Introduction to Multiple Sclerosis
Multiple sclerosis (MS) is an unpredictable, potentially disabling disease of the central nervous system (CNS) largely affecting young adults. The mean age at diagnosis is typically between 20 and 49 years; however, the prevalence in children and adolescents (<18 years) and in later adulthood (>50 years) is increasing.
In 2020 an estimated 2.8 million people, or 35.9 per 100,000, were affected with MS worldwide, although prevalence increases with increasing latitude. Rates are higher in Europe and North America, estimated at 127.0 to 164.6 per 100,000, respectively, and lower in Africa at only about 2.8 to 3.3 per 100,000 population. The prevalence of MS is two to four times higher in women; however, men experience poorer prognosis and worse disease course.
MS is characterized by focal lesions disseminated throughout the brain and spinal cord. These lesions, or plaques, result from damage to the myelin sheaths caused by the immune system’s release of autoreactive lymphocytes that cross the blood-brain barrier to attack the oligodendrocytes, the myelin producing cells in the CNS. Originally it was thought that MS attacks only myelin in the white matter of the CNS, but more recent evidence shows the presence of plaques, neurodegeneration, and gliosis in the gray matter of the brain and spinal cord as well. Demyelination and axonal damage impair or completely block neural transmission between the different regions of the CNS and between the CNS and its effectors (e.g., the skeletal muscle and body organs). In the more progressive stages of the disease there is profound brain tissue loss and atrophy, further compounding the poor neural transmission resulting from MS.
The cause of MS is not known, although environmental and genetic causal factors have been identified and may interact with lifestyle and other modifiable risk factors.
The diagnosis of MS is made through obtaining a complete medical history, a full neurological examination, and clinical and laboratory tests, including blood tests, lumbar puncture and cerebrospinal fluid assessment, magnetic resonance imaging (MRI), and electrophysiological tests, such as measurement of evoked potentials. A diagnosis is made based on the presence of at least two lesions in different areas of the brain, which occur at two different times, and when other causes of the neurological signs and symptoms can be eliminated.
MS is a heterogeneous and unpredictable disease. The clinical signs and symptoms can vary over time and in severity, within and between persons with MS, depending on the location and extent of the lesions in the brain and spinal cord. Symptoms of MS are related to the location and extent of the damage in the CNS and include sensorimotor, cognitive, and emotional symptoms, as detailed in Table 9.1 .
|Bowel and bladder disturbance|
The course of MS is also variable, ranging from benign, with mild symptoms and little to no disability, to rapidly progressing, with severe disability and, potentially, death. There are four main clinical courses of MS: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS), outlined in Table 9.2 . Both SPMS and PPMS can be further classified as active, that is, with relapses or new MRI activity, or not active, and with progression or without progression.
|Clinically isolated syndrome (CIS)||The first episode of neurological symptoms due to inflammation in the CNS that lasts at least 24 hours.|
|Relapsing-remitting MS (RRMS)||Patients experience relapses, or periods of new or worsening MS signs and symptoms not caused by another illness and that last more than 48 hours, interspersed with periods of stability; typically, patients with RRMS will return to functional ability at or at least close to prior to the relapse.|
|Secondary progressive MS (SPMS)||RRMS can eventually transition to SPMS, wherein a patient’s neurological function and disability will progressively worsen over time.|
|Primary progressive MS (PPMS)||Diagnosed when the onset of symptoms is followed by progressive worsening of neurological function and accumulation of disability, without relapses and remission.|
Although, in general, women are two to four times more likely to have MS than men, in RRMS women are more affected than men, and in PPMS women and men are equally represented. Defining the clinical course of MS is critical to determining treatment options and prognosis. Persons with RRMS or SPMS experience more inflammation and disruption of myelin, and more brain lesions than those with PPMS. Persons with PPMS generally have more spinal cord lesions than brain lesions.
Comorbidities and Secondary Conditions In MS
The experience of MS is complicated by the presence and extent of comorbidities, defined as a total burden of the chronic disease.
Physical comorbidities, such as hypertension, hyperlipidemia, and chronic lung disease, can exacerbate or increase the rate of progression of disability. However, psychiatric comorbidities, such as those related to mood and anxiety, can also have a negative impact and may require intervention. Nearly 25% of adults with MS have a depressive disorder. Chronic pain is also a prevalent comorbidity, affecting more than half of those with MS. Sleep disorders, including primary insomnia and obstructive sleep apnea, are also common.
Several lines of evidence suggest that at least some of the disability that occurs after MS is due to secondary deconditioning, and not just brain and spinal cord damage alone. Furthermore, people with MS are known to be less physically active than those without MS. Therefore exercise is an important component of rehabilitation in MS, critical for combating the progression of disability and deconditioning that occurs due to the symptoms, such as fatigue and pain, and heat sensitivity, environmental barriers, and poor self-efficacy for physical activity and exercise.
Medical Management of MS
Medical Assessment In MS
The American Academy of Neurology (AAN) provides recommended performance measures to facilitate optimal quality of MS management. These measures include clinical and laboratory assessments to determine diagnosis, comparison MRI within 24 months of MS diagnosis, and measures of current level of disability, fall risk, bladder dysfunction, level of physical activity, fatigue, cognitive impairment, depression, and quality of life.
Measures of Disability
Measures of disability can include clinically administered tests or patient-reported outcome measures (PROMs). The most widely used clinical measures are the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Originally developed in 1983 by Dr. John Kurtzke, the EDSS provides a scoring system based on the integrity of eight different functional systems to determine a person’s level of disability. Functional systems are functional neural networks or regions of the CNS and include pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual function, and cerebral function. Scores for the EDSS range from 0 (no limitations) to 10 (death) in 0.5 unit increments. EDSS scores below 5.0 refer to people who are able to walk without a walking aid and are determined based on the number of functional systems affected, whereas those above 5.0 are determined largely by mobility impairment.
The MSFC comprises three independent functional measures: timed 25-foot walk test (walking), nine-hole peg test (arm and hand function), and the paced auditory serial addition test (PASAT; cognitive processing speed).
Other less frequently utilized clinical measures include the European Database on MS Grading System, Functional Independence Measure, and the Guy’s Neurological Disability Scale.
It is now well recognized that the patient’s perspective on their disease status and impact, as well as their health and quality of life, is a critical component of their disease management and rehabilitation. PROMs are those captured directly from patients or their care partners. PROMs of disability can be used to replace or to supplement the clinical assessment, or as a surrogate for clinical assessments when patients are being managed remotely. Measures of disease progression and disability include the patient-determined disease steps (PDDS) and the MS rating scale, revised. PROMs can also be used to collect information related to symptoms, health status, and quality of life. For instance the 12-item MS walking scale has been shown to be correlated with clinical assessments of walking and thus may be a useful tool when it is not possible to safely perform the timed 25-foot walk test or 2- or 6-minute walk tests remotely.
While potentially of great use, especially for telemedicine and telerehabilitation approaches for MS care, the use of PROMs in MS can also be challenging. An important consideration is that many PROMs were designed for pen and paper delivery, and remote use would require a more accessible option, such as through an electronic or internet-delivery mechanism. Furthermore, cognitive impairment or physical limitations may pose barriers to a patient’s ability to complete PROMs remotely. Thus strategies are necessary for systematically delivering PROMs remotely. Nonetheless, PROMs may be an important tool for bridging the gap between remote assessments and delivery of care.
Disease Management In MS
There is no known cure for MS; thus medical management of MS is directed at slowing or halting the disease process and ameliorating MS symptoms. Medical management for RRMS and SPMS is different from that for PPMS. Disease-modifying therapies (DMTs) are used to decrease the immune-mediated attacks and inflammation in the CNS, speed the recovery after relapse, slow the progression of the disease, and manage MS symptoms. There are several DMTs for persons with RRMS and SPMS. In contrast, there is only one DMT available to persons with PPMS. DMTs can be delivered using injection, orally, or via infusion. Table 9.3 presents the DMTs currently available to persons with MS.
|Interferon beta medications|
|Glatiramer acetate (Copaxone, Glatopa)|
|Dimethyl fumarate (Tecfidera)|
|Diroximel fumarate (Vumerity)|
|Alemtuzumab (Campath, Lemtrada)|