or changes in core temperature. These relapses must occur after more than 30 days of clinical stability, and the neurological deficit must be established objectively by clinical evaluation (history and/or examination).

In early disease, recovery after a relapse (remission) is often near complete, but incomplete recovery is common in established disease with patients often accruing disability with each successive relapse (Figure 3.1).

Secondary progressive disease. In most cases (up to 75% of people with RRMS), there is an eventual progression to SPMS. This is defined as an initial relapsing remitting disease course followed by progression with or without occasional relapses, minor remissions and plateaus (Figure 3.2). Risk factors for progression to SPMS are shown in Table 3.1. ⁴ The progression of disease from relapsing remitting to the secondary progressive stage is usually noted retrospectively: for example, when a patient with MS has accumulated disability over 6–12 months without any discrete episodes of relapse. Neuroaxonal loss without any ‘overt’ features of inflammation (clinical or radiological) is thought to underlie this phase of MS (Figure 3.3).

Figure 3.2 In SPMS, patients (a) may or (b) may not continue to have relapses.

TABLE 3.1

Risk factors associated with progression to SPMS⁴

•Older age at disease onset

•Short interval between the first and second relapses

•Higher and increasing T2 lesion load

•Motor deficit with incomplete recovery

Primary progressive disease comprises approximately 10–15% of patients with MS. It does not present with discrete relapses, but a gradual progression of disability, often attributable to spinal motor involvement (Figure 3.4). PPMS typically has a later onset than RRMS.

Figure 3.3 The natural history of MS. Silent inflammatory activity almost certainly begins before the first clinical event (CIS). Lesions compatible with inflammatory demyelination discovered incidentally by MRI during the preclinical phase represent the RIS. The incorporation of MRI into modern diagnostic criteria permits determination of DIT in the absence of a second clinical event, when new T2 (or contrast-enhancing) lesions are present on follow-up imaging. The 2010 McDonald criteria first permitted a diagnosis of MS to be made at the time of a CIS if there are both enhancing and non-enhancing lesions (indicating DIT) on MRI. In parallel with the development of relapses and new T2 lesions, there is progressive loss of axons, neurons and synapses from the earliest phases of the disease, which manifests clinically with secondary progression when neuroaxonal reserves are exhausted, indicated here by the ‘clinical threshold’. In this secondary progressive phase of MS, acute discrete inflammatory events (contrast-enhancing lesions, new T2 lesions) wane and progressive brain atrophy dominates the MRI picture.

Progressive relapsing disease. A small number of patients present with gradually progressive disease onto which are ‘superimposed’ periods of worsening that may be...

Table of contents

• Cover
• Title Page
• Copyright
• Contents
• List of abbreviations
• Introduction
• Epidemiology and genetics
• Pathology
• The clinical picture
• Treatment of relapses and symptoms
• Disease-modifying treatment
• Emerging therapies
• Special MS populations
• Lifestyle considerations and the multidisciplinary team
• Advanced MS
• Useful resources
• Index