Multiple Sclerosis (MS)


Multiple sclerosis (MS) is characterized by immune-mediated demyelination with associated axonal damage, neurodegeneration, and gliosis.1 It can lead to a number of life-threatening complications as the disease progresses. The progressive damage to the central nervous system (CNS) leads to increasing levels of disability commonly measured using the Expanded Disability Status Scale (EDSS), which monitors progression from no disability and a normal neurological exam (a score of 0), through limited mobility (scores 4-8), to confinement to bed (score of 9), and ultimately death due to MS (score of 10).2

With the loss of function and mobility, patients become more susceptible to several complications, such as problems with coordination, muscle spasms, involuntary movements, muscle paralysis, and rigidity, which can make them more prone to infections, pressure ulcers, depression, and accidents.

Infections

Among patients with MS, infections can be one of the most life-threatening complications. Several studies have found that MS patients are at a higher risk for contracting transmissible disease leading to serious infection than the general population.3-5 Among these infections, septic, pulmonary, and genitourinary infections were the most life-threatening.3 The increased risk of infections could be due to hospitalization or the use of immunosuppressive/immunomodulatory treatments, but could also be related to progression of the disease.

Pulmonary

Pulmonary infections in patients with MS may be due to a number of different factors. As the disease progresses, patients begin to lose muscular strength, have bulbar dysfunction, and have a decreased ability to clear secretions.4 These factors combine to reduce pulmonary function and can lead to an increased risk of lung infections.6 Lesions involving the cranial nerves, corticobulbar tracts, cerebellum, brainstem, and cortex can lead to dysphagia and an increased risk of aspiration and subsequent pneumonia.7 The use of immunosuppressive and immunomodulatory treatments, such as alemtuzumab and teriflunomide, can also increase the risk of pulmonary diseases, including latent tuberculosis.8

Urinary

An estimated 50% to 80% of patients with MS develop urinary symptoms, such as incontinence and incomplete voiding, over the course of their disease.9 These symptoms, which are often referred to as “neurogenic bladder,” along with related risk factors such as urinary stasis, high bladder pressure, bladder stones, and the need for catheterization, can increase a patient’s risk of urinary tract infections (UTIs).9 Since the symptoms of UTIs are similar to those of neurogenic bladder encountered by patients with MS, they can lead to missed diagnosis and eventually upper urinary tract infections leading to kidney damage.9 If the infection continues to be untreated, it can lead to systemic infections, sepsis, and ultimately death.9 Undetected UTIs in combination with immunosuppressive medications, such as steroids, can lead to worse infections.9

Pressure Ulcers

Patients with MS are at a higher risk of developing pressure ulcers due to reduced mobility, sensation, and cognitive abilities as the disease progresses.10 These ulcers can alter a patient’s quality of life by further affecting mobility and causing pain that can lead to sleep difficulties as well as odors from tissue necrosis that can lead to isolation and affect the mood and psychological well-being of patients.10 Pressure ulcers can also lead to systemic infections and sepsis in some patients.

Depression

Depression appears to be 2-3 times more common in patients with MS compared to the general population.11 The exact etiology of depression is not fully known but the causes are most likely multifaceted and include neurological factors, such as accumulation of MS lesions, activation of the hippocampal microglia, and regional neural atrophy, as well as psychosocial aspects of living with a progressive, debilitating disease.11 Severe depression may result in an increased risk of MS patient suicide.12

Accidents

Neurodegeneration usually affects balance, coordination, and muscular strength in patients with MS. These combine to affect mobility early in disease progression and can lead to increased risks of falls and other accidents.13 Reduced activity and mobility in patients with MS along with lower bone density (osteopenia) can lead to an increased risk of osteoporosis, which can result in greater injury during falls.14

The immunosuppressive or immunomodulatory effects of MS treatments, such as natalizumab, prednisolone, dimethyl fumarate, fludarabine, and rituximab, can also lead to possible complications in patients. The use of these medications can cause secondary immunodeficiency resulting in opportunistic infections, including progressive multifocal leukoencephalopathy (PML) caused by the John Cunningham virus (JCV).15 Decreased immune function may also increase the risk of infection-related cancers, such as cervical cancer caused by the human papillomavirus (HPV).15

Some treatments have also been shown to increase the risk of secondary autoimmune disorders, such as autoimmune thyroid disease, idiopathic thrombocytopenic purpura, and Goodpasture’s syndrome.15 Another treatment-related complication is thrombotic microangiopathy (TMA), which has been linked to long-term exposure to recombinant interferon beta.15

Other Possible Complications

Several other life-threatening complications may occur in patients with MS, including cardiovascular disease,3 pulmonary disease,3 and certain cancers such as melanoma.16 Some evidence points to cardiovascular disease risk being increased in patients with  MS due to less physical activity, autonomic nervous system impairment, oxidative stress, and endothelial dysfunction, alterations in the structure of myocytes, and chronic inflammation. It is, however, unclear whether these are all functions of disease progression or comorbidities requiring further investigation.17

Respiratory dysfunction in patients, such as respiratory failure, sleep-disordered breathing, neurogenic pulmonary edema, abnormal control of breathing, bulbar dysfunction, and respiratory muscle weakness, may be due to neuronal degeneration, lesions of the brainstem or spinal cord.18

Conflicting results have been shown regarding risks of cancer and MS,  and it is unclear whether they are causative of each other or just comorbidities of underlying immune dysfunction or lifestyle factors.19 There has, however, been a link shown between certain therapies, as mentioned above, and increased cancer risks.

References

  1. Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 2011;122(2):155-170. doi:10.1007/s00401-011-0840-0
  2. Kurtzke JF. Historical and clinical perspectives of the expanded disability status scale. Neuroepidemiology. 2008;31(1):1-9. doi:10.1159/000136645
  3. Goodin DS, Corwin M, Kaufman D, et al. Causes of death among commercially insured multiple sclerosis patients in the United States. PLoS One. 2014;9(8):e105207. doi:10.1371/journal.pone.0105207
  4. Nelson RE, Xie Y, DuVall SL, et al. Multiple sclerosis and risk of infection-related hospitalization and death in US veterans. Int J MS Care. 2015;17(5):221-230. doi:10.7224/1537-2073.2014-035 
  5. Montgomery S, Hillert J, Bahmanyar S. Hospital admission due to infections in multiple sclerosis patients. Eur J Neurol. 2013;20(8):1153-1160. doi:10.1111/ene.12130
  6. Srour N, LeBlanc C, King J, McKim DA. Lung volume recruitment in multiple sclerosis. PLoS One. 2013;8(1):e56676. doi:10.1371/journal.pone.0056676
  7. Ansari NN, Tarameshlu M, Ghelichi L. Dysphagia in multiple sclerosis patients: diagnostic and evaluation strategies. Degener Neurol Neuromuscul Dis. 2020;10:15-28. doi:10.2147/DNND.S198659
  8. Epstein DJ, Dunn J, Deresinski S. Infectious complications of multiple sclerosis therapies: implications for screening, prophylaxis, and management. Open Forum Infect Dis. 2018;5(8):ofy174. doi:10.1093/ofid/ofy174
  9. Nikseresht A, Salehi H, Foroughi AA, Nazeri M. Association between urinary symptoms and urinary tract infection in patients with multiple sclerosis. Glob J Health Sci. 2015;8(4):120-126. doi:10.5539/gjhs.v8n4p253
  10. McGinnis E, Andrea Nelson E, Gorecki C, Nixon J. What is different for people with MS who have pressure ulcers: a reflective study of the impact upon people’s quality of life? J Tissue Viability. 2015;24(3):83-90. doi:10.1016/j.jtv.2015.05.003
  11. Patten SB, Marrie RA, Carta MG. Depression in multiple sclerosis. Int Rev Psychiatry. 2017;29(5):463-472. doi:10.1080/09540261.2017.1322555
  12. Kalb R, Feinstein A, Rohrig A, Sankary L, Willis A. Depression and suicidality in multiple sclerosis: red flags, management strategies, and ethical considerations. Curr Neurol Neurosci Rep. 2019;19(10):77. doi:10.1007/s11910-019-0992-1 
  13. Carling A, Forsberg A, Nilsagård Y. Falls in people with multiple sclerosis: experiences of 115 fall situations. Clin Rehabil. 2018;32(4):526-535. doi:10.1177/0269215517730597
  14. Gupta S, Ahsan I, Mahfooz N, Abdelhamid N, Ramanathan M, Weinstock-Guttman B. Osteoporosis and multiple sclerosis: risk factors, pathophysiology, and therapeutic interventions. CNS Drugs. 2014;28(8):731-742. doi:10.1007/s40263-014-0173-3 
  15. Soleimani B, Murray K, Hunt D. Established and emerging immunological complications of biological therapeutics in multiple sclerosis. Drug Saf. 2019;42(8):941-956. doi:10.1007/s40264-019-00799-1
  16. Capkun G, Dahlke F, Lahoz R, et al. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: an observational study using the US Department of Defense administrative claims database. Mult Scler Relat Disord. 2015;4(6):546-554. doi:10.1016/j.msard.2015.08.005
  17. Mincu RI, Magda LS, Florescu M, et al. Cardiovascular dysfunction in multiple sclerosis. Maedica (Bucur). 2015;10(4):364-370.
  18. Tzelepis GE, McCool FD. Respiratory dysfunction in multiple sclerosis. Respir Med. 2015;109(6):671-679. doi:10.1016/j.rmed.2015.01.018
  19. Magyari M, Sorensen PS. Comorbidity in multiple sclerosis. Front Neurol. 2020;11:851. doi:10.3389/fneur.2020.00851

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.