Introduction

Spinal cord injury (SCI) is a significant global cause of mortality and morbidity. In 2007, the global incidence was estimated to be 23 cases per million per annum, ranging from 15 cases per million in Australia to 29 cases per million in sub-Saharan Africa ( ).

Most people with SCI sustain their injuries in their second or third decade of life. Because of improvements in both the acute management and long-term supportive care, their life expectancy after injury has increased significantly. As such, secondary diseases and impairments that are a direct consequence of the SCI have significant impacts for many years. Sleep disorders, especially sleep-disordered breathing (SDB), periodic and/or restless leg syndromes (PLM/RLS), and circadian rhythm disorders, are all prevalent disorders after SCI. This chapter focuses on these particular sleep disorders because while insomnia, generalized fatigue, and other sleep-associated disorders affect people living with SCI just as the general population, the increased prevalence and altered pathogenicity due to the spinal lesion per se of SDB, PLMs, and circadian rhythm disorders after SCI deserves special consideration ( ). Population prevalence, known physiological differences in causation, response to therapies, and longer-term consequences of sleep disorders in these sleep disorders after SCI are discussed.

Sleep-disordered breathing

Sleep-disordered breathing is an umbrella term that includes obstructive sleep apnea (OSA), central sleep apnea (CSA), and sleep-related hypoventilation. OSA is repeated partial (narrowing/hypopnea) or complete (occlusion/apnea) closure and interruption to ventilation at the level of the upper airway during sleep. The drive to breath is generally maintained during OSA, whereas CSA is characterized by periods of diminished or absent ventilatory drive with associated reductions in ventilation. Both OSA and CSA result in periodic oxygen desaturation and fragmentation of sleep typically resulting excessive daytime sleepiness. Hypoventilation refers to periods during which arterial carbon dioxide homeostasis is not maintained because minute ventilation inadequately matches metabolism. The consequence of hypoventilation is a raised arterial carbon dioxide. All three disorders may exist separately or together in the same person and to various degrees over, and indeed within, sleep periods ( ). The most common risk factors for OSA in the general population are being male and having a raised body mass index (BMI).

There is very little published research into respiratory sleep disorders in paraplegia. While little data reduces our ability to be certain, it is believed that the pathophysiology, risk factors and prevalence of respiratory sleep disorders in those living with paraplegia is not substantially different to the general population. Conversely, tetraplegia has been studied extensively. Despite substantial overall respiratory muscle weakness, ( ) tetraplegia is not routinely associated with hypoventilation, but rather with OSA ( ). The upper airway muscles derive motor innervation from the cranial nerves, predominantly the hypoglossal, rather than from the spinal segmental nerves. Hence, an injury that disrupts, for example, C6 should not have any effect on the genioglossus. Yet while OSA is highly prevalent ( Fig. 1 ), hypoventilation appears rare at a population level. In a recent large, multi-center randomized controlled trial of continuous positive airway pressure (CPAP) for SDB in acute tetraplegia ( ), only eight of the 212 otherwise eligible participants (3.8%) were excluded due to hypoventilation (PaCO ₂ > 45 mmHg) ( ). Hypoventilation has been reported, particularly at sleep onset in physiological studies ( ) and in association with a reduced ventilatory reserve for carbon dioxide ( ), but there is little evidence for increased hypoventilation prevalence across all those living with tetraplegia. Clinically however, if a raised carbon dioxide is detected in a particular patient, this relatively rare sign demands immediate clinical attention.

Prevalence estimates and their relationships to general population data for mild, moderate, and severe sleep-disordered breathing in tetraplegia. Forest plots of individual study data, pooled estimates of prevalence in studies of people with tetraplegia, and ranges of general population estimates at mild (AHI > 5), moderate (AHI > 15), and severe (AHI > 30) levels of SDB severity ( ). These graphs illustrate the substantially higher prevalence of sleep-disordered breathing in tetraplegia across all ranges of severity. Solid bands across the mild and moderate data ranges are general population estimates ranges ( ). AHI = apnea hypopnea index (measured in events per hour).

Prevalence of sleep-disordered breathing after tetraplegia

The prevalence of disordered breathing during sleep is estimated to be between 9% and 38%, and increases with age ( ). In previous cross-sectional population studies of sleep disorders in patients with tetraplegia, the prevalence of SDB has been estimated to be between 27% and 97% ( ; ). However, a recent meta-analysis of the published population estimates in tetraplegia presented the pooled estimates at various cut-off severities ( ). Twelve articles across 20 years were included, nine of which presented data amenable to meta-analysis (combined n = 630). The reported SDB prevalence rates from the 12 studies ranged from 46% to 97%. Following meta-analysis the mean prevalence of at least mild (apnea hypopnea index AHI ≥ 5 events per hour), moderate (AHI ≥ 15), and severe (AHI ≥ 30) SDB were 83% (95% CI = 73–91), 59% (46–71), and 36% (26–46), respectively. As illustrated in Fig. 1 , the prevalence of SDB after cervical SCI is clearly elevated at all levels of severity compared with general population estimates ( ).

Sleep-disordered breathing is an acute and direct consequence of cervical SCI

As noted above, the upper airway is innervated directly from the brain via the cranial nerves, not by the spinal segmental nerves. Notwithstanding this, an acute cervical spinal cord injury appears to directly compromise upper airway patency during sleep within weeks of the injurious event. Berlowitz et al. studied all patients presenting to the specialized SCI unit in Melbourne, Australia, over an 18-month period and undertook full, bedside polysomnography to determine when SDB appeared after injury ( ). As illustrated in Fig. 2 , approximately 10% of the cohorts were at increased risk of the SDB prior to injury as estimated by a prediction algorithm that incorporates signs and symptoms. Within 2 weeks of injury, the measured prevalence of clinically important disease had increased to 60% and peaked at over 80% 3 months after initial injury. Most people with SDB have an insidious onset of the disorder over a number of years as they age and gain weight. In contrast, tetraplegia appears to be the only model of acute SDB in humans. As such, the pathophysiology in acute tetraplegia is likely different from the general population and is not yet fully understood ( ).

Proportion of those with sleep-disordered breathing in a prospective, acute cohort study. Solid bar graphs refer to the proportion of the cohort with SDB at each assessment. The pre-injury proportion with an AHI score greater than 10 (vertical striped bar) was estimated using a prediction algorithm that incorporates, age, sex, body mass index and (participant recalled) symptoms to give a likelihood of an AHI > 10 ( ). SDB = sleep-disordered breathing as defined by a respiratory disturbance index (RDI) > 10 events per hour.

Sleep-disordered breathing after tetraplegia has clinically important impacts

Alongside the cardinal SDB signs of nightly intermittent hypoxia, repeated arousals from sleep, and excessive daytime sleepiness, SDB is also associated with increased cardiovascular risk and clinically important degrees of neurocognitive dysfunction. In the general population, numerous reviews have described the deleterious impact of SDB on neuropsychological functioning and demonstrated impairment in the domains of attention, information processing, executive function, memory, and learning ( ). While SDB in the general population is associated with hypertension, altered diurnal blood pressure patterns and heart rate variability (HRV), these relationships are not as uniformly observed in those with tetraplegia and SDB. Goh and colleagues demonstrated that tetraplegia is associated with relative nocturnal hypertension and “reverse dipping” or a loss of the usual reduction in blood pressure overnight ( ). In contrast, Sankari et al. have demonstrated that those with tetraplegia and SDB are also more likely to have diagnosed hypertension and cardiovascular disease ( ). However, Fang et al. were unable to show any difference in the 24-h, night-time, and daytime blood pressure patterns in those with tetraplegia and mild, moderate, severe or no SDB ( ).

SDB has been associated with worse quality of life in tetraplegia. A study investigating the relationships between quality of life and sleep disorders in chronic tetraplegia measured both health-related quality of life (Assessment of Quality of Life) and SDB severity with a full, portable home-based sleep study ( ; ). As illustrated in Fig. 3 , quality of life and health utility scores were worse in the group with complete lesions compared with incomplete lesions. This single co-morbidity reduces health-utility by an approximately five times the minimally clinically important difference. As such, any effective treatment is likely to have an important impact on those living with both tetraplegia and SDB.

Tetraplegia severity and obstructive sleep apnea independently modify health status. Colored bands represent the Australian population averages for categories of self-reported health status. Health utility ranges from one (self-rated “perfect health”), through zero (self-rated health state equivalent to death), and down to a health status of − 0.04 (self-reported health status that is perceived to be “worse than death”). The Australian population average (95% confidence interval) score is located between “good” and “very good” ( ). The pink vertical bar represents the minimal clinically important difference in health status (0.06) and the associated confidence interval of this difference. People with tetraplegia are categorized by the presence or not of sleep apnea and of motor and sensory complete spinal injury (ASIA impairment scale A vs B, C, or D). Open circles represent individual participant scores, and the horizontal bars represent group mean values ( ). OSA = obstructive sleep apnea as defined by an apnea hypopnea index (AHI) > 10 events per hour.

In patients living with chronic SCI, published neuropsychological evaluation data that were performed concurrently with a diagnostic sleep study in 40 people who had been living with tetraplegia for many years ( ). The neuropsychological functions most affected were verbal attention and concentration, immediate and short-term memory, cognitive flexibility, internal scanning and working memory. These impairments are similar to those observed in the able bodied with OSA, which suggested that even if the pathogenesis of SDB is different immediately after SCI, the cognitive consequences of living with SDB for decades appear similar.

As noted earlier, our group recently completed a large, multi-center randomized controlled trial of CPAP for SDB in acute tetraplegia ( ; ). Baseline data from that study was utilized to investigate the relationship between apnea severity and neuropsychological function in patients with acute-onset tetraplegia and SDB dysfunction ( ). Study enrolment analyses showed more severe sleep apnea was significantly associated with poorer attention, information processing, and immediate recall. Higher pre-injury intelligence and being younger reduced the associations with sleep-disordered breathing; however, these protective factors were insufficient to counter the damage to attention, immediate recall, and information processing associated with the sleep-disordered breathing. As illustrated in Table 1 , these deficits in attention and information processing, as measured by the PASAT, were clinically important, being well within the range of values reported in moderate to severe isolated head injury ( ). Attention and information processing as measured on the PASAT naturally decline as we age, but the reduction seen in those with severe SDB compared with milder SDB was equivalent to an additional 31 years of ageing.

Why do people with tetraplegia have sleep-disordered breathing, predominantly obstructive sleep apnea?

It is apparent that SDB in SCI is not simply due to peri-accident neuroanatomical compromise; however, the exact etiology remains unknown. Obesity, as measured by increased weight, body mass index (BMI), waist, abdominal, and neck girth, is associated with OSA in both SCI and the general population ( ; ). Obesity results in upper airway narrowing in both lateral pharyngeal tissues and the tongue in the general population, as well as those with SCI ( ; ). Truncal obesity reduces lung volume and distal tethering of the trachea which in turn leads to decreased upper airway caliber during sleep ( ). In chronic SCI, several authors have observed associations between OSA prevalence and increasing age, BMI and neck circumference, ( ; ; ; ) but these relationships appear weaker in the immediate period after injury ( ).

Many people living with SCI are prescribed medications (sedatives, muscle relaxants, and narcotics) that can affect breathing, especially during sleep. Loud snoring (a typical OSA sign) has been associated with the use of anti-spasticity medications and obesity in SCI in one cross-sectional study ( ). There have been no controlled studies in SCI of the effect of medication provision or withdrawal on SDB severity; however, a smaller proportion of those in the intervention (CPAP treatment for SDB) arm of the COSAQ study were prescribed baclofen at end-study ( ), and a non-significant reduction in baclofen prescription rates was observed in those whose SDB improved over time in another cohort trial ( ).

People with tetraplegia and those with lesions above T6, also develop increased nasal and total upper airway resistance due to increased parasympathetic tone. This increased nasal resistance may contribute to upper airway narrowing by increasing negative (collapsing) pressure in the upper airway during inspiration ( ; ). While this increased upper airway resistance can be acutely reduced with topical sympathomimetic application, no difference in SDB was observed in a pilot, cross-over randomized controlled trial of topical sympathomimetic application (phenylephrine) in people with tetraplegia and SDB ( ).

Our research group in Melbourne, Australia and colleagues in Detroit, USA have undertaken the majority of these physiological sleep studies and both centers have used comparable physiological measures ensuring that our data are complementary. By comparing people with tetraplegia and SDB with control participants (no SCI) that had SDB, a number of putative physiological factors have been examined. The reflex response of genioglossus to negative upper airway pressure was reduced and delayed in people with both OSA and SCI compared to those with OSA but without SCI ( ). This reflex is an important protective response of the upper airway and a reduction predisposes the upper airway to collapse during sleep. The critical closing pressure of the upper airway (P _CRIT ) is determined by first stabilizing the upper airway during sleep with small amounts of continuous positive airway pressure and then reducing that external pressure until the upper airway collapses. Sankari et al. demonstrated that the P _CRIT in tetraplegia and SDB is not different to non-disabled people with SDB ( ). Data examining arousal responses and muscle recruitment remain equivocal.

The upper airway is a collapsible tube where patency is largely dependent on the surrounding soft tissue, phasic and tonic muscle tone, fat pad volume, and extraluminal tissue pressure from blood, lymph, and extracellular water. A series of magnetic resonance imaging studies in people with SDB and tetraplegia have compared the structure and function of the upper airway with non-disabled controls and observed that while SCI OSA patients have heterogeneous pharyngeal dilator muscle responses to the negative pressures occurring during inspiration, as a group they are more similar to able-bodied OSA patients than healthy controls of similar age and BMI ( ; ).

Clinical management of sleep-disordered breathing in people with SCI

Despite the high prevalence of SDB and its detrimental effects on health and quality of life, surveys indicate that less than 25% of people with SCI are diagnosed and treated for the disorder ( ; ). The “gold-standard” method for diagnosing SDB is a Level I, overnight, attended polysomnography (PSG). Clinical practice guidelines recommend PSG for people with SCI and signs and symptoms of SDB ( ). However, access to this test, which requires an overnight stay in a sleep laboratory, is often poor. At least two studies have investigated the use of limited channel studies to detect SDB in SCI with results demonstrating moderate accuracy of this less intensive method ( ; ). These limited channel sleep studies may provide alternatives to PSG, particularly when access to sleep specialist services is poor.

Treatments for SDB in SCI are essentially the same as for the general population. Continuous positive airway pressure (CPAP) is the first-line treatment for SDB. CPAP provides a continuous positive airway pressure of typically between 4 and 20 mmHg, via a mask, to prevent upper airway collapse during sleep. Our COSAQ study, described earlier, is the first and only controlled trial to investigate the effects of CPAP in people with SCI. It demonstrated that CPAP effectively improved daytime sleepiness in people with acute tetraplegia, although there was no effect of CPAP on neurocognition ( ). CPAP effectiveness is limited by poor adherence and acceptance of the therapy in both SCI and the general population. When defined as an average of at least 4 h per night, CPAP adherence in people with tetraplegia and SDB has been estimated at approximately 25% ( ; ). A qualitative study seeking to understand the barriers and enablers to CPAP use among people with tetraplegia found that both the burdens and the benefits of using CPAP were substantial, and patients actively weighed these burdens and benefits to decide whether to continue with the therapy ( ).

Other potential treatments for SDB in SCI include bi-level positive airway pressure (PAP), mandibular advancement splints (MAS) and positional therapy. Bi-level PAP is a more expensive PAP therapy than CPAP, which delivers a higher inspiratory than expiratory pressure and is commonly used for hypoventilation disorders. Some clinicians prefer to use it to treat SDB in patients with more severe SCI (i.e., high tetraplegia) and greater respiratory compromise, and in those with a predominance of central than obstructive events. However, there is no research evidence to support the use of bi-level PAP over CPAP for treating SDB in SCI, and vice-versa. MAS are commonly prescribed in the general population to those who are unable to tolerate CPAP or as a first-line therapy to treat mild OSA. The mouthguard-like device is worn on the upper and lower jaw and is designed to pull the lower jaw forwards to open the airway while simultaneously increasing tension in the soft tissues and preventing collapse. Research has demonstrated that MAS devices can effectively improve the symptoms of OSA in the general population ( ). As yet, there have been no published studies investigating MAS in SCI.

Recent qualitative research aiming to describe and understand the management of SDB in SCI rehabilitation centers has identified that the management of SDB is highly varied in SCI ( ). The most common management pathway for people with SCI suspected of having SDB involves referral from the primary care or rehabilitation doctor to a specialist sleep/respiratory physician for investigation and management ( ). However, this care model often presents significant access barriers to people with tetraplegia and may contribute to the low rates of detection and treatment seen in this population ( ). The same study identified three spinal cord injury (SCI) rehabilitation centers that had developed an “in-house” SDB management model in response to poor access to specialist sleep services. In each center, a multi-disciplinary team provides screening, diagnosis and treatment of uncomplicated SDB using portable equipment and without direct specialist sleep service involvement. This demonstrates that it is feasible for multi-disciplinary SCI rehabilitation teams to independently manage un-complicated SDB ) and further research investigating the safety and effectiveness of SDB management provided by the rehabilitation team is urgently needed.

How does SCI alter the circadian rhythm?

Following a complete cervical SCI, afferent somatic and autonomic fiber pathways below the SCI are disrupted and the efferent sympathetic innervation of the pineal gland via the superior cervical ganglion is interrupted. This anatomical disruption alters the circadian rhythmicity of melatonin regulation and production in tetraplegia and those with paraplegia lesions associated with autonomic dysfunction, typically T6 and higher. Under normal conditions, light striking the retina stimulates afferent pathways through the suprachiasmatic nuclei (SCN) that in turn pass to the superior cervical ganglion and onward to the pineal gland to inhibit melatonin production. Darkness removes this inhibition, and melatonin is produced. The fibers from the SCN travel alongside those from the sympathetic system to exit the spine between the first and sixth thoracic levels. The SCN to pineal pathway then ascends outside the spinal canal to the superior cervical ganglion, back into the cortex, and on to innervate the pineal gland. This circuitous pathway exposes melatonin regulation to disruption after SCI ( Fig. 4 ).

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