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Respiratory Physiology & Neurobiology 188 (2013) 344– 354

Contents lists available at ScienceDirect

Respiratory Physiology & Neurobiology

jou rn al h omepa g e: www.elsev ier .com/ locate / resphys io l

eview

he impact of spinal cord injury on breathing during sleep�

avid D. Fullera,b,∗, Kun-Ze Leec, Nicole J. Testera,d

Department of Physical Therapy, University of Florida, Gainesville, FL 32610, United StatesMcKnight Brain Institute, University of Florida, Gainesville, FL 32610, United StatesDepartment of Biological Sciences, College of Science, National Sun Yat-sen University, Kaohsiung, TaiwanBrain Rehabilitation Research Center, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, United States

r t i c l e i n f o

rticle history:ccepted 11 June 2013

eywords:pinal cord injury

a b s t r a c t

The prevalence of sleep disordered breathing (SDB) following spinal cord injury (SCI) is considerablygreater than in the general population. While the literature on this topic is still relatively small, and insome cases contradictory, a few general conclusions can be drawn. First, while both central and obstruc-tive sleep apnea (OSA) has been reported after SCI, OSA appears to be more common. Second, SDB after

leep disordered breathingleep apnea

SCI likely reflects a complex interplay between multiple factors including body mass, lung volume, auto-nomic function, sleep position, and respiratory neuroplasticity. It is not yet possible to pinpoint a “primaryfactor” which will predispose an individual with SCI to SDB, and the underlying mechanisms may changeduring progression from acute to chronic injury. Given the prevalence and potential health implica-tions of SDB in the SCI population, we suggest that additional studies aimed at defining the underlying

ed.

mechanisms are warrant

. Introduction

The focus of this review article is on sleep disordered breath-ng (SDB) following spinal cord injury (SCI). This topic has beeneviewed recently (Biering-Sorensen et al., 2009), and our primaryntent is to update the evidence indicating that the prevalencef SDB increases after SCI, and to provide a discussion of thenderlying physiologic mechanisms. In particular we have focusedn possible mechanisms leading to increases in obstructive sleeppnea (OSA) following SCI. We begin with an overview of how SCImpacts the respiratory neuromuscular system and then discusshe prevalence and mechanisms of SDB after SCI.

. Impact of SCI on the respiratory system

The impact of SCI on pulmonary function has been the subject ofeveral recent articles (Tollefsen and Fondenes, 2012; Winslow andozovsky, 2003; Zimmer et al., 2008) and is briefly discussed here.pproximately half of all SCIs occur in the cervical region caus-

ng hypoventilation (Winslow and Rozovsky, 2003) and impairedbility to sigh and cough (Bolser et al., 2009). Pulmonary functiontudies reveal that the extent of SCI-induced deficits correspondso the segmental level of the injury (i.e., more rostral lesions tend to

� This paper is part of a special issue entitled “Sleep and Breathing”, guest-editedy Dr. James Duffin, Dr. Leszek Kubin and Dr. Jason Mateika.∗ Corresponding author. Tel.: +1 352 273 6634; fax: +1 352 273 6109.

E-mail address: ddf@phhp.ufl.edu (D.D. Fuller).

569-9048/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.resp.2013.06.009

© 2013 Elsevier B.V. All rights reserved.

produce greater functional impairments) (Tollefsen and Fondenes,2012). It should be emphasized, however, that injuries to thethoracic cord are also associated with respiratory-related impair-ments, with the most prominent feature being impaired ability tocough (DiMarco et al., 2009).

Impaired respiratory muscle control after SCI results from inter-ruption of bulbospinal synaptic projections to spinal motoneuronsand interneurons (i.e., white matter lesions; (Lane et al., 2009;Sandhu et al., 2009)) as well as direct gray matter damage (Laneet al., 2012; Reier et al., 2002). Cervical gray matter damage canresult in loss of phrenic motoneurons (Lane et al., 2012; Nicaiseet al., 2012), as well as propriospinal circuitry which may modulaterespiratory motor output (Lane et al., 2009). Respiratory controldeficits can be further exacerbated by atelectasis and chest wallmuscle spasticity which reduce the compliance of the lung andchest wall (Winslow and Rozovsky, 2003). In addition, impair-ments in accessory inspiratory muscles contribute to “paradoxical”diaphragm contractions that are associated with inward movementof the rib cage during inspiration. Despite these complications,many individuals with incomplete cervical SCI can breathe inde-pendently but often with diminished tidal volume and elevatedbreathing frequency (Loveridge et al., 1992). However, even whenadequate alveolar ventilation can be maintained without externalsupport, SCI individuals remain at high risk for respiratory-relatedcomplications.

2.1. Plasticity in respiratory neurons and networks after SCI

It is well established that SCI induces neuroplastic changes inthe neurons and networks that regulate breathing (reviewed by

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oshgarian, 2009). Following SCI, time-dependent changes occurhroughout the respiratory neuraxis including spinal respiratory

otor neurons (Mantilla et al., 2012), propriospinal networks (Lanet al., 2009), and brainstem respiratory neurons (Golder et al.,001; Zimmer and Goshgarian, 2007). Respiratory neuroplastic-

ty has been characterized at the molecular level (e.g., increasedxpression of serotonin and glutamate receptors in the spinal cordMantilla et al., 2012)), the anatomical level (e.g., changes in theistribution of respiratory interneurons in the spinal cord (Lanet al., 2009)) and the functional level (e.g., progressive increasesn phrenic motor function (Goshgarian, 2009)). In general, it haseen assumed that spontaneous respiratory neuroplasticity occur-ing over days–months post injury is beneficial to respiratory motorecovery, but the possibility that “maladaptive neuroplasticity”ould impair the control of breathing should be considered. In par-icular, to our knowledge there have been no studies of the neuralegulation of respiratory motoneurons during sleep following SCIn either animal models or humans. Thus, the functional impact ofCI-induced respiratory neural plasticity on the control of breathinguring sleep remains an open question.

.2. Plasticity in respiratory muscles after SCI

The primary muscle of inspiration, the diaphragm, appears to berofoundly sensitive to periods of inactivity. For example, mechan-

cal ventilation results in rapid diaphragm atrophy (i.e., withinours) and significant contractile dysfunction (Powers et al., 2009).

mportantly, this finding has been demonstrated in both humansnd animals, and has been confirmed by independent laboratoriesreviewed by Jaber et al., 2011). In our opinion, the most likely rea-ons for diaphragm atrophy during inactivity are decreased proteinynthesis along with a rapid increase in proteolysis (Powers et al.,009). Thus, high cervical SCI – which is associated with dimin-

shed or absent respiratory muscle activity – is also likely to result introphy of the diaphragm with associated losses of contractile func-ion. The overall extent of respiratory muscle atrophy is likely to beetermined by the segmental level and functional completeness ofhe injury, both of which will impact the relative degree of pre-erved muscle activity. Studies in animal models have confirmediaphragm atrophy following cervical SCI (Mantilla et al., 2013;icaise et al., 2012). Collectively the literature suggests that the

unction of respiratory “pump muscles” will be compromised fol-owing SCI – not only due to injury-induced paralysis, but also dueo the subsequent muscle atrophy. Changes in pump muscle mor-hology and function could impact breathing during sleep both vialterations in pulmonary pressures and muscle afferent feedback.owever, to our knowledge, the impact of SCI on upper airway mus-le morphology and function, including the muscles of the tongue,as not been systematically evaluated. This is of considerable inter-st since the pharyngeal muscles are integral to maintaining airwayatency.

. Sleep and SCI

.1. Sleep quality after SCI

As reviewed by Biering-Sorensen et al. (2009), SCI individualsre highly likely to self-report sleeping difficulty. For exam-le, increased difficulty falling asleep and increased reliance onleep medications are common after SCI (Biering-Sorensen andiering-Sorensen, 2001). In addition, when persons with SCI are

nterviewed regarding their sleep quality, they are much more

ikely to report an overall reduced quality (Norrbrink Budh et al.,005). Snoring is common after SCI, as is daytime sleepiness (Jensent al., 2009) and both of these features are hallmarks of SDB.owever, sleep difficulties following SCI may be unrelated to SDB

Neurobiology 188 (2013) 344– 354 345

per se, and other factors such as pain, spasms, and postural influ-ences must be considered (Norrbrink Budh et al., 2005; Scheer et al.,2006).

3.2. SDB after SCI

We were able to identify 29 published studies examining theimpact of SCI on breathing during sleep (see Table 1). In addition,we found 13 related clinical case reports (Biering-Sorensen et al.,1995; Danielpour et al., 2007; Goh and Li, 2004; Graham et al., 2004;Heike et al., 2007; Howard et al., 1998; Kam et al., 2009; Kawaguchiet al., 2011; Miyano et al., 2009; Nagaoka et al., 2006; Russian et al.,2011; Star and Osterman, 1988; Vella et al., 1984). Collectively, thisliterature demonstrates unequivocally that the incidence of SDBincreases after SCI, with estimates ranging from 2 to 5 fold over thegeneral population (Burns et al., 2000; Klefbeck et al., 1998b; Leducet al., 2007; Stockhammer et al., 2002). There is evidence that sleepapnea is more likely to occur with higher neurologic level of injury(i.e., more rostral lesions) (Berlowitz et al., 2012; Burns et al., 2001),but this finding has not been consistent in all reports (Table 1). Inaddition, most studies have failed to find a relationship between theprevalence of sleep apnea and the extent of motor impairment asdetermined by the American Spinal Cord Injury Association (ASIA)impairment scale (Burns et al., 2005; Tran et al., 2010), althoughthis has not been a universal finding (Berlowitz et al., 2012).

3.3. Classification of sleep apnea

Sleep apnea is common even in the general population, andis identified by prolonged periods in which inspiratory airflow iseither absent or considerably reduced (i.e., hypopnea). Apneic andhypopneic events during sleep are associated with frequent oxy-gen desaturations and arousals. The patterns of respiratory muscleactivity during periods of oxygen desaturation have resulted inthree general classifications. Central apneas are associated withdecreased or absent respiratory motor drive during sleep (i.e., alack of “respiratory effort”). Centrally mediated apnea is a rela-tively rare condition in the absence of neurological disease or injury(De Backer, 1995). In contrast to central apneas, obstructive apneasare characterized by narrowing and/or collapse of the pharyngealairways during inspiratory efforts (i.e., pharyngeal collapse whilethe respiratory pump muscles are contracting). Estimates are thatapproximately 2–7% of the general population experience OSA,and both gender and age related differences have been reported(Punjabi, 2008). Lastly, complex or “mixed” apneas represent acombination of central and obstructive events.

3.4. Central apneas after SCI

Several brain regions (e.g., raphe nuclei, locus coeruleus,hypothalamus) play an important role in state-dependent regula-tion of respiratory motoneuron activity. Synaptic inputs from thesestructures increase the excitability of respiratory motoneurons, andthese inputs are gradually reduced when progressing from wak-ing to sleep (Gestreau et al., 2008; Horner, 2000). Thus, sleep isassociated with a “normal” reduction in respiratory motoneuronexcitability and output, and would be predicted to be associatedwith hypoventilation when coupled with injury-induced impair-ments of bulbospinal synaptic inputs to respiratory motoneurons(Berlowitz et al., 2005). Indeed, neurologic injuries are associatedwith increases in respiratory disturbances during sleep (Dykenet al., 2012). Burns et al. (2000) studied 20 men with a range of

SCI severity (including motor complete and incomplete), and foundthat 40% of subjects had sleep apnea, with 25% of the cases beinga predominately centrally mediated pattern. On the other hand,Tran et al. (2010) examined 16 subjects with SCI (SCI level of T12

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188 (2013) 344– 354Table 1Studies examining the impact of SCI on breathing during sleep.

Author Subjects Injury level Injuryclassification/diagnosis

Durationpost-injury

Criteria of SDB Major findings

Braun et al. (1982) M: 10 & F: 1Age: 17–57 yrs

Cervical: 7Thoracic: 4

Complete Unknown • N/A • 9.1% (1/11) had SpO2 <85%• 18.2% (2/11) had SpO2 <90%• Age, but not lesion level or % predicted ERV,significantly correlated with desaturationamount

Wang et al. (1987) M: 13 & F: 13Age: 4 mos–6 yrs

n = 9, upper cervicalspinal cordcompression

Achondroplasia (congenitaldwarfism) leading to spinalcord compression

N/A • N/A • Sleep apnea cited as predominant clinicalconcern

Bonekat et al.(1990)

M: 4Age: 38–70 yrs

Cervical: 3Thoracic: 1

Unknown 2–26 yrs • Apneic event: apnea (≥10 s)associated with ≥4% O2

desaturation• Sleep apnea: ≥5 apneas/hr or≥30 apneic events during nightsleep

• 100% (4/4) had OSA

Gilgoff et al. (1992) M: 17 & F: 2Age: birth–19 yrs

C2–C5 Complete – requiringportable, positive pressureventilators

Unknown • Adequate ventilation: SpO2

>96%• Apnea: interval >12 secbetween recorded breaths withrecorded VT less than 25% ofresting VT

• Upper airway mechanics differ betweensleep and wakefulness and may affect air leakaround tracheostomies• 82% (9/11) children on volume controlledsystems were found to be inadequatelyventilated during sleep, while substitutionwith cuffed tracheostomies allowed adequateventilation during wakefulness and sleep• Pressure controlled ventilation improvesadequacy of gas exchange during sleep andwakefulness

Flavell et al. (1992) M: 10Age: 17–55 yrs

C4–C6 Frankel grade A or B 5 mos–29 yrs • Severe O2 desaturations:<90% for ≥10% of night• Mild-moderate O2

desaturations: <90% for <10%of night

• 30% (3/10) showed severe desaturations(SpO2 minimums at 38–56%)• 30% (3/10) had mild-moderate desaturations(SpO2 minimums ranging from 62 to 80%)• Direct relationship between BMI and timespent below 90% SpO2

• Weight, level of injury, and extent ofrespiratory muscle weakness correlated withmean overnight SpO2

Short et al. (1992) M: 20 & F: 2Age: 40–77 yrs

Cervical: 15Thoracic: 7

Frankel grade A, B, or C 0.3–46 yrs • Hypoxic dips: ≥4% O2

desaturation• Obstructive apnoea: absenceand/or decrease in oronasalairflow with continuing ribcageand/or abdominal effort• Central events: absence orreduction in oronasal airflow,continuing ribcage effort, andabdominal effort• Apnoea index: number oforonasal airflow cessations inexcess of 10 s per hr• Abnormal respiration:hypoxic dips >15/hr

• 45.5% (10/22) had >5 hypoxic dips/hr – causewas obstructive apneas in most cases• 27.3% (6/22) had abnormal respiration• No correlation between degree of hypoxicdipping and age, level or duration of injury,obesity index, neck circumference, or lungfunction

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Cahan et al. (1993) M: 16Age: 23–78 yrs

Cervical: 12Thoracic: 4(C4–T5)

Unknown 0.5–32 yrs • Apnea: absence of airflow≥10 s

• 37.5% (6/16) showed >4% reduction of SpO2

(SpO2 values lower than normative valuesduring 70% of recorded time)• 42.9% (3/7) undergoing polysomnographyhad sleep apnea (AHI = 12, 53, and 54)consisting of both obstructive and centralevents

Bach and Wang(1994)

M: 9 & F: 1Age: 34–77 yrs

C4–C7 Complete motor 6 mos–19 yrs • Abnormal SpO2: >94% • 60% (6/10) had SpO2 >90% at 0.5 yrspost-injury• At 5-yr follow-up, 50% (5/10) had increasednumber of transient O2 desaturations• Over 5-yr period, detected a general decreasein nocturnal SpO2 (80% had SpO2 >90%) andsignificant increase in nocturnal ETCO2

McEvoy et al.(1995)

M: 37 & F: 3Age: 19–60 yrs

Cervical Frankel grade A, B, or C >0.5 yrs Unknown • 27.5% (11/40) had RDI ≥15 with SpO2 from49 to 95%• 30% (12/40) had AI ≥575% (9/12) had obstructive sleep apneas25% (3/12) of these had central or mixed sleepapneas• SDB was associated with increased neckcircumference

Sajkov et al. (1998) M: 34 & F: 3Age: 19–60 yrs

Cervical Frankel grade A, B, or C >0.5 yrs • SDB: AHI >15/hr • 29.7% (11/37) had SDB, with most apnoeasobstructive in type• 18.9% (7/37) showed SpO2 <80%• Major associations between sleepapnoea-related hypoxia and cognitive function

Klefbeck et al.(1998a)

M: 8 & F: 1Age: 22–42 yrs

Cervical (C5–C6) Frankel grade A: 4Frankel grade B: 5

2–25 yrs ODI = average number ofdesaturations ≥4% per hour

• 0% (0/9) had OSA• 18.9% (1/9) patients had ODI = 8• 44.4% (4/9) had SpO2 <90% due to centralhypoventilation

Klefbeck et al.(1998b)

M: 28 & F: 5Age: 22–59 yrs

C4–T1 Complete: 17Incomplete: 16

1–33 yrs ODI: number of O2

desaturations ≥4% per sleepinghourOSA: ODI ≥6 and >45% periodicrespiration time out of the totalestimated sleeping timeOSAS: OSA criteria above, plusreports of sleep disturbances,excessive daytimetiredness/sleepiness, andsnoring

• 15% (5/33) had OSA, with additional 18%(6/33) cases considered borderline• 9% (3/33) had OSAS• Inverse correlation between O2 desaturationindex and ASIA motor score in subjects withcomplete injury, but no such correlation inentire study group• No significant correlations between ODI orperiodic respiration and BMI, age, or time sinceinjury

Burns et al. (2000) M: 20Age: 24–73 yrs

Cervical: 12Thoracic orlumbar: 8

ASIA A or B: 14ASIA C or D: 6

2–29 yrs • Apnea: pause of chestmovement or oronasal airflow• Hypopneas: >50% decreasesin airflow >10 s with a ≥3% O2

desaturation airflow >10 s• SAS: elevated AI, inconjunction with daytimesomnolence

• 40% (8/20) patients had sleep apnea25% (2/8) – central sleep apnea50% (4/8) – OSA25% (2/8) – mixed sleep apnea• Trend toward greater prevalence of sleepapnea with tetraplegia (58% – 7/12) comparedto paraplegia (12.5% – 1/8)• No associations with age or BMI• 75% (6/8) with sleep apnea were unable totolerate CPAP. Of the 2 that tolerated it, apneicepisodes decreased

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188 (2013) 344– 354Table 1 (Continued)

Author Subjects Injury level Injuryclassification/diagnosis

Durationpost-injury

Criteria of SDB Major findings

Lu et al. (2000) M: 29 & F: 7Age: 19–77 yrsDelayedcatastrophic apneain n = 8; others(n = 28) recruited ascontrols with SCI,but no apnea

C4–C8 Frankel grade A: 30Frankel grade B: 6

Unknown • Unknown • Sleep was the most common associatedevent when apnea developed (with delayedonset), occurring in 62.5% (5/8)

Burns et al. (2001) M: 584 Cervical: 42Thoracic: 9Lumbar: 2(injury levelinformation is frompatients who hadsleep apnea)

ASIA A: 17ASIA B: 9ASIA C: 7ASIA D: 9

Unknown • Unknown: (retrospectivereview of medical chartdiagnosis)

• 9.1% (53/584) diagnosed with sleep apnea• 14.9% (42/282) tetraplegics had sleep apnea• 3.7% (11/302) paraplegics had sleep apnea• Sleep apnea associated with obesity andhigher neurologic level, but not ASIA• Medical co-morbidities more frequent, andtreatment acceptance was poor with higherlevel motor-complete injuries

Tow et al. (2001) M: 41 & F: 16Age at injury:23.2 ± 9.1 yrs

Cervical: 57 Frankel grade A: 38Frankel grade B & C: 17Frankel grade C: 2

10 & 20 yrs • Unknown • 5.3% (3/57) had sleep apnea

Ayas et al. (2001) M & F: 197Age: 51.2 ± 14.8 yrs

• Snoring • 42.6% (84/197) were habitual snorers• Use of antispasticity medications with BMI ≥25.3 kg/m2 significantly increased risk forsnoring• Neurological motor completeness, injurylevel, age, and duration post-injury wereunrelated to snoring

Wang et al. (2002) M: 12 & F: 2Age: 19–56 yrs

Cervical Complete >6 mos • SpO2 and ETCO2 • Resistive inspiratory muscle strength trainingcan ameliorate SDB

Stockhammer et al.(2002)

M: 40 & F: 10Age: 20–81 yrs

C3–C8 ASIA A or B: 40ASIA C or D: 10

0.5–37 yrs • SDB: RDI ≥15• Sleep apnea: RDI ≥15 & AI ≥5• Hypopnea: a reduction inairflow of 50–90% from thebaseline value, lasting ≥10 s• Apnea: a reduction in airflowof 90–100% from the baselinevalue, lasting ≥10 s

• 62% (31/50) had SDB• 48% (24/50) had sleep apnea• No correlations between RDI and lesion level,ASIA, or spirometric values• Significant correlations between RDI and age,BMI, neck circumference, time post-injury,gender, and cardiac medications

Berlowitz et al.(2005)

M: 25 & F: 5Age: 14–70 yrs (13completed 12 mosfollow-up)

Cervical ASIA A: 17ASIA B: 7ASIA C: 3ASIA D: 3

2 days–1 yr • SDB: AHI ≥10• Apnea: complete cessation ofairflow• Hypopnea: >50% reduction inrespitrace signal or <50%reduction in respitraceassociated with either >3% O2

desaturation or cortical arousal

• 0% (0/30) had SDB at 2 days post-injury• >60% patients had SDB from 2 to 52 wkspost-injury; 60% at 2 wks post-injury; 62% at4 wks post-injury; 83% at 13 wks post-injury;68% at 26 wks post-injury; 62% at 52 wkspost-injury

Burns et al. (2005) M: 401Age:60.1 ± 11.0 yrs2Age:55.6 ± 10.3 yrs1Treatment2No treatment

Cervical: 37Non-cervical: 3

All participants with SCIand diagnosed with SAS

122.0 ± 18.5 yrs215.3 ± 12.4 yrs

• N/A • CPAP tried by 80%, but only 63% continued touse, suggesting treatment was beneficialcompared to side effects for many, but notthose that chose to discontinue treatment

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Scheer et al. (2006) M: 5Age: 27–42 yrs

Cervical: 3Thoracic: 2

Frankel grade A 4.7–18.5 yrs • Respiratory events scoredusing the American Academyof Sleep Medicine Task Forcecriteria (1999)

• 40% (2/5, 1 cervical and 1 thoracic) had mildsleep apnea (AHI between 10 and 20/hr)

Leduc et al. (2007) M: 34 & F: 7 Cervical ASIA A: 21ASIA B: 7ASIAC: 6ASIA D: 7

0.5–38 yrs • Apnea: complete oronasalairflow interruption• Hypopnea: ≥50% reduction ofairflow or <50% reduction ofairflow associated with >3% O2

desaturation or arousal• Mild OSAHS: AHI = 5–14• Moderate OSAHS:AHI = 15–30• Severe OSAHS: AHI >30

• 53% (22/41) had AHI ≥54.5% (1/22) had moderate OSAHS36.4% (8/22) had severe OSAHS

Berlowitz et al.(2009)

M: 17 & F: 2Age: 20–70 yrs

C3–C7 ASIA A: 12ASIA B: 3ASIA C: 3

Acute • OSA: AHI >10 • 73.7% (14/19) had OSA50% (7/14) adhered to CPAP for 3 mos and hadimproved sleepiness

Shoda et al. (2009) M: 3 & F: 26Age: 28–81 yrs

Cervical Rheumatoid arthritispatients planning onundergoing surgery foroccipitocervical lesions dueto progressive myelopathy

Unknown • Sleep apnea: AHI >5 • 79.3% (23/29) diagnosed with sleep apnea (allobstructive)• Gender, age, BMI, and radiographicparameters were significantly associated withthe presence of sleep apnea

Tran et al. (2010) M: 11 & F: 5Age: 34.1 ± 12.3 yrs

Cervical: 8Thoracic: 8

ASIA A: 11ASIA B: 5

6–8 wk post-SCI &repeat evaluationat 6 mos post-SCIfor n = 12

• SDB: AHI >5Mild SDB: AHI = 5–15Moderate SDB: AHI = 15–30Severe SDB: AHI >30

• 68.8% (11/16) had SDB at 6–8 wks post-injury54.5% (6/11) had mild SDB45.5% (5/11) had moderate/severe SDB• 75% (9/12) had SDB on repeatpolysmonography at 6 mos post-injury25% (3/12) were moderate-severe• All obstructive, and no central apneas• No associations between severity of sleepapnea and ASIA, level of injury, or gender• AHI did not correlate with BMI, neckcircumferences, or SpO2

Bensmail et al.(2012)

SCI: 6M: 4 & F: 2Other neurologicaldisorder: 5

T4–T11 Unknown Unknown • Mild SAS: RDI = 5–15• Moderate SAS: RDI = 16–29• Severe SAS: RDI ≥ 30

• Increases in RDI, obstructive apneas, mixedapneas, and central apneas were observedfollowing bolus intrathecal baclofen. Valuesdecreased, but still remained above baseline(pre-treatment) following continuousadministration of intrathecal baclofen

Berlowitz et al.(2012)

M: 59 & F: 19Age: 18–70 yrs

C1–T1 Complete: 35Incomplete: 43

Unknown • OSA: AHI >10 • 91% with complete injuries had OSAHS• 55.8% with incomplete injuries had OSAHS

Le Guen et al.(2012)

M: 20 & F: 5Age: 46.9 ± 14.2

Tetraplegia(Cervical)

Complete: 11Incomplete: 14

Acute: 15Chronic: 10

• Respiratory event scoredaccording to the AmericanAcademy of Sleep Medicinecriteria (1999)

• No significant difference in AHI betweencomplete versus incomplete groups• No significant difference in CPAP betweenacute and chronic groups• No significant correlation between AHI andeffective CPAP or between AHI and BMI• Significant correlation between effectiveCPAP and BMI

Abbreviations: AIH, Apnea/Hypopnea Index (number of apneas and/or hypopneas per hour of sleep); AI, Apnea Index; ASIA, American Spinal Injury Association scale of motor and sensory impairment; BiPAP, Bilevel PositiveAirway Pressure; BMI, body mass index; C, cervical; CPAP, Continuous Positive Airway Pressure; d(s), day(s); ETCO2, end-tidal partial pressure of carbon dioxide; M, male; F, female; hr, hour; IPPV, Intermittent Positive PressureVentilation; L, lumbar; N/A, not applicable; OA, obstructive apnea; ODI, Oxygen Desaturation Index; OSA, obstructive sleep apnea; OSAHS, obstructive sleep apnea hypopnea syndrome; ODI, O2 Desaturation Index (the averagenumber of >4% O2 desaturations/hr of sleep); RDI, Respiratory Disturbance Index (respiratory events per hr of sleep); REM, rapid eye movement; SA, sleep apnea; SAS, sleep apnea syndrome; SCI, spinal cord injury; SDB, sleepdisordered breathing; sec/s, second; SpO2, saturation of peripheral oxygen; T, thoracic; VT, tidal volume; wk(s), week(s); yr(s), year(s).

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nd higher); and while greater than 70% of the subjects had sleeppnea, central apnea was not observed. In cases where central sleeppnea is detected after SCI, it seldom occurs alone. More often, thisccurs in combination with upper airway obstruction as a mixedpnea (Biering-Sorensen et al., 1995; Burns et al., 2000; McEvoyt al., 1995; Short et al., 1992).

. OSA and SCI

.1. Mechanisms of OSA

Before addressing the prevalence of OSA in the SCI populationsee 4.2), we briefly comment on the mechanisms underlying OSAn spinal intact individuals since this provides a framework fornderstanding how SCI exacerbates the problem. Cephalometricata indicate that OSA patients often have an enlarged soft palate,ongue and uvula (Cuccia et al., 2007). Excessive fat depositionround the pharynx can also cause upper airway narrowing, ands often present in OSA patients (Horner et al., 1989). Watanabet al. (2002) reported that OSA patients tend to have smaller andeceded mandibles, and an inferior shift of the hyoid bone has alsoeen described (Tangugsorn et al., 1995). In addition to anatomicactors, the relative amount of upper airway muscle activity duringleep is particularly important. This is perhaps best illustrated byhe observation that apnea/hypopnea during sleep coincides withecreases of upper airway muscle activity (Katz and White, 2004;emmers et al., 1978). In addition, both animal and human studiesemonstrate that electrically stimulating upper airway muscles orotor nerves can reduce airway collapse ability (Fuller et al., 1999;

chwartz et al., 2012a), and can also reduce obstructive events dur-ng sleep (Eastwood et al., 2011). Collectively, it is clear that OSA isaused by an increase in the collapsibility of the pharyngeal airwayuring sleep, with both anatomical and neural factors contributingo the disorder (Schwartz et al., 2011).

.2. Prevalence of OSA following SCI

Initial reports indicated that OSA is considerably more prevalentollowing SCI when compared to the general population (Klefbeckt al., 1998b; McEvoy et al., 1995; Short et al., 1992; Stockhammert al., 2002) (also see Table 1). One of the first comprehensiveeports was provided by McEvoy and colleagues in 1995 who stud-ed 40 quadriplegic patients with SCI at C8 or above. They observedhat approximately 30% of their subjects had significant SDB thatas primarily obstructive in nature. In 2000, Burns et al. evalu-

ted the prevalence of sleep apnea in a randomly selected samplef 20 individuals with chronic (2–29 years post-injury) SCI. Theybserved a 40% prevalence of “moderate” sleep apnea with anverage apnea index of 17 per hour. Apnea was more prevalent

able 2n overview of the mechanisms potentially contributing to the increased incidence of

he increased incidence of OSA, are likely to occur due to a complex interaction betweenhanging during the progression from acute to chronic SCI. While it is not yet possible tof these variables listed in the left hand column can be altered by SCI and could theoreticlease see the text for a more detailed discussion of each variable, and how it is changed

Variable Potential change after SCI P

Neck circumference Increase IBody mass/obesity Increase IWaist size Increase RLung volume Decrease RTime in supine sleep position Increase IParasympathetic and/or sympathetic tone Altereda BBrainstem activity Altereda UCentral chemosensitivity Altereda UMedication Increased R

a In some cases, we elected to list the variable as “altered” since the changes are likely

Neurobiology 188 (2013) 344– 354

in tetraplegic compared to paraplegic subjects, and was commoneven with incomplete injury. Berlowitz et al. (2005) subsequentlyperformed a longitudinal assessment of breathing during sleep dur-ing the first year following SCI. While none of the subjects in theirstudy demonstrated SDB at 48 h post injury, by 2 weeks post injury60% had evidence for SDB, and this percentage was maintainedover the course of the 1-year study (Berlowitz et al., 2005). Leducet al. (2007) evaluated the presence of OSA following SCI with rigidadherence to the diagnostic criteria recommended by the Ameri-can Association of Sleep Medicine. From a sample of 41 individualswith incomplete and complete cervical injuries, 22 were diagnosedwith OSA. Interestingly, they noted that the occurrence of obesityin their sample of SCI individuals was not greater than the preva-lence in the general population. This observation has importantimplications for the mechanism(s) underlying OSA after SCI (see4.3). Since the publication from Leduc and colleagues, several addi-tional reports (Biering-Sorensen et al., 2009; Jensen et al., 2009;Tran et al., 2010) have all reached the same fundamental conclu-sion: the prevalence of SDB following SCI greatly exceeds rates inthe general population, and OSA is the predominant form of SDB.

4.3. Mechanisms of OSA after SCI

The physiologic mechanisms resulting in the increase in OSAin individuals with SCI are not clearly defined. At first glance, onewould not necessarily predict increased airway collapsibility dur-ing sleep after SCI when compared to the spinal-intact condition.Specifically, the pharyngeal muscle activation, which makes a pri-mary contribution to the regulation of upper airway patency, istypically not impaired after even high cervical SCI. However, a num-ber of mechanisms can be plausibly suggested to contribute to theincreased prevalence of OSA after SCI (see Table 2 for a summary).As is the case in the general population, it is our opinion that theconsiderable increase in the prevalence of OSA after SCI reflects thecomplex interplay between several different physiologic mecha-nisms.

4.3.1. Body mass and obesityObesity and neck circumference are primary risk factors for OSA

in the general population (Cuccia et al., 2007). Following SCI, weightand body mass index (BMI) are often increased, and in the UnitedStates, 44–66% of the SCI population is considered overweight orobese (Chen et al., 2011; Gupta et al., 2006; Johnston et al., 2005;Tomey et al., 2005; Weaver et al., 2007). Indeed, BMI increases byapproximately 1 kg/m2 with each 10-year increase in age follow-

ing SCI (de Groot et al., 2010). Given the same BMI, individuals withSCI also typically have a higher percentage of body fat than theirnon-disabled counterparts (Spungen et al., 2000, 2003). Findingsin the SCI population, however, are somewhat contradictory. Some

SDB after SCI. Changes in breathing during sleep following SCI, and in particular multiple variables. In addition, the mechanisms driving SDB may be dynamically

draw definitive conclusions regarding underlying physiological mechanisms, eachally contribute to an increase in upper airway narrowing or collapse during sleep.

following SCI.

otential physiological impact

ncreased parapharyngeal tissue pressurencreased parapharyngeal tissue pressureeduction of caudal traction of the upper airwayeduction of caudal traction of the upper airway

ncrease upper airway collapsing forceronchoconstriction; changes in upper airway vasculature and/or mucosal liningnclearncleareduced respiratory motor activity

to be extremely complex and difficult to classify as “increased vs. decreased”.

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tudies suggest a robust and direct relationship between BMI andSA (Burns et al., 2001; Flavell et al., 1992; Stockhammer et al.,002), while others have failed to detect a relationship (Burns et al.,000; Short et al., 1992; Tran et al., 2010). For example, Burns et al.2001) used regression to assess the relationship between obesitynd sleep apnea in tetraplegic patients. They found a statisticallyignificant relationship between these two variables, and interest-ngly there was no relationship of apnea severity and the extent of

otor deficits. Similarly, Stockhammer et al. (2002) reported thatDB was significantly correlated with BMI and neck circumferencen tetraplegic patients ranging from 0.5 to 37 years post-SCI. In con-rast, Tran et al. (2010) did not find a relationship between sleeppnea severity and BMI or neck circumference in a cohort of 16CI subjects. However, this study was conducted within the first

months of injury. This is significant since Berlowitz et al. (2005)oted that OSA was actually associated with a reduced BMI acutely

ollowing SCI. Accordingly, the mechanisms driving upper airwayollapse during sleep after SCI may be dynamically changing as thendividual transitions from the acute to chronic stage. For exam-le, swelling of the neck in the acute injury phase could lead toSA independent of the body mass index (Berlowitz et al., 2005). Inur opinion, the literature collectively suggests that obesity and/orncreases of neck circumference are likely to make a contributiono the increased prevalence of OSA following SCI, but this is proba-ly not the primary mechanism in all cases, particularly during thecute phase after injury.

.3.2. Loss of traction force associated with reduced lung volumesSCI often results in reduced lung volumes (Schilero et al., 2009),

nd this could alter “traction forces” (Schwartz et al., 2012b) whichan impact airway patency. In other words, lung volume can influ-nce upper airway airflow resistance via a mechanical influence onhe geometry and collapsibility of the upper airways. Schwartz et al.1996) have described a mechanical model by which increasinghe volume of the lung reduces extraluminal upper airway tissueressure and increases longitudinal tension in the upper airways a result of caudal tracheal displacement. Indeed, caudal move-ent of the trachea can increase airflow rates, and decrease the

ritical pressure (i.e., Pcrit) required for pharyngeal airway nar-owing and/or collapse (Kairaitis et al., 2007, 2012; Rowley et al.,996). Accordingly, following SCI, chronic reductions in lung vol-me could lead to increases of pharyngeal airway collapsibility andhus contribute to the increased prevalence of OSA.

.3.3. Increased time in supine positionBody position during sleep has a substantial impact on SDB

Berger et al., 1997). For example, many OSA patients experience50% increase in apneic events when sleep position is shifted fromhe side to prone (Oksenberg et al., 1997). Thus, increase in obstruc-ive events following SCI could reflect increased or even exclusiveleeping in the supine position (McEvoy et al., 1995; Tran et al.,010). McEvoy et al. (1995) reported that quadriplegics who slept

n the supine position had a significantly greater number of apneicnd hypopneic events per hour compared to those who slept inther positions. Another consideration, however, is that pulmonaryunction may be enhanced in the supine position after SCI (Baydurt al., 2001).

.3.4. Altered balance of parasympathetic and sympathetic toneAutonomically driven changes in the upper airway vasculature

nd mucosal lining could directly impact airway resistance and leado OSA (Berlowitz et al., 2005). In addition, autonomically mediated

hanges in lower airway caliber and/or regulation can influenceverall pulmonary resistance, and this could also contribute to SDB.n regards to SCI and airway caliber, an important considerations that injuries to the cord can create an “imbalance” between

Neurobiology 188 (2013) 344– 354 351

parasympathetic and sympathetic outflow. Thus, parasympatheticinnervation of the lungs and airways is usually preserved after SCI,but sympathetic inputs can be profoundly disrupted (Radulovicet al., 2008). For example, autonomic dysreflexia following SCIis thought to result, at least in part, from impaired regulation ofsympathetic motor outflow. In the case of the pulmonary system,after SCI there can be an unopposed cholinergic (parasympathetic)modulation of airway tone that triggers excessive bronchoconstric-tion. There are reports of reduced airway caliber after SCI (Schileroet al., 2005), and also airway hypersensitivity (Almenoff et al., 1995;Grimm et al., 1999; Schilero et al., 2005) Any reductions in airwaycaliber could contribute to changes in pulmonary resistance andthus increased prevalence of SDB.

4.3.5. Brainstem plasticity and/or alterations in chemosensitivityThere has been a limited amount of work in this area, but in

our opinion, the literature supports the hypothesis that changesin brainstem respiratory neurons and networks are likely to occurafter SCI (Johnson and Creighton, 2005). For example, Golder andcolleagues showed that inspiratory motor drive to the tongue isaltered following high cervical SCI in rats (Golder et al., 2001). Thus,medullary respiratory motor output can be influenced by injuries tothe cervical spinal cord. In addition, Zimmer and Goshgarian (2007)reported significant alterations in brainstem neurochemistry aftera cervical SCI, albeit in a neonatal rat model.

Another consideration is that central chemosensitivity may bealtered after SCI (Manning et al., 1992), and this has the potential toimpact SDB. Simon et al. (1995) showed that individuals with highcervical SCI initiated inspiratory electromyogram (EMG) activity ata lower end-tidal CO2 as compared to able-bodied controls (i.e.,after SCI there was a lower CO2 recruitment threshold). A simi-lar finding has been reported in a rat model (Golder et al., 2011).A reduction in the CO2 “apneic threshold” after SCI could reflectan increase in the CO2 sensitivity of respiratory neurons and/ornetworks. However, other experiments indicate that the slope ofthe hypercapnic ventilatory response curve is actually blunted afterSCI (Kelling et al., 1985; Manning et al., 1992). For example, Kellinget al. (1985) reported that able-bodied control subjects had a ven-tilatory response slope (i.e., l min−1 mmHg−1) more than 2 foldgreater than quadriplegic subjects. Manning et al. (1992) confirmedthis finding. A blunted ability to increase inspiratory diaphragmEMG activity during hypercapnic respiratory challenge has alsobeen reported following mid-cervical contusion injury in rats (Laneet al., 2012). On the other hand, Pokorski et al. reported that venti-latory chemoresponses were not altered in quadriplegics, althoughtheir ability to compensate for a resistive respiratory load was con-siderably impaired (Pokorski et al., 1990).

We suggest that the limited available data indicate that neu-roplastic changes in the medullary respiratory control circuitry arelikely after SCI, although functional impact is not certain. Changes inthe overall chemosensitivity of respiratory motor output are possi-ble after SCI, but the role of muscle afferent feedback in modulatingchemoresponsiveness must be carefully considered (Simon et al.,1995). Clearly, the impact of SCI-induced respiratory neuroplastic-ity on breathing during sleep is an area requiring additional study.

4.3.6. MedicationsSeveral authors have raised the possibility that use of medica-

tions could predispose SCI patients to SDB. For example, the GABABreceptor agonist baclofen, which is commonly administered to treatspasticity following SCI, could trigger or exacerbate SDB (Bensmailet al., 2012). However, most studies have been unable to detect a

strong relationship between baclofen use and the prevalence of SDB(Burns et al., 2001; Klefbeck et al., 1998b; Short et al., 1992). Benzo-diazepines such as diazepam are also used as anti-spasticity drugsfollowing SCI, and these compounds are capable of suppressing

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52 D.D. Fuller et al. / Respiratory Physio

espiratory motor activity. These drugs may exacerbate SDB sinceerlowitz et al. (2005) reported a strong tendency for a decrease

n the AHI during sleep when benzodiazepine use was discontin-ed in tetraplegic patients. On the other hand, the same groupas unable to find a correlation between benzodiazepine use andHI in tetraplegics in a subsequent publication (Berlowitz et al.,012). In addition, the use of cardiac medication to treat hyperten-ion and arrhythmia is more frequent in tetraplegic patients withigher respiratory disturbance indices (Stockhammer et al., 2002).verall, pharmacologically induced changes in respiratory motorrive cannot be completely ruled out, and the medication status ofhe individual should obviously be considered when assessing SDBfter SCI. However, the available data suggest that factors otherhan medications are likely making a considerably greater contri-ution to the increased prevalence of SDB after SCI (Table 1).

.3.7. GenderIn the general population, age and body mass matched males

ave a greater prevalence of OSA when compared to pre-enopausal women (Young et al., 1993). To our knowledge,

owever, there have not yet been any studies specifically designedo evaluate the relationship between gender and SDB following SCI.onclusions are difficult to draw from the literature, since the over-ll prevalence of SCI is substantially greater in males than femalesNational Spinal Cord Injury Statistical Center, 2013), and thus, theumber of female subjects is generally smaller than male subjects

n previous SCI studies (Table 1). In the general population, gen-er differences in OSA prevalence have been suggested to relateo obesity patterns (centripetal in males vs. peripheral in females)nd also the influence of sex hormones. For example, the preva-ence of OSA increases in post-menopausal women (Redline et al.,994), and following menopause, hormone replacement therapyan lower the risk for OSA (Bixler et al., 2001). Both obesity patternsnd sex hormones could be influenced by SCI, and this could impacthe relationship between gender and OSA. At the present time,owever, it is not clear if gender differences in OSA persist afterCI, and future studies which specifically investigate this questionre warranted.

. SCI and SDB: current therapeutic approaches

Therapeutic approaches for SDB in the general populationnclude both surgical and non-surgical options (Goodday, 2011).he most widely used non-surgical treatment is continuous posi-ive airway pressure (CPAP). CPAP acts as a “pneumatic splint” toold the upper airway open, and has been shown to improve oxygenaturation and sleep architecture in SCI patients (Biering-Sorensent al., 1995; Burns et al., 2000; Stockhammer et al., 2002). Berlowitzt al. (2009) have demonstrated the feasibility of “auto-titrating”PAP in patients with acute tetraplegia. The auto-titration CPAPevice can automatically adjust the amount of positive airway pres-ure to ensure airflow. Of 19 subjects in their study, 14 had OSA, and

were able to successfully adhere to the CPAP therapy. CPAP effec-ively maintained ventilation during sleep, and patients reportededuced daytime sleepiness. Le Guen et al. (2012) recently com-ared the CPAP requirements and effectiveness between a samplef 219 able-bodied and 25 tetraplegic patients. While CPAP wasffective in both groups, the authors found that the able-bodiedubjects actually required a significantly greater level of CPAP toffectively manage OSA. This is an extremely important observa-ion as it may suggest that tetraplegic OSA patients have a lessollapsible pharyngeal airway as compared to spinal intact individ-

als with OSA. If this can be validated through studies of pharyngealcrit (Schwartz et al., 1996), it would indicate that neurologichanges in regulation of the upper airway may be a primary factoreading to OSA after SCI.

Neurobiology 188 (2013) 344– 354

Unfortunately, in both the general and SCI population, adher-ence to CPAP therapy tends to be poor. Interference with sleepand/or mask discomfort have been reported by SCI patients asreasons for discontinuing CPAP use (Burns et al., 2000, 2001). Fur-thermore, many individuals with SCI may be reliant on assistancefrom caregivers due to limited hand function, thereby compound-ing difficulties with mask placement and adjustment. Berlowitzet al. (2009) found that if tetraplegic patients received “intensiveclinical support” during initial CPAP trials, those patients who wereable to tolerate a minimum of four hours during initial treatmentswere more likely to continue using the therapy. In addition, theauthors commented that patients who were older, “sleepier”, andhad more severe OSA were more likely to maintain the use of CPAP.Castriotta and Murthy (2009) have suggested that some relativelynewer devices (e.g., averaged volume assured pressure support andadaptive servo-ventilators) used to treat OSA in the general popu-lation should be applied to SCI patients.

6. Conclusions

SDB is a significant complication of SCI, and as suggested by Tranet al., screening for SDB in the SCI population should be considered(Tran et al., 2010). In the general population, SDB is associated withcardiovascular disease, cognitive impairments, daytime sleepiness,and reduced quality of life. Thus, following SCI, SDB will likelyexacerbate an already medically, physically, and emotionally chal-lenging condition. For example, Sajkov et al. reported that cognitiveimpairments in tetraplegic patients were significantly correlatedwith the severity of hypoxic episodes during sleep (Sajkov et al.,1998). The authors noted that deficits in the ability to concentrate,memory function, and learning also correlated with the severity ofoxygen desaturation during sleep. Berlowitz et al. (2012) studieda large sample of tetraplegic individuals, and convincingly demon-strated a relationship between the self-reported quality of life andhealth scores and the severity of SDB. Specifically, as the nocturnalapnea–hypopnea index increased, the overall quality of life scoresdecreased. The authors concluded that in the tetraplegic popula-tion, OSA makes a considerable contribution to the decrease inoverall health status.

It appears that obstructive apnea is more common than cen-tral apnea following SCI (Table 1). While mechanisms leading toincreased OSA prevalence after SCI are not yet clearly defined, theincrease in pharyngeal airway collapsibility during sleep is likely toreflect a complex interaction between multiple variables (Table 2).These variables include body mass, lung volume, sleeping position,autonomic function, and respiratory neuroplasticity. In addition,the mechanisms driving OSA may be dynamically changing as anindividual progresses from acute to chronic SCI. Lastly it is con-ceivable that individuals with OSA are more likely to have a SCI(i.e., in some cases OSA might be a pre-existing condition) (Tranet al., 2010). For example, in the general population OSA is asso-ciated with more frequent automobile accidents (George et al.,1987). Further study of this problem and delineation of the mech-anisms causing OSA after SCI should lead to improved therapeuticapproaches for this condition. In particular, we feel that studiesof the neural regulation of the pharyngeal muscles during sleepfollowing both acute and chronic SCI are needed.

Acknowledgements

by the VA RR&D Service (B7182W and F2182C). KZL was supportedby National Science Council (NSC) NSC100-2320-B-110-003-MY2,National Health Research Institutes (NHRI-EX102-10223NC) andNSYSU-KMU Joint Research Project (2013-I006).

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