Multiple sclerosis (MS) is a disabling condition that is managed medically through an ever growing list of pharmaceutical treatments. Clinical pathways that focus primarily on treatments for the disease overlook associated medical complications, including but not limited to depression, contractures, spasticity, and fatigue. This can potentially lead to poorer outcomes for patients with MS. Clinical pathways for MS should address these concurrent health problems associated with the condition and also acknowledge the expanded role of primary care providers in helping patients to manage their disease.
MS is a progressive autoimmune demyelinating condition characterized by axonal damage and subsequent delay in nerve conduction. MS is more common in women than in men, and the most common age range of presentation is between 25 and 35 years of age.1 The course of relapsing-remitting MS (RRMS) can be benign, where the patient maintains neurologic function 15 years after diagnosis (Table 1). In contrast, progressive-relapsing MS is a rapidly progressing, disabling course that typically arises within 5 years of the original diagnosis.
The exact etiology that results in the clinical picture of patients with MS is unknown, although a complex interplay of the immune system, genetics, and the environment has been implicated.1 Given that much about the disease remains unknown, clarity in the form of guidelines can provide direction to ensure patients are appropriately treated, especially when it comes to often missed MS symptoms. Medical management of MS through the ever growing list of pharmaceutical treatments is a critical element of any clinical pathway for this disease. Treatments for RRMS have progressed from the commonly used interferons therapies to far more advanced disease-modifying agents (Table 2).
Additionally, it is equally important for MS clinical pathways to address conditions that are commonly seen in patients with MS, including depression; contractures, spasticity, and fatigue; and bladder dysfunction. Primary care providers (PCPs) play an essential role in identification and treatment of the many manifestations and comorbid conditions common among patients with MS.
Depression in Patients With MS
Depression, which is often underdiagnosed in patients with MS, can lead to a decline in quality of life.2 The lifetime risk of depression in patients with MS is estimated to range between 22.8% and 54%; comparatively, lifetime prevalence of depression is 13% in those with chronic illnesses other than MS and 8% in the general population.3 Interestingly, patients with MS tend to have more severe depressive symptoms.2
Depression in patients with MS is thought to have a multifactorial etiology.2 The psychosocial effects of disability resulting from MS, the effect of demyelinating lesions on the regulation and maintenance of mood, as well as immune dysfunction, are contributing factors.2
Social support, disability, and employment status correlate with depression in patients with MS. Unemployment is associated with a negative change in standard of living; additionally, unemployment was found to have a strong positive correlation with depression.2 Disease progression inevitably leads to increase in disability, the resultant loss of independence, decrease in socialization, and increase in reliance on caregivers occurs.2 All of these can contribute to greater caregiver burden.2 Patients who were more physically disabled tended to have higher levels of depression. Females, unmarried/uncoupled persons, and those with health insurance were more likely to be on antidepressants.3 Additionally, patients receiving interferon therapy were found to have higher rates of depression, though it is not established whether the depression is a side effect of the medication or as a result of MS.3
Magnetic resonance imaging has been utilized to study the location of MS lesions and resultant depressive symptoms. Lesions in the arcuate fasciculus and superior frontal and superior parietal areas are positively associated with depression.2 Patients with depression were also found to have increased numbers of activated T cells and acute phase proteins and higher production of proinflammatory cytokines.2
Health care providers treating MS should screen and appropriately treat patients with MS for depression.3 Similar to the general population, if left untreated, depression in patients with MS is likely to worsen. Risk factors of suicide include diagnosis before age 30 years, male gender, and hopelessness. Cognitive behavioral therapy has been consistently demonstrated as an effective method of treating depression.2 In terms of medications, the tricyclic antidepressants with their anticholinergic properties are beneficial in patients with neurogenic bladder symptoms.2 Selective serotonin reuptake inhibitors are also a safe and effective treatment choice.
Contractures, Spasticity, and Fatigue in MS
Much of the management of MS involves managing of symptoms such as contractures, spasticity, and fatigue. A study conducted in Australia found a 60% prevalence rate of contractures affecting at least one joint in patients with MS and a positive correlation between disability and contractures.4 Contractures in the ankle joints are quite common in the MS population, which severely limit mobility.4 Weakness often occurs in conjunction with contractures, though no causal relationship has been established.4 The Modified Ashforth Scale (MAS) involves the passive range of motion of a joint; a score between 0 and 4 (with 0 being normal) is given. Motor diseases are associated with higher MAS scores as compared with healthy individuals.5
Central nervous system lesions result in impairment of signal transmission in spinal pathways, resulting in the loss of inhibitory control over spinal pathways. This results in the spasticity seen in MS,5 which is closely related to decrease in quality of life.5 Spasticity occurs most commonly in the lower extremities, impairing walking, maintenance of posture, and activities of daily living.5 Spasticity results in changes in gait, affecting speed of walking as well as stride and range of motion.5 These patients are also at a higher risk of falls, with about half of falls requiring medical evaluation.5
There are various classes of medications to help treat spasticity—GABA agonists, aα agonists, and botulinum toxin—although their efficacy is not well established.5 Common side effects of these medications include weakness, dizziness, and nausea.5 Exercise has also shown to have a beneficial effect on spasticity.5
Impaired conduction of motor impulses secondary to demyelination is thought to play a role in fatigue.6 It is considered by patients to be one of the most taxing aspects of their condition.6 An estimated one-third of patients with MS experience fatigue impacting their daily lives.6 Fatigue can be present with or without concurrent depression or weakness and can sometimes signal an oncoming relapse; it is more prevalent later in the day.6 Fatigue in patients with MS is significant enough that patients will decrease their activity.6 Patients also complain of mental fatigue, which is characterized by inability to concentrate or detriment in decision-making capability.7
Exercise programs help with preventing deconditioning, but providers should be vigilant to prevent overexertion in their patients.6 Comorbidities that could be contributing to or worsening fatigue should be addressed; for example, antidepressants may help those with coexisting depression, and sleep aids may help patients with insomnia.6
Bladder Dysfunction in Patients With MS
Additional issues that arise for patients with MS include bowel, bladder, and sexual dysfunction. These issues are commonly associated with MS and can occur at any time during the disease course, resulting in considerable disability as well as decreased quality of life.8
The prevalence of bladder dysfunction is estimated to be 50% to 80% of patients. A study found that bladder dysfunction is positively associated with impaired physical functioning in both early and late stages of MS.8 Bladder dysfunction is associated with a poorer quality of life.8 The most common type of bladder dysfunction in patients with MS is neurogenic overactive bladder; common symptoms include frequency, urgency, incontinence, and nocturia.9 These symptoms are often overlooked in patients with MS and, as a result, they are not referred to urologists.9 On the other hand, some patients’ symptoms are inadequately treated, as they are unable to tolerate medication.9 There are newer treatments that seem promising, such as sacral neuromodulation and posterior tibial nerve stimulation, but their role in treatment specifically for patients with MS requires further research.9 Onabotulinum toxin A was approved by the US Food and Drug Administration in 2011 for treatment of neurogenic detrusor overactivity and appears to be beneficial in patients with MS. Two large trials in patients with MS have shown considerable reduction in incontinence symptoms.9
The Role of PCPS
While clinical pathways focus primarily on treatment recommendations, it is equally important to consider which health care providers are most likely to provide care for patients with MS as well as in which settings care will be provided. For example, given the limited availability of MS specialists, even among neurologists, much of the responsibility of caring for patients with MS will fall upon PCPs. PCPs have a primary role in the identification and treatment of the many manifestations and comorbid conditions common among patients with MS. In addition, PCPs have a role in recognizing periods of relapse and treatment failure such that adjustments in primary MS medications are required. These changes can be accomplished in consultation with a neurologist or an MS specialist; however, given access issues, these consultations are increasing occurring via telemedicine-facilitated interactions. As such, PCPs can play a critical role in the identification and management of MS and its complications, resulting in improved outcomes for MS throughout the course of disease including at end of life.
Conclusion
Treatment for MS has advanced considerably, but is not curative and can have severe side effects. There are numerous classes of drugs available that can help prevent progression of the disease. Because most clinical pathways focus primarily on treatments for the disease, identification and management of disease symptoms is often missing, leading to substantially poorer outcomes for patients with MS. This calls out the importance of including these elements in any clinical pathways for MS. MS is condition with many associated medical complications, including but not limited to depression, contractures, spasticity, and fatigue. Depression is exceedingly common, as are fatigue, bladder dysfunction, and contractures; these conditions should be appropriately treated to prevent worsening of disability. Clinical pathways for MS should be cognizant of the numerous concurrent health problems associated with the condition and treat appropriately as well as detailing for providers the opportunities for an expanded role of PCPs.
References
1. Beretich BD, Beretich TM. Explaining multiple sclerosis prevalence by ultraviolet exposure: a geospatial analysis. Mult Scler. 2009;15(8):891-898.
2. Wallin MT, Wilken JA, Turner AP, Williams RM, Kane R. Depression and multiple sclerosis: Review of a lethal combination. J Rehabil Res Dev. 2006;43(1):45-62.
3. Cetin K, Johnson KL, Ehde DM, Kuehn CM, Amtmann D, Kraft GH. Antidepressant use in multiple sclerosis: epidemiologic study of a large community sample. Mult Scler. 2007;13(8):1046-1053.
4. Hoang PD, Gandevia SC, Herbert RD. Prevalence of joint contractures and muscle weakness in people with multiple sclerosis. Disabil Rehabil. 2014;36(19):1588-1593.
5. Sosnoff JJ, Motl RW. Management of spasticity in multiple sclerosis: the possible roles of acute and chronic exercise. Curr Med Lit Mult Scler. 2012;4(2):29-36.
6. Comi G, Leocani L, Rossi P, Colombo B. Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol. 2001;248(3):174-179.
7. Greim B, Benecke R, Zettl UK. Qualitative and quantitative assessment of fatigue in multiple sclerosis (MS). J Neurol. 2007;254(suppl 2):II58-II64.
8. Vitkova M, Rosenberger J, Krakovcova M, et al. Health-related quality of life in multiple sclerosis patients with bladder, bowel and sexual dysfunction. Disabil Rehabil. 2014;36(12):1987-1992.
9. Campeau L. Current management of refractory neurogenic overactive bladder and multiple sclerosis parkinsonism. AUANews. 2015;20(11):8.
10. Madell R, Gotter A. MS stages: what to expect. Healthline. https://www.healthline.com/health/multiple-sclerosis/stages#Progressive-RelapsingMS7. Accessed September 15, 2016.
11. Cowen & Company. Pharmaceutical Therapeutic Categories Outlook. September 2016.
12. Hersh CM, Fox RJ. Multiple sclerosis. June 2014. https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/. Accessed September 15, 2016.
13. Oh J, O’Connor P. An update of teriflunomide for treatment of multiple sclerosis. Ther Clin Risk Manag. 2013;9:177-189.
14. Capobianco M, Motuzova Y, Bertolotto A, et al. Natalizumab in aggressive multiple sclerosis after haematopoietic stem cell transplantation. Neurol Sci. 2012;33(4):863-867.
15. Duddy M, Haghikia A, Gold R, et al. Managing MS in a changing treatment landscape. J Neurol. 2011;258(5):728-739.
