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Sleep and Respiratory Control
Dysfunction
Abnormalities of the respiratory control centers of the brain
stem impair normal breathing patterns and contribute to
significant respiratory dysfunction in patients with MS.
Involvement of neurons of the dorsal medullary group
(responsible for inspiration and breathing rhythm) and ventral
medullary group (responsible for expiration) of the respiratory
control center located in the pons leads to dysrhythmic
breathing. Patients experience loss of voluntary and autonomic
respiratory control, paroxysmal ventilation, and apneustic
breathing. In a study by Tantucci et al, measuring mouth
occlusion pressures, patients with MS were found to have
increased baseline respiratory drive when compared with
control subjects. Their breathing response to carbon dioxide
was preserved but failed to generate an adequate ventilatory
response, which may reflect underlying muscle dysfunction.
8
Patients with MS have more abnormalities in sleep patterns
than the general population. 9 They report a greater degree of
abnormal sleep initiation and maintenance, snoring, nighttime
shortness of breath, sleep adequacy, and higher levels of
daytime somnolence. Brainstem involvement increases the risk
of developing obstructive sleep apnea and central sleep apnea.
10
Additionally, patients with significant respiratory muscle
weakness may also develop nocturnal hypoventilation,
although this is typically manifested in very advanced disease
in bedridden patients.
6
Respiratory Failure
Two patterns of respiratory dysfunction are observed in
patients with MS: acute respiratory failure secondary to
lesions in the medulla and cervical spinal cord and chronic
respiratory failure secondary to atelectasis, aspiration, and
pneumonia caused by respiratory muscle dysfunction.
Although uncommon, acute respiratory failure can occur in
patients with new extensive demyelinating plaques and is
suggestive of extensive bulbar disease. 2 These patients often
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present with acute-onset dyspnea, orthopnea, or confusion in
the setting of other motor findings typical of patients with MS,
including findings such as quadriparesis and spastic paraplegia
with upper arm weakness. 1 Commonly reported respiratory
symptoms include progressive breathlessness, impaired cough,
difficulty handling secretions, orthopnea, and sleep
disturbances. When compounded by secondary systemic
factors such as dehydration, aspiration pneumonitis, and
sepsis, patients in acute respiratory failure often require
mechanical ventilatory support and antibiotics.
11
Chronic respiratory failure develops in the terminal stages of
disease. These patients are severely debilitated, often
wheelchair bound with significant limb and respiratory muscle
weakness. They have recurrent bouts of mucous plugging,
atelectasis, aspiration with subsequent pneumonia secondary
to respiratory muscle weakness, abnormal control of breathing,
and an impaired cough.
Morbidity and Mortality
Respiratory muscle weakness is a known complication of MS
and is identified in patients who are both ambulatory and
bedbound. Assessment of muscle function is of critical value
so that patients who are at high risk are identified early so that
measures can be taken to prevent both upper and lower
respiratory tract infections. Although demyelination of
respiratory motor tracts is the most common cause of muscle
weakness, additional causes such as deconditioning,
malnutrition, and steroid-induced myopathy may also play a
role.
Mortality data in patients with MS have been conflicting, with
some reporting only slightly higher mortality than that of the
general population, 12 whereas others report rates three times
higher than non-MS cohorts 13 (Figure 13.3). Regardless,
almost half of MS deaths are related to respiratory disease
14,15
(Table 13.1). Therefore, general supportive measures such as
influenza and pneumococcal vaccinations, cough assist
devices, and chest physiotherapy with aggressive suctioning
should be instituted early. Additional treatment measures such
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as respiratory muscle training, although shown to improve
respiratory muscle function, have yet to show any clinical
benefit such as improved cough efficacy or decreased need for
invasive or noninvasive ventilation.
16
FIGURE 13.3 Forest plots of crude MRRs for all-cause
mortality and selected causes leading to death in the MS
cohort versus the non-MS cohort. Error bars indicate 95%
confidence intervals (CIs). MR, mortality rate; MRR, mortality
rate ratio; MS, multiple sclerosis. aexcluding MS; bexcluding
cardiac arrest; cexcluding respiratory arrest; dexcluding
suicide.
Reproduced with permission from 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.
TABLE 13.1
Causes of Death in the MS and Non-MS Cohort
a
Cause Leading to
Death
Primary
Underlying
Cause of Death
Immediate Cause
of Death
Mortality
Rate
Ratio
95%ClMortality
Rate
Ratio
95%ClMortality
Rate
Ratio
95%
Cl
Causes of Death
b
Cardiac/respiratory
arrest
2.30 0.58-
9.20
1.85 0.58-
5.89
3.62 2.76-
4.77
Suicide
2.56 1.26-
5.16
2.56 1.26-
5.16
NA NA
Other Causes of Death (by ICD-10 Category)
c
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Cause Leading to
Death
Primary
Underlying
Cause of Death
Immediate Cause
of Death
Mortality
Rate
Ratio
95%ClMortality
Rate
Ratio
95%ClMortality
Rate
Ratio
95%
Cl
Certain infectious
and parasitic
diseases
6.24 4.17-
9.36
3.50 1.99-
6.16
5.77 3.65-
9.13
Neoplasms
1.24 0.97-
1.57
1.20 0.96-
1.49
1.27 0.99-
1.64
Diseases of the
nervous system
(excluding MS)
5.75 3.66-
9.04
6.45 3.68-
11.31
2.92 1.67-
5.11
Diseases of the
circulatory system
(excluding cardiac
arrest)
2.12 1.68-
2.66
1.74 1.36-
2.24
1.91 1.48-
2.47
Diseases of the
respiratory system
(excluding
respiratory arrest)
4.99 3.86-
6.44
2.20 1.47-
3.29
4.80 3.64-
6.32
Injury, poisoning,
and certain other
consequences of
external causes
(excluding suicide)
1.52 0.87-
2.68
NA NA 1.92 1.23-
2.97
a
Of those who died, cause of death data were available for
89.6% of individuals in the MS cohort and 86.6% of
individuals in the non-MS cohort. Cause of death data were
not available for all patients because of the 2-year delay in
NDI reporting.
b
For MS as a CoD the MRR outcome for each CoD category
was NA.
c
A full list of the conditions in each CoD category is provided
in the World Health Organization International Statistical
Classification of Diseases and Related Health Problems 10th
Revision (World Health Organization, 2010).
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Reproduced with permission from 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. CI, confidence interval; CoD, cause of
death; ICD-10, International Classification of Diseases 10th revision; MRR,
mortality rate ratio; MS, multiple sclerosis; NA, not applicable.
References
Howard RS, Wiles CM, Hirsch NP, Loh L. Respiratory involvement in multiple
sclerosis. Brain. 1992;115:479-494.
Gosselink R, Kovacs L, Decramer M. Respiratory muscle involvement in multiple
sclerosis. Eur Respir J. 1999;13:449e-454e.
DeTroyer A, Pride NB. The respiratory system in neuromuscular disorders. In:
Roussos C , Macklem PT , eds. The Thorax: Lung Biology in Health and
Disease. New York: Marcel Dekker; 1985;29:1089-1121.
Smeltzer SC, Utell MJ, Rudick RA, Herndon RM. Pulmonary function and
dysfunction in multiple sclerosis. Arch Neurol. 1988;45:1245-1249.
Smeltzer SC, Skurnick JH, Troiano R. Respiratory function in multiple sclerosis:
utility of clinical assessment of respiratory muscle function. Chest.
1992;101:479-484.
Tzelepis G, McCool D. Respiratory dysfunction in multiple sclerosis. Respir Med.
2015;109(6):671-679.
Man WD, Kyroussis D, Fleming TA, et al. Cough gastric pressure and maximum
expiratory mouth pressure in humans. Am J Respir Crit Care Med.
2003;168:714e-717e.
Tantucci C, Massucci M, Piperno R, Betti L, Grassi V, Sorbini CA. Control of
breathing and respiratory muscle strength in patients with multiple sclerosis.
Chest. 1994;105:1163-1170.
Bamer AM, Johnson KL, Amtmann D, et al. Prevalence of sleep problems in
individuals with multiple sclerosis. Mult Scler. 2008;14:1127e-1130e.
Braley TJ, Segal BM, Chervin RD. Sleep-disordered breathing in multiple sclerosis.
Neurology. 2012;79:929e-936e.
Boor JW, Johnson RJ, Canales L. Reversible paralysis of automatic respiration in
multiple sclerosis. Arch Neurol. 1977;34:686-689.
Ragonese P, Aridon P, Salemi G, et al. Mortality in multiple sclerosis: a review. Eur
J Neurol. 2008;15:123e-127e.
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.
Hirst C, Swingler R, Compston DA, et al. Survival and cause of death in multiple
sclerosis: a prospective population-based study. J Neurol Neurosurg Psychiatry.
2008;79:1016e-1021e.
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Phadke JG. Survival pattern and cause of death in patients with multiple sclerosis. J
Neurol Neurosurg Psychiatry. 1987;50:523-531.
Reyes A, Ziman M, Nosaka K. Respiratory muscle training for respiratory deficits
in neurodegenerative disorders: a systematic review. Chest. 2013;143:1386e1394e.
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C H A P T E R 1 4
Public Health Considerations
in Multiple Sclerosis
Nida Naushad Catherine Stratton Yetsa A. Tuakli-Wosornu
Introduction
The fundamental goal of public health is to prevent disease;
promote physical, mental, and social health; and prolong life at
the population level (World Health Organization [WHO]).
Chronic diseases such as multiple sclerosis (MS) have widereaching population-level impacts, so an understanding of
these conditions is a central component of public health
science. Today, MS affects approximately 2.5 million people
worldwide, and the prevalence of this condition is growing.
Given the morbidity and long-term disability associated with
MS, which may include weakness, chronic pain, gait
disturbance, and bladder dysfunction, it is important to
understand the disease from a public health perspective. In this
chapter, we discuss:
Screening and prevention strategies
Health disparities related to MS
The socioeconomic impact of MS
Population-level awareness about MS
Better understanding of these aspects of MS can lead to the
creation of programs and policies that promote prevention and
early diagnosis, increase access to care and support, and
improve overall quality of life for the millions of people living
with MS.
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Risk Factors
MS is a multifactorial disease, which likely arises as a result of
a combination of genetics plus environmental exposures that
lead to disease phenotype. Researchers have identified a
number of genetic and environmental risk factors, which we
also reviewed in our discussion of the epidemiology of MS in
Chapter 1 (Table 14.1).
Table 14.1
Factors That May Influence MS Development
Genetics (e.g., HLA type)
Gender
Latitude
Month and place of birth
High-salt diet
Gut microbiome
Vitamin D
Psychological or emotional stress
Cigarette smoking
Organic solvents
Obesity
Sex hormones
EBV
Early life infections
EBV, Epstein-Barr virus; HLA, human leukocyte antigen; MS,
multiple sclerosis.
Risk Factors and Interventions
Genetics
In the 1890s, scientists noted a familial aggregation of MS,
which led to the question of the role genetic factors played in
disease development. 1 It has been concluded that first-degree
relatives are at a 15- to 25-fold greater risk of developing MS
compared with the general population. 2 A study of half-
siblings in Canada found that there was an increased risk of
MS among maternal half-siblings versus among paternal halfsiblings, which informed how important maternal
susceptibility to MS is for inheritance risk. 3 Furthermore,
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another study investigated a group of interracial marriages in
Canada between Caucasians and North American Aboriginals;
the study found that index cases with a Caucasian mother and
North American Aboriginal father had a higher rate of sibling
recurrence versus patients with an Aboriginal mother and a
Caucasian father, supporting the role of maternal genetics in
MS development.
4
Sex
Similar to many other autoimmune diseases, MS is more
common among women than among men. 5 Incidence rates are
rising more quickly among women as well, so recent statistics
estimate that the ratio of women to men with MS is 2.3 to
3.5:1. 6 Of note, pregnancy appears to be a protective factor
that is associated with lower risk of onset and better prognosis
in MS. 7 Despite the greater incidence of disease among
women, research suggests that men have an increased
likelihood of developing a more severe presentation of disease,
8
follow a more malignant course, 9 and have worse recovery
after an initial flare-up in their symptoms.
10
Epstein-Barr Virus
The Epstein-Barr virus (EBV) is a double-stranded DNA γherpesvirus causing lifelong infection in over 90% of the
world’s adult population. 11 Delayed primary infection with
EBV, evidenced by infectious mononucleosis, seems to be an
important factor in developing MS. 12 MS is less common
among those with early childhood infection, which is often
asymptomatic or mild. 13 There is also a low risk of developing
MS among those who were never infected. 13 This
understanding of EBV has numerous implications for
treatment strategies. Studies show that antiviral therapy may
reduce relapses or reduce the number of new active brain
lesions in some of those affected. One study found that therapy
with acyclovir decreased the relapse rate by 34% in patients
with relapsing-remitting MS. 11 The apparent relationship
between EBV and MS has broader public health implications;
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researchers have posited the utility of a vaccine against MS or
early exposure to EBV as a means of prevention.
13
Vitamin D Hypothesis
With some exceptions, there is an increased incidence of MS
among those living further from the equator. This distribution
exists even after accounting for HLA-DRB1 allele
frequencies, suggesting that there is an environmental factor
associated with latitude, such as ultraviolet (UV) radiation
exposure/vitamin D. 14 UV radiation exposure has been
associated with reduced MS risk, 20-fold stronger than other
environmental factors. 15 However, an unusual relationship is
found in northern Scandinavia, where there is a lower MS
prevalence in spite of the weak sunlight. 14 Of note, this
population has a much higher dietary vitamin D intake than
that found in the rest of Europe. 14 A move to encourage
increased vitamin D intake (e.g., via supplementation) could
be a public health initiative in at-risk populations.
Smoking
Smoking cigarettes and exposure to secondhand smoke have
been associated with an increased risk of MS. 16 Duration of
exposure to passive smoking was associated with MS risk in a
dose-dependent manner among never smokers. Those who
reported smoking more than 10 pack-years and exposure to
passive smoking for more than 20 years had nearly three times
higher risk of developing MS compared with those who
reported no exposure to tobacco smoke. Furthermore, smoking
is associated with worse MS prognosis, with those who started
smoking at a younger age being the most likely to develop
progressive disease at an earlier onset. 17 Thus, public health
initiatives to decrease rates of smoking may also help improve
MS outcomes. The following are examples of programs that
promote smoking cessation:
A multipronged approach, which combines both
pharmacotherapy and behavioral support, increases rates
of smoking cessation compared with usual care or
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