Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disorder of the central nervous system (CNS). It is the most common cause of nontraumatic disability in young adults. Approximately 400,000 individuals are affected with MS in the United States. MS can present in numerous ways and affects several functional and cognitive systems. This patient population often develops challenges with gait, spasticity, cognition, fatigue, weakness, bladder, bowel, and wounds.
Physiatrists are well equipped to manage many of the symptomatic challenges that may otherwise go undetected or unacknowledged. An understanding of the pathogenesis, pharmacologic, and rehabilitative options for persons with MS (PwMS) is vital for the practicing physiatrist. The first disease-modifying therapy (DMT) for MS was approved in 1993. Since then, there has been rapid growth in the treatment options for MS. There are currently 10 DMT options for PwMS. As the availability of increased and more effective DMTs for MS increases, patients and families continue to expect improved quality of life and would like treatment options extending into optimal management of their myriad of symptoms. The role of physiatry for PwMS will continue to expand. It is vital that the practitioner be familiar with the specificities of MS, what differentiates it from other diseases, and how impactful rehabilitation intervention is for this population.
Costs
MS is one of the costliest illnesses to treat. The estimated annual cost for MS is $28 billion. Most DMTs for MS are distributed by a specialty pharmacy. Specialty drug costs of oncology, rheumatoid arthritis, and MS comprised 51% of the annual spending for specialty drugs for a major insurance company. These specialty drugs cost approximately $87 billion in 2012 and comprised approximately 3.1% of national health spending. It is estimated that specialty drug spending will quadruple and comprise approximately 9.1% of national health spending over the next several years as more effective treatment options become available for patients with chronic illness. The annual direct and indirect costs of MS per person is estimated to be $8528 to $54,244. Direct costs make up 77% of the total cost and is largely attributable to the cost of the prescription medication. Contrary to the laws of supply and demand, each new DMT that is introduced has not driven market competition to lower prices. The first generic DMT, glatiramer acetate, is currently under review by the U.S. Food and Drug Administration.
Epidemiology
Females are typically affected two to three times as often as males. Although females have a higher risk of having MS, those males who are affected tend to have a more aggressive course, difficulty with recovery after attack, and more rapid accumulation of disability. The peak age of diagnosis is believed to be 20 to 40 years of age ( Figure 46-1 ). Compared with Asian, black, and Hispanic populations, the disease is more common in non-Hispanic whites, with a lifetime incidence of approximately 1 in 400. It remains a disease that largely afflicts whites.
MS is more common in Europe, the United States, Canada, New Zealand, and Australia and rare along the equatorial countries and the Asian continent. Migration studies observed that individuals who move from high-risk to low-risk areas during adolescence or early childhood adopt the risk of the new area. The opposite has been shown to be true when moving from low-risk to high-risk areas, but with less robustness. In addition, birth month has shown to be of importance in MS development. A review of 40,000+ cases of MS in Canada, Denmark, Sweden, and Scotland saw increased numbers of patients born in May and June. Researchers postulated that these individuals received the least amount of sunlight in utero. The opposite pattern was observed in Australia; the lowest numbers of individuals with MS were born in May or June, lending further support to the season of birth theory.
Pathogenesis
Genetic Linkage
MS is thought to be an autoimmune disease in which immune and inflammatory cells attack the CNS, damaging the myelin, axons, and neurons. Similar to many complex human diseases, MS develops in a genetically susceptible host that has experienced several environmental triggers. This hypothesis is supported by the familial clustering of MS. Monozygotic twins have a 35% concordance rate. Dizygotic twins and first-degree relatives both have approximately 4% concordance rate of MS if a family member or sibling is affected. Also, serologic typing has found that human leucocyte antigen (HLA) is associated with the major histocompatibility complex (MHC) of humans with various immune-mediated diseases and gave rise to the field of immunogenetics. In MS, the HLA-DRB1*1501, located on chromosome 6p21, has been found to be strongly associated with development of MS. The HLA genes have been the only consistent genetic linkage noted in MS. Heterozygous carriers have three times and homozygous carriers have six times increased risk of developing MS. The DR15 haplotype is also associated with narcolepsy and systemic lupus erythematosus ( Table 46-1 ).
| Relative with Multiple Sclerosis | Chance of Developing Multiple Sclerosis (%) |
|---|---|
| Monozygotic twin | 25 to 30 |
| Dizygotic twin | 3 to 5 |
| First-degree relative (child or full sibling) | 2 to 4 |
Environmental Factors
Environmental factors have been evaluated for their effect on the risk of developing MS as well as its influence on progression. The incidence of MS increased with distance from the equator. The effects of vitamin D have demonstrated that reduced levels of vitamin D increases the risk of MS development, particularly in whites. A typical multivitamin contains approximately 400 International Units of vitamin D. Twenty minutes of whole-body sun exposure equates to approximately 10,000 International Units of vitamin D. More research supports changing the minimum daily consumption of vitamin D because it is found to be protective in several other diseases. Studies are currently being conducted to examine the influence of vitamin D levels on disease progression in MS.
Infection with Epstein-Barr virus (EBV) or human herpes virus 4 as an adolescent or young adult increases the risk of MS development. Approximately 50% of children have EBV exposure by the age of 5 years and approximately 80% to 90% of the population is exposed by 20 years of age. Primary EBV infection is typically symptomatic in infants and presents as infectious mononucleosis (IM) when reactivation occurs in adolescents or young adults. Proponents of the “Epstein-Barr virus hypothesis” have found that individuals exposed to late EBV and IM increase their risk of MS development by 2.3 times those individuals exposed to EBV without IM. No exposure to EBV reduced the risk of MS by one tenth compared with individuals exposed to EBV ( Figure 46-2 ).
Cigarette smoking is now a known risk factor in the development of MS. MS risk is approximately 50% higher in smokers and is associated with intensity and duration of smoking. Although it seems that men are more susceptible to the adverse effect of smoking, the increasing ratio of female smokers to male smokers has been proposed as an explanation for the increasing female-to-male ratio in MS incidence in several countries. A cumulative dose response exists between years and intensity of years and intensity of smoking and MS risk; cigarette smoking also appears to increase the rate of MS disease progression to secondary progressive MS (SPMS). The detrimental effects of smoking decline after 10 years of smoking cessation, despite the duration and intensity of abuse. Moist tobacco “snuffing” did not have the same effect or causation, causing researchers to study the lung-irritating effect on the immune system as a possible causation. Interestingly, alcohol consumption, in a dose-dependent manner, seems to protect the person from developing MS and attenuates the detrimental effects of smoking.
Other Factors
A strong correlation has been observed to exist between the body mass index (BMI) of females at 10 and 20 years of age. A BMI of >20 increases the risk of MS and a BMI ≥27 increased the risk by twofold. Obese females between 10 and 20 years old seem to be at greater risk than males during the same time period. An even stronger correlation of developing MS was demonstrated in females with a BMI ≥27 and HLA-DRB1*15 status.
Increased clinical and radiologic activity with increased sodium intake has been suggested as another cause of MS. This has been demonstrated in small scale studies and is under additional investigation. Concerns about the risk of exposure to mercury, trace metal, organic solvents, or crude oil have not demonstrated convincing evidence.
Immunology
MS exhibits considerable heterogeneity in clinical presentation and disease course. It is considered an autoimmune disease by most experts, but what initiates the abnormal immune response is not clear.
Most of the knowledge about the immunopathogenesis of MS comes from the study of animal models, mainly experimental autoimmune encephalomyelitis (EAE), in which immunization of an animal (e.g., a mouse or a rat) with myelin components lead to a CD4 + lymphocyte orchestrated inflammatory response in the CNS.
The pathologic hallmarks of acute MS lesions are perivenular immune cell infiltrate, demyelination, myelin laden macrophages, edema, and axonal damage. Relapses in MS are thought to be mediated by CNS-targeting peripherally activated helper lymphocytes. These autoreactive lymphocytes could have been activated through “molecular mimicry,” in which foreign antigens (e.g., viral or bacterial proteins) that are similar to CNS antigens activate the lymphocytes that will eventually react against the self-antigens. On the other hand, antigens leaked from the CNS, probably resulting from a previous unknown insult, can trigger the immune response by activating CD4 + helper T cells. These cells facilitate the recruitment and activation of other immune cells—for example, monocytes and macrophages, B cells, CD8 + cytotoxic T cells, and natural killer cells. The immune cells enter the brain and spinal cord through interaction with endothelial cells of the blood-brain barrier. Upon reactivation with autoantigens by CNS-resident antigen-presenting cells, they damage the myelin, axons, and neurons by various effector mechanisms. Antigen-specific and bystander CD4 + and CD8 + T cells, reactive microglia and infiltrating macrophages, natural killer cells, CNS reactive antibodies, inflammatory cytokines (e.g., tumor necrosis factor-alpha, interleukin-17, and osteopontin), reactive nitrogen and reactive oxygen species, metalloproteinase, and glutamate-induced excitotoxicity all contribute to CNS injury in acute and chronic MS lesions.
It is not clear which autoantigen(s) ignite the autoimmune process in MS. One possibility is activation of the peripheral immune system by CNS antigens that have been carried to the secondary lymphoid organs. It is now clear that the CNS is under immune surveillance and antigen-presenting cells carrying myelin antigens have been recognized in the cervical lymph nodes. Myelin proteins, mainly, myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and myelin proteolipid protein (PLP), are possible autoantigens in MS, because immunization of animals with peptides derived from these proteins can induce EAE in animals. No single antigen has emerged as the main target of the immune response in MS and it might be explainable by the heterogeneity of the disease. In fact, as inflammation increases the access of the immune system to previously compartmentalized antigens, “epitope spreading” may happen and new epitopes in the same protein or other proteins become new targets of the immune attack.
Molecular mimicry is an alternative explanation for the initial activation of the immune system. It has been shown that T cell receptors are capable of binding with high affinity to a few peptide/MHC ligands. Peptides from several viruses, including influenza and EBV, can activate T cells that cross-react with myelin antigens.
CD4 + T cells, based on the cytokine milieu during the activation, can differentiate into functionally different effector cells. Based on the cytokine profile they produce and their lineage specific transcription factor, these cells have been categorized into T helper 1 (Th1), Th2, and Th17 cells. The phenotype of the T helper cell, to a great extent, affects the outcome of the adaptive immune response. For years, it was thought that EAE and MS are mediated by interferon-gamma (IFN-γ) producing Th1 cells. However, it has been shown that both Th1 and Th17 cells are capable of inducing EAE in mice, although the disease phenotype might be different. The plasticity of Th17 cells, known to be important players in several autoimmune diseases, further complicates the picture. Multiple MS therapies, including IFN-β, glatiramer acetate, and fingolimod, have been shown to dampen both Th1 and Th17 responses. In the context of autoimmune inflammatory demyelination, Th2 cell responses are considered to be protective and antiinflammatory, and several MS disease-modifying drugs are thought to shift the immune system toward the Th2 response.
In contrast to effector T cells, multiple subsets of regulatory T (Treg) cells are capable of suppressing the immune response. Natural Treg cells, characterized by surface expression of CD25 and nuclear expression of Foxp3, show decreased suppressive activity and reduced migratory capacity in patients with MS.
Cerebrospinal fluid oligoclonal bands, produced by B cell–derived plasma cells, are the most consistent immunologic abnormality in patients with MS. Also, B cell depletion by monoclonal antibodies effectively decreases the inflammatory disease activity in MS (as manifested by new gadolinium-enhancing lesions on magnetic resonance imaging [MRI]). It is more likely that non–antibody-dependent B cell functions, such as antigen presentation and regulatory activities, are behind the beneficial effects seen after B cell depletion. B cells from patients with MS are deficient in production of suppressive cytokine, interleukin-10, and express higher amounts of costimulatory molecule, CD80, on their surface, leading to increased effector T cell activity.
There is mounting evidence that the cells, cytokines, and receptors of the innate immune system are important in the pathogenesis of MS. Natural killer cells are capable of regulating the activity of autoreactive T cells.
MS was initially defined as a demyelinating disease of the CNS. However, it is now known to involve white matter, axonal and neuronal degeneration, and gray matter. All are present at the earliest stages and are thought to be the underlying cause of irreversible and progressive disability that develops in most PwMS. Neurodegeneration is directly or indirectly the result of inflammation and demyelination. Several studies have shown that the risk and the latency of entering the secondary progressive phase are not related to the number of exacerbations in the relapsing phase. Measures of neurodegeneration, such as brain atrophy and cortical gray matter lesion load, have stronger correlation with different measures of motor and cognitive disability. Several immunomodulatory medications have consistently demonstrated efficacy in decreasing the number of attacks in patients with relapsing forms of MS.
Subtypes
Relapsing-remitting MS (RRMS) is the most common subtype and affects approximately 50% to 65% of PwMS. This is characterized by periods of exacerbation followed by periods of remission. SPMS is the period of time when a patient with RRMS no longer has exacerbations and now has persistent accumulation of disability occurring over time. There is no biomarker that signifies the progression from RRMS to SPMS. The rate of disability accumulation varies from patient to patient. Primary progressive MS (PPMS) affects males and females equally (1 : 1) and comprises approximately 10% to 15% of PwMS. This differs from RRMS in a noticeable lack of exacerbations; instead, there is disability accumulation over time. The speed of accumulation varies from person to person. The least common and most aggressive type is progressive relapsing. This affects less than 5% of PwMS with high rates of mortality.
Diagnosis
Because of the similarity MS has to various other neurologic, rheumatologic, and vascular diseases, MS remains a diagnosis of exclusion. In addition, it is important to distinguish and exclude other demyelinating disorders, including neuromyelitis optica (NMO), acute transverse myelitis, and acute disseminated encephalomyelitis (ADEM). Criteria for diagnosis of NMO include both optic neuritis and acute myelitis, plus two of the following three factors: contiguous spinal cord involvement spanning three spinal segments or more, exclusion of MS, and NMO–immunoglobulin G (IgG) seropositive status. The NMO antibody test is readily available in most laboratories and targets the aquaporin-4 antigen. It is greater than 90% specific with a sensitivity of 75% for NMO and not detected in patients with classic MS. Differentiation of NMO from MS is vital because treatment is distinct for each disorder. Acute transverse myelitis presents acutely, may be monophasic or multiphasic, and has a clearly defined sensory level with exclusion of other causes. It is a focal inflammatory disorder of the spinal cord and may result in abnormalities in motor, sensory, or autonomic function.
Common presenting symptoms in MS include optic neuritis, sensory loss, paresthesias, motor dysfunction, ataxia, and weakness. MS may also present as overwhelming fatigue or weakness. This symptom may be misconstrued as fatigue caused by other nonmedical factors (busy lifestyles or excessive demands because of family or work obligations). Fatigue may be attributable to metabolic, hematologic, or other nonneurologic issues ( Boxes 46-1 and 46-2 ).
- •
Activities of daily living
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Ataxia/apraxia
- •
Neurogenic bowel
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Neurogenic bladder
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Cognition
- •
Fatigue
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Heat sensitivity/intolerance
- •
Gait disorders
- •
Mood disturbance
- •
Pain
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Spasticity
- •
Optic neuritis
- •
Weakness
- •
Sexual dysfunction
- •
Numbness/paresthesias
- •
Neuromyelitis optica
- •
Acute disseminated encephalomyelitis
- •
Transverse myelitis
- •
Neurosyphilis
- •
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
- •
Behçet disease
- •
Neurosarcoidosis
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B12 deficiency
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Folate deficiency
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Vasculitis process
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Mixed connective tissue disease
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Neurosarcoidosis
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Rheumatoid arthritis
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Lyme disease
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Systemic lupus erythematosus
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Sjögren syndrome
- •
Carcinoma
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Wegener granulomatosis
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Hypercoagulable state
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Migraine history
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Hypertension
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Mitochondrial disorders
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“Normal”
In addition to clinical symptoms, MRI is recommended for the diagnostic evaluation in MS. Radiologic imaging can supplement or support clinical and laboratory data. The International Panel on Diagnosis of MS (the Panel) recommends screening with MR sequencing. The McDonald criteria are the most current and widely used to diagnose MS ( Table 46-2 ). The McDonald criteria have gone through updates in 2001, 2005, and most recently in 2010. This was based on research published by the MAGNIMS (European Magnetic Resonance Network in MS) group of MRI centers in Europe. What has remained consistent despite each update is that MS may be diagnosed based on clinical symptoms alone. Two clinical attacks at two separate points in time fulfill the criteria to diagnose a PwMS. Dissemination in space is met by having one or more T2 lesions in two out of four locations in the CNS: periventricular, juxtacortical, infratentorial, and spinal cord ( Box 46-3 ). Dissemination in time was met by the presence of a new T2 and/or gadolinium-enhancing lesion on a follow-up MRI, irrespective of the timing or the simultaneous presence of asymptomatic gadolinium-enhancing lesions and nonenhancing lesions ( Box 46-4 ).
| Clinical Presentation | Additional Data Needed for MS Diagnosis |
|---|---|
| ≥2 attacks † ; objective clinical evidence of ≥2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a previous attack ‡ | None § |
| ≥2 attacks † ; objective clinical evidence of 1 lesion | DIS, demonstrated by: ≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) ‖ ; or Await a further clinical attack † implicating a different CNS site |
| 1 attack † ; objective clinical evidence of ≥2 lesions | DIT, demonstrated by: Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack † |
| 1 attack † ; objective clinical evidence of 1 lesion (clinically isolated syndrome) | Dissemination in space and time, demonstrated by: For DIS: ≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) ‖ ; or Await a second clinical attack † implicating a different CNS site; and For DIT: Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack † |
| Insidious neurologic progression suggestive of MS (PPMS) | 1 year of disease progression (retrospectively or prospectively determined) plus 2 of 3 of the following criteria ‖ : Evidence of DIS in the brain based on ≥1 T2 lesions in the MS-characteristic regions (periventricular, juxtacortical, or infratentorial) Evidence for DIS in the spinal cord based on ≥2 T2 lesions in the cord Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index) |
* If the criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is “MS”; if suspicious, but the criteria are not completely met, the diagnosis is “possible MS”; if another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is “not MS”.
† An attack (relapse, exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurologic examination, but some historical events with symptoms and evolution characteristic for MS, but for which no objective neurologic findings are documented, can provide reasonable evidence of a previous demyelinating event. Reports of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurologic examination, visual-evoked potential response in patients reporting previous visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurologic symptoms.
‡ Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of documented objective neurologic findings, can include historical events with symptoms and evolution characteristics for a previous inflammatory demyelinating event; at least 1 attack, however, must be supported by objective findings.
§ No additional tests required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these criteria. If imaging or other tests (e.g., CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS, and alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence must be present to support a diagnosis of MS.
‖ Gadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in individuals with brainstem or spinal cord syndromes.
DIS can be demonstrated by ≥T2 lesion *
* Gadolinium enhancement of lesions is not required for DIS.
in at least two of four areas of the CNS:- •
Periventricular
- •
Juxtacortical
- •
Infratentorial
- •
Spinal cord †
† If an individual has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the criteria and do not contribute to the lesions count.
CNS, Central nervous system; DIS, dissemination in space; MRI, magnetic resonance imaging.
DIT can be demonstrated by:
- •
A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI
- •
Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time
DIT, Dissemination in time; MRI, magnetic resonance imaging.
Clinical Decision-Making
In addition to its usefulness in diagnostic decision-making, MRI is frequently used in the clinical decision choices regarding the effectiveness of DMTs ( Figure 46-3 ). MRI can reflect subclinical and preclinical changes and is useful in monitoring any underlying disease activity. Suggested MR images for diagnostic and clinical decision-making include T1 images with and without contrast, T2 images, and fluid attenuated inversion recovery (FLAIR) sequencing. T1 images with and without contrast determine the presence of “active” lesions. Areas of breakdown in the blood-brain barrier characterized by an inflammatory defect or disruption result in perivascular changes and allow update of gadolinium. These lesions will subsequently enhance on T1 images. Contrast-enhancing lesions will remain so for approximately 4 to 12 weeks and are associated with new or active lesions and are indicative of clinically active disease. This is often used as a marker for disease control in both a clinical and research setting. Key technical factors include waiting approximately 15 minutes after contrast infusion to ensure accurate imaging. Gadolinium-enhancing lesions have been weakly correlated with disability or impairment accumulation.
“Black hole” lesions are hypointense, nonenhancing T1 lesions. These are correlated with chronic axonal damage and loss on MR sequences as well as histopathology. Their presence is associated with worsening cognitive function. Widening of the third ventricle is also associated with cortical atrophy and is correlated with cognitive dysfunction. Reduction in T1 “black hole” formation is used as a biomarker for neuroprotection.
FLAIR imaging suppresses the cerebrospinal fluid (CSF) hyperintense signal in T2 images and allows for clearer demarcation of hyperintensities associated with the MS plaques. The short T1 inversion recovery (STIR) sequence is a relatively new technique used to better visualize the spinal cord. Plaques and hyperintensities are significantly better viewed with STIR imaging than previous T2 or proton density views ( Figure 46-4 ).
Imaging frequency is often clinician preference. New T2 or FLAIR lesions as well as active lesions help determine efficacy of DMT and correlate with long-term disability accumulation.
Some studies have evaluated clinical and radiologic risk factors to help predict conversion to clinically definite MS. Clinically isolated syndrome (CIS) refers to the first demyelinating event incurred by a patient. A 14-year longitudinal study of patients with CIS evaluated the correlation between T2 lesion burden and conversion to MS. Study participants with one T2 lesion or more had an almost 90% chance of conversion to MS. Another important point from this study was the modest correlation between lesion burden and disability, which is clinically significant for the physiatrist. The radiologically isolated syndrome has been used to help determine a patient’s risk for conversion to clinically definite MS. This suggests that asymptomatic lesions that are ovoid, well-circumscribed lesions in the brain or spinal cord that cannot be explained by other causes may predict one’s risk for MS conversion. Current predictors of a demyelinating event are age younger than 37 years, male sex and spinal cord involvement. Optical coherence tomography is a noninvasive technique to determine the thickness of the retinal nerve fiber layer. It is sensitive in detecting subclinical presence of optic neuropathy that affects approximately 25% to 50% of PwMS. Its use as a biomarker for disease progression, response to DMT, and disability in MS continues ( Figure 46-5 ).
Although MRI is often helpful in the diagnostic workup process, it is not required for the diagnosis. As stated previously, clinical impression alone can suffice. In the setting of a patient with no abnormal or nonspecific MRI findings, other testing, including CSF analysis and evoked potential studies may be needed for additional support. The “gold standard” for analyzing CSF fluid is by isoelectric focusing, which has the highest sensitivity and specificity in diagnosing MS. The presence of oligoclonal bands represents intrathecal synthesis. The role of oligoclonal bands in MS remains unclear; their presence correlates with a diagnosis of MS. An elevated albumin index represents blood-brain barrier disruption because albumin is synthesized and metabolized outside of the CNS. Other factors to consider include abnormalities in the IgG index, IgG synthesis, and an elevated leucocyte count. CSF fluid analysis not the sine qua non for a diagnosis of MS, it can provide corroborative evidence in support of the diagnosis.
Neurophysiologic testing such as visual, somatosensory, and brainstem auditory evoked potential may also be helpful in cases where clinical, radiologic, or CSF testing is inconclusive. Evoked potential testing is noninvasive and detects abnormalities throughout the length of the sensory pathway. This is helpful in cases where patients may have clinical symptoms of optic neuritis, including periorbital pain, photosensitivity, or visual change. A prolongation in the p100 pathway is considered abnormal. Occasionally, a prolongation in the p100 pathway of the unaffected eye may also be seen. Somatosensory evoked potentials detect delays along the median and tibial motor pathways. Brainstem auditory evoked potentials detect delays along the auditory pathway. There is some evidence that combining visual-evoked potential and somatosensory-evoked potential testing significantly increases the diagnostic yield. Currently, only visual-evoked potentials are included in the MS diagnostic guidelines.
The Expanded Disability Status Scale (EDSS) is an ordinal clinical rating scale ranging from 0 (no impairment) to 10 (death) ( Figure 46-6 ). It is based on a detailed neurologic examination and includes functional systems evaluating pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral/mental, and miscellaneous functions. An EDSS score ≤4.0 implies minimal disability with no ambulation restriction, an EDSS score ≥6.0 signifies ambulation with the use of an assistive device, and an EDSS score ≥8.0 identifies a person who is essentially bed bound. The EDSS is one of the most widely used scales clinically and for research purposes. From a functional perspective, Dr. Kurtz should be credited for his emphasis on disability measurement and its correlation to other systems at such an early time.
Pharmacologic Management
Disease-Modifying Therapies
IFN-β1 b was the first DMT and was introduced for the treatment of RRMS in the mid-1990s. Over time, several doses of IFN-β became available as well as glatiramer acetate. However, the landscape of DMT has remarkably changed within the past 5 years. This has added new complexities for the decision-making process of both physicians and patients. What was previously a fairly simple treatment process has become more complex while more medications become available with different degrees of efficacy and safety profiles.
First-Generation Disease-Modifying Therapies
Interferon β (IFN-β).
Although the mechanism of action is not fully understood, IFN-β (Avonex, Betaseron, Extavia, Rebif) reduces blood-brain barrier disruption and modulates T cell, B cell, and cytokine function. IFN-β1 a is available in low and high doses. Low-dose IFN-β1 a is a once-weekly intramuscular injection. The high-dose IFN medications are all given subcutaneously three times a week in various dose regimens. IFNs are associated with flulike side effects ranging from increased fatigue, headache, myalgia, and joint pain. These gradually decrease over time and can be well controlled with nonsteroidal antiinflammatory medications taken in conjunction with the injections. All of the IFNs are associated with possible blood and bone marrow abnormalities, liver dysfunction, hypothyroidism, and mood dysfunction. There is a possibility of developing IFN antibodies, and persistently high titers of IFN antibodies are associated with diminished efficacy. It is recommended to monitor a complete blood count, liver profile, and thyroid function with treatment. IFN treatment has been known to be associated with increased risk of depression. Gradual titration of medication and routine screening is advised.
Glatiramer Acetate.
The mechanism of glatiramer acetate (Copaxone) is also unclear but is probably attributable to stimulation of Treg cells. The initial dose was 20 mg administered by subcutaneous injection daily. The U.S. Food and Drug Administration (FDA) recently approved a new dose of 40 mg three times a week. Occasionally, patients experience postinjection systemic reactions that are associated with flushing, palpitations, and shortness of breath and resolve after 5 to 10 minutes. All of the medications that are administered by subcutaneous injection are associated with injection site reactions, including glatiramer acetate. They can also result in lipoatrophy over time.
Because IFNs and glatiramer acetate have favorable long-term safety profiles, they remain the common first-line treatment choices for most practitioners despite the recent availability of new oral medications. They are similar in efficacy and reduce relapses by 30% in the platform studies. However, adherence remains a problem with greater than 25% of patients discontinuing therapy within 1 to 2 years. IFNs and glatiramer acetate are limited in their ability to control disease activity for some patients. Therefore, patients with progressive disability related to ongoing disease activity may need to escalate DMT.
Oral Therapies
Fingolimod.
Fingolimod (Gilenya) is the first oral agent that became commercially available for the treatment of RRMS. It is phosphorylated by sphingosine kinase 2 and mimics sphingosine 1-phosphate (SIP) binding to lymphocytes, which results in lymphocyte sequestration within the lymph nodes. Fingolimod also enters the CNS and affects neurons and supports glia that express SIP receptors. It is associated with a 50% reduction in relapse rate versus placebo.
Adverse effects of fingolimod are related to lymphopenia as well as the other subtypes of SIP receptors that are expressed on tissues. Although few opportunistic infections have occurred, there is a risk of viral infections. Documentation of varicella zoster immunity is required before starting therapy. Disseminated zoster infection has occurred. All patients must obtain a baseline electrocardiogram because of the known risk of bradycardia and possible risk of arrhythmias before starting treatment and undergo subsequent cardiovascular monitoring. Other possible safety concerns include the possibility of macular edema and elevated liver enzymes. Safety assessments include ophthalmology assessments and ongoing laboratory monitoring with complete blood counts with manual differential and liver function tests.
Teriflunomide.
Teriflunomide (Aubagio) is a selective immunosuppressant with antiinflammatory properties. It is the active ring malononitrile metabolite of leflunomide, a prodrug that is used for rheumatoid arthritis. It exerts immunologic effects by inhibiting dihydroorotate dehydrogenase, an enzyme required for de novo pyrimidine synthesis in proliferating cells. Alternative modes of action may include reduced IFN-γ and interleukin-10 production by T cells, interference in the interaction between T cells and antigen-presenting cells, and changes in integrin signaling during T cell activation as well as possible antioxidant effects. Two doses of teriflunomide, 7 and 14 mg, were approved following two large placebo-controlled studies that revealed a 31% reduction in annualized relapse rate. Improvements in disability progression were only shown with the 14-mg dose. Common side effects include lymphopenia, elevated transaminases, acute renal failure, and alopecia. It is a pregnancy category X resulting from teratogenicity associated with leflunomide. It has a prolonged half-life and is contraindicated in pregnancy. It is excreted in breast milk and semen. Cholestyramine may help fully eliminate the drug.
Dimethyl Fumarate.
Dimethyl fumarate (BG-12; Tecfidera) is a fumaric acid ester that is a newly approved twice-daily oral DMT for relapsing MS. It is hydrolyzed into monomethylfumarate and is eliminated through respiration. It has minimal hepatic or renal excretion. The mechanism of dimethyl fumarate is not completely clear but is known to activate the nuclear-related factor-2 transcriptional pathway. This can impact oxidative stress as well as modulate nuclear factor-κB that could have antiinflammatory effects. There were two large placebo-controlled trials involving dimethyl fumarate that revealed a 45% to 50% reduction in annualized relapse rate. It appears to have a relatively favorable safety profile, although concern was raised regarding recent publications of a few cases of progressive multifocal leukoencephalopathy (PML) with dimethyl fumarate treatment in Germany. There has been no association of PML related to treatment of dimethyl fumarate for MS. Risk factors appear to be prolonged lymphopenia and cotreatment with other immunosuppressive medications. Other potential side effects with treatment include flushing, gastrointestinal upset, lymphopenia, and elevated liver enzymes.
Intravenous Therapies
Natalizumab.
Natalizumab (Tysabri) is a humanized monoclonal antibody targeting α4β1-integrin. It inhibits leukocyte migration across the blood-brain barrier by blocking the interaction between α4-integrin on leukocytes and vascular cell adhesion molecule-1 on endothelial cells and other CNS ligands. Two large placebo-controlled trials revealed a 68% reduction rate in relapses as well as a 43% reduction in disability. Natalizumab was initially approved for the treatment of RRMS in 2004 and was voluntarily removed from the market after the development of three cases of PML in 2005. Two of the cases were in patients treated for MS who were also receiving IFN-β1 a . Natalizumab was reapproved for treatment in conjunction with a safety monitoring program (Touch program) in 2006. Risk factors for developing PML include evidence of previous John Cunningham (JC) virus exposure, duration of natalizumab therapy, and previous use of immunosuppressant treatment such as mitoxantrone, azathioprine, or methotrexate. The risk of PML increases with increasing duration of therapy (0.6 per 1000 less than 2 years, 5 per 1000 at 2 to 4 years), particularly if there is a history of immunosuppression (1.6 per 1000 less than 2 years, 11 per 1000 at 2 to 4 years). There are concerns regarding possible rebound disease activity after stopping natalizumab.
In terms of monitoring for PML, patients using natalizumab who are JC seropositive should undergo MRI surveillance every 6 months to detect early, subtle signs that would be suggestive of PML. Clinical or MRI evidence of PML should prompt natalizumab discontinuation until further assessment is obtained. Diagnosis is confirmed by CSF analysis for JC virus DNA by polymerase chain reaction. Treatment is needed by rapid removal of natalizumab with plasmapheresis. A short course of intravenous methylprednisolone may be administered in an effort to mitigate additional damage that can occur from the immune reconstitution syndrome.
Additional adverse effects that can occur from natalizumab treatment include a mild increased risk of infections, such as urinary tract or upper respiratory tract infections. Approximately 6% of patients can develop infusion reactions. These individuals are at a higher risk of developing antibodies against Natalizumab, which may lessen the efficacy of treatment. There is also a potential for elevated liver enzymes.
Mitoxantrone.
Mitoxantrone (Novantrone) is a chemotherapeutic agent that has been approved to treat aggressive-relapsing MS and SPMS. It is a cytotoxic agent that inhibits B cells, T cells, and macrophage proliferation. It is administered as an intravenous infusion, four times per year (12 mg, m 2 ) with a maximum cumulative dose of 100 to 140 mg/m 2 . It is known that there is a dose-dependent risk of cardiomyopathy. Before initiation of therapy, left ventricular ejection fraction should be obtained by echocardiogram, multigated radionuclide angiography, or MRI. Before each infusion with mitoxantrone, an electrocardiogram should be performed. A qualitative reevaluation of left ventricular ejection fraction should be assessed after termination of mitoxantrone using the same method that was performed at baseline.
Other potential adverse reactions of mitoxantrone are lymphopenia and elevated liver enzymes. Mitoxantrone should not be administered when the neutrophil count falls less than 1500 mm 2 . A complete blood count with manual differential and liver enzymes should be tested before administration. During therapy, patients should avoid receiving live virus vaccinations. Mitoxantrone is assigned a pregnancy category D. Patients should be informed of the potential risk that it may cause sterility if they have not completed their family planning. A pregnancy test should be completed before each dose.
Alemtuzumab.
Alemtuzumab (Lemtrada) is a humanized monoclonal antibody against CD52 that is expressed on lymphocytes and monocytes and causes rapid and profound lymphopenia. The recovery of lymphopenia is variable and subset dependent. An application has been submitted in the United States based on the results of two large placebo-controlled studies that revealed significant efficacy of alemtuzumab for the treatment of relapsing MS. Secondary autoimmunity has been reported in up to 20% of treated patients. Although the etiology is unclear, it may be related to secondary immune reconstitution syndrome that results in B cells emerging before Treg cells. Patients can develop thyroid disease, idiopathic thrombocytopenia, and possibly Goodpasture syndrome. There is some implication that interleukin-21 may help mitigate this risk. Treatment requires frequent laboratory monitoring with complete blood count with manual differential, thyroid functioning, and liver functioning. Clinical trials are ongoing in efforts to minimize additional autoimmune disease risk.
Other potential side effects include infusion reactions such as urticaria, pyrexia, and rigor. Pretreatment with corticosteroids and antihistamines may improve tolerability. Infections can occur with alemtuzumab given the severe leukopenia. There have been cases of PML associated with alemtuzumab treatment reported in patients treated for chronic lymphocytic leukemia and non-Hodgkin lymphoma ( Table 46-3 ).
| Medication | Route | Frequency | Adverse Effects | Pregnancy Class |
|---|---|---|---|---|
| Interferon β1 a | Intramuscular | Weekly | Interferon side effects Leukopenia, hepatotoxicity, thyroid changes, mood changes | C |
| Interferon B1 a Interferon B1 b | Subcutaneous | MWF 3 times weekly | Interferon side effects Leukopenia, hepatotoxicity, thyroid changes, mood changes Injection site reactions | C |
| Glatiramer acetate | Subcutaneous | 20 mg SQ daily or 40 mg 3 times per week | Injection site reactions Postinjection systemic reactions | B |
| Fingolimod | Oral | Daily | Lymphopenia Macular edema Bradycardia/AV block Risk of infections | C |
| Teriflunomide | Oral | Daily | Lymphopenia Risk of infections Alopecia Hepatotoxicity Renal failure Teratogenicity | X Requires negative pregnancy test before starting treatment |
| Dimethyl fumarate | Oral | Twice a day | Lymphopenia Gastrointestinal upset Hepatotoxicity | C |
| Natalizumab | IV | Every 4 weeks | Increased risk of infection, primarily concerning risk of PML Infusion reactions Hepatotoxicity | C |
| Mitoxantrone | IV | Every 12 weeks | Lymphopenia Cardiotoxicity Increased risk of infections Risk of malignancy Possibility of sterility | D Requires negative pregnancy test before starting treatment |
Rehabilitation, Exercise, and Symptom Management
Physical Activity
A person with a disability is prone to inactivity and deconditioning. Current recommendations for physical activity are meant for individuals without physical disability and those guidelines are often not applicable to the population with disabilities. PwMS were previously advised to not exercise for fear of worsening disease course. In addition, PwMS would be advised to avoid exercise so as to prevent overheating. Immune profile studies have demonstrated no change in the physiologic variables of patients with MS compared with control groups after being subjected to 30 minutes of aerobic exercise. However, multiple studies have demonstrated the safety and benefit of exercise in PwMS, regardless of MS subtype, in terms of aerobic fitness, quality of life, and overall health. Advice on exercise and physical fitness recommendations was the most sought-after request among individuals with MS and was surprisingly ahead of questions on medication.
The first and only consensus panel convened in an effort to review the available evidence and formulate guidelines for physical fitness in PwMS. The review determined there was sufficient evidence to formulate guidelines to improve aerobic capacity and muscle strength. The consensus panel did not find sufficient evidence to provide guidelines for mobility, fatigue, or health-related quality of life benefits ( Table 46-4 ). These recommendations are based on the recommendations for physical activity of the MS Society of Canada.
| Aerobic Activity | Strength Training Activity | |
|---|---|---|
| How often? | Two times per week | Two times per week |
| ||
| How much? | Gradually increase your activity so that you are doing at least 30 minutes of aerobic activity during each workout session. | Repetitions are the number of times you lift and lower a weight. Try to do 10 to 15 repetitions of each exercise. This counts as one set. Gradually work up to doing two sets of 10 to 15 repetitions of each exercise. |
| How hard? | These activities should be performed at a moderate intensity. Moderate-intensity physical activity is usually a 5 or 6 on a scale of 10, and causes your heart rate to go up. As a general rule, if you are doing moderate-intensity activity you can talk, but not sing a song, during the activity. | Pick a resistance (free weights, cable pulleys, bands, etc.) heavy enough that you can barely, but safely, finish 10 to 15 repetitions of the last set. Be sure to rest for 1 to 2 minutes between each set and exercise. |
| How to? | Some options for activity include: | |
Aerobic activities
| Strength training activities for the upper and lower body
| |
| Other types of exercise that may bring benefits Elastic resistance bands Aquatic exercise Calisthenics | ||
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