In this carefully controlled study, patients with MS referred for clinical sleep studies had more severe OSA, as well as more severe CSA, than referred individuals without MS. Furthermore, MS patients with clinical or radiographic evidence of brainstem involvement showed a mean AHI of 21, nearly double the result (11) for patients without brainstem involvement. Mean and median CAI values were also substantially higher among MS patients with brainstem involvement than among those without brainstem involvement. In exploratory analyses, DMT use was associated with lower apnea scores, and a trend suggested a relationship between progressive subtypes of MS and sleep apnea. Although a causal relationship cannot be proven from cross-sectional data, our findings provide strong evidence that regional brainstem dysfunction due to MS plaque formation might contribute to both obstructive and central sleep apnea severity. Furthermore, apnea severity may be influenced by disease subtype and DMT use. These results could have important implications for the care of patients with MS, among whom fatigue is one of the most common and debilitating symptoms.15
The findings also may shed light on neuroanatomic and pathophysiologic mechanisms that can produce OSA and CSA.
OSA is characterized by upper airway obstruction during sleep, despite efforts to resume normal respiration.16
Upper airway patency, normally maintained by afferent sensory input to cranial nuclei and efferent output to the upper airway, is altered in OSA.17–19
Cases of both OSA and CSA in structural and ischemic brainstem syndromes are well documented,20–27
yet few studies have addressed the association between MS-related brainstem pathology and OSA. Our study is novel in that it explores MS clinical features that may increase OSA risk, while controlling for other MS-unrelated clinical features known to influence this risk. Although some data suggest an increased prevalence of SDB in patients with MS,8
other studies have produced conflicting results. Two cases of OSA were identified in a recent study of 28 subjects with MS.9
Although these 2 patients, compared with the remainder, showed no difference in MRI lesion location, the small sample of subjects with OSA may have precluded detection of clinically meaningful differences. In another study of 25 patients with MS and 25 age- and sex-matched controls,28
3 patients with MS had an AHI of >5, and 2 of these had predominantly central apnea. This study was one of the first to address the effect of infratentorial lesions on nocturnal respiration, but the report did not specify for these 3 patients the specific infratentorial locations involved.
In contrast to OSA, CSA results from recurrent complete or partial absence of respiratory effort. CSA can be caused by impaired respiratory control at the level of the medullary reticular formation. Although in the general population the prevalence of CSA is lower than that of OSA, patients with disorders such as MS that affect the brainstem may be at increased risk for CSA or apnea-related sudden death.29
It is noteworthy that 2 additional MS variables, DMT use and disease subtype, emerged as predictors of apnea severity. DMT use in particular eclipsed the individual effects of other modeled variables known to influence AHI. This finding may be explained in part by multicollinearity, because nearly all predictor variables were associated with each other to some extent in bivariate analyses. Furthermore, the exclusion of controls in these models reduced the sample size, decreasing our power to detect significant associations. Nonetheless, considering the strong predictive power of our model as a whole, our data suggest that the remaining variables still influence AHI but are perhaps overshadowed by the effects of DMT use.
Definitive conclusions on the relationship between DMT use and OSA cannot be drawn from exploratory analyses that were not the focus of our original hypotheses; however, these findings raise interesting questions about the pathogenesis of OSA. Inflammatory cytokines tumor necrosis factor-α and interleukin-6 are expressed at higher levels in individuals with OSA,30
and treatment with agents that influence these cytokine levels may improve apnea severity.31
Our data allow speculation that systemic or local inflammation not only reflects OSA but could contribute to it.
Among potential study limitations, observed differences in sleep apnea severity between patients with MS and controls could conceivably reflect referral practices. Because of the high prevalence of MS-related fatigue, physicians who see patients with MS may have a tendency to refer only the most obviously symptomatic patients for sleep evaluations. Although we cannot exclude this possibility, it is unlikely to explain the association between brainstem involvement and elevated AHI and CAI.
In addition, because this study was retrospective, some potential variables that could influence apnea severity were not available in a format that could be useful in the analyses. These include information on whole-brain quantitative MRI lesion burden, spinal cord involvement, respiratory function, and medications (such as antispasmodic drugs or narcotics) that are often used by patients with MS. The possibility exists that the association between CAI and disease subtype in our exploratory analyses may in part reflect overall MRI lesion burden, because patients with progressive subtypes of MS are more likely to have widespread parenchymal damage that may affect both brainstem and nonbrainstem pathways that control nocturnal respiration. Patients with progressive MS may also require more antispasmodic drugs and pain medications. However, medication use would not be expected to differ substantially between MS patients with and without brainstem findings.
Patients with OSA often have concomitant central apneas. The reason is not well understood but may involve alterations in hypocapnic sensitivity thresholds32
that can be reversed by continuous positive airway pressure.33
Conceivably, the increase in CAI among patients with MS may be explained in part by concomitant OSA. However, given the disproportionate elevation in CAI among patients with brainstem involvement, specific effects of brainstem lesions seem more likely.
Finally, the available number of MS patients with evidence of brainstem involvement forced their consideration within one category and did not allow for further substratification to distinguish between midbrain, pontine, or medullary locations that could differentially influence sleep apnea risk. This may also explain in part the large AHI and CAI standard deviations within the brainstem lesion group.
Despite these limitations, the robust differences between subjects with MS and controls indicate that MS and, in particular, MS-related brainstem pathology, could increase vulnerability to OSA and central sleep apnea. This vulnerability may be further influenced by other MS-specific variables including MS subtype and use of DMT. The data suggest that complaints of fatigue from patients with MS may frequently merit consideration of sleep apnea as a potential cause. Patients with sleep apnea complain about fatigue, lack of energy, or tiredness more often than sleepiness.3
This observation is particularly relevant to patients with MS who already experience, presumably because of their neuroimmunologic disorder, disproportionate disability and fatigue. Moreover, fatigue and related complaints, in addition to sleepiness, tend to improve when sleep apnea is treated.34
Results of this study indicate that patients with MS referred for PSG, compared with those without MS, may be at risk for more severe OSA and CSA and that patients with evidence of brainstem involvement may be particularly susceptible. Our findings underscore the importance of screening MS patients for sleep apnea and considering referral for PSG. The latter may be particularly useful for patients with signs of lower cranial nerve dysfunction, infratentorial lesions, and perhaps those with progressive MS or lack of DMT.