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For some of these individuals, disruption of breathing in sleep results in worsening of their overall condition and improvement in breathing results in a global benefit. In others, however, the sleep-related breathing issue appears to parallel their neurological condition and treatment may result in little benefit. Unfortunately for the clinician, the distinction between these two groups is not always clear. Although obstructive sleep apnea (OSA) may be one of the more common sleep-related breathing disorders (SRBDs), clinicians must also be aware that other respiratory issues may impact patients with neurological disorders. Treatment of any SRBD offers an opportunity to improve quality of life. In this chapter, we will explore the relationship of sleep and breathing to a variety of neurological condi- tions and describe some of the therapeutic approaches and pitfalls. NEUROLOGICAL LOCALIZATION OF RESPIRATION The organ of control over breathing, the brain, orchestrates respiration through many layers of neural circuitry. From the respiratory-related muscles, peripheral receptors and nerves to brainstem, midbrain and cortical feedback loops, a variety of inputs augment and regulate ventilation and respiration. This multilayered control system permits for a variety of ventilatory patterns that can give clues to the site of potential neurological dysfunction (1) (Table 1). The ventilatory cycle relies upon sensory inputs to estimate the somatic requirements. This sensory input is derived primarily from three components: (i) the vagus nerve relaying information from the pulmonary stretch receptors in the lung and aorta, (ii) the intercostals nerves and spinal cord relaying positional sense from the chest wall, (iii) and the chemoception. Chemoception utilizes two sensory areas: central and peripheral. Central chemoceptors are predominantly on the ven- tral aspect of the medulla. These receptors sense acid and carbon dioxide. The peripheral chemoceptors are in the aorta and carotid body and their information are relayed via the glossopharyngeal nerve. The carotid chemoceptors detect the oxygen content of the arterial blood. These sensors increase their firing rates when oxygen levels fall. These sensory nerves are typically myelinated but also convey some input via partially myelinated and unmyelinated axons. Processes such as diabetes 22 368 Alattar and Vaughn mellitus, Guillain-Barré syndrome or porphyria can damage these nerves. Although pure sensory loss of these nerves is exceedingly rare, damage of these nerves is typi- cally accompanied with loss of motor function. If pure sensory nerve loss did occur the peripheral feedback of information to the medulla would be diminished, and patients would rely upon central chemoceptors for feedback regulation. At the level of the medulla, we find the first layers of respiratory cycle genera- tors. Neurons in the nucleus solitarius, ambiguous, and retroambigualis work in concert to initially match ventilation to respiratory demand. The ventilatory cycle is composed of three phases: inspiration, postinspiration, and expiration. Respiratory neurons in the medulla and pons discharge in a pattern correlating to one of these phases. Together these neurons form the central pattern generator that orchestrates the cyclic activation of the respiratory musculature. This central pattern generator is composed of predominately three neuronal groups. Nogues categorized these as dorsal respiratory group, ventral respiratory group, and pontine respiratory group (2). The dorsal respiratory group is in the ventrolateral subnucleus of the nucleus tractus solitarius. This neuronal group is TABLE 1 Central and Peripheral Nervous System Lesions and Their Associated Neurological Disorders, Ventilatory Patterns, and Potential Sleep-Related Breathing Disorders Location Non-state-dependent breathing issue Disorders of the area Potential sleep- related breathing disorder Cerebral cortex Cheyne-Stokes post- hyperventilation pause Stroke, tumor, multiple sclerosis, trauma, encephalitis Obstructive sleep apnea, central sleep apnea, Cheyne-Stokes breathing Midbrain Central hyperventilation Progressive supranuclear palsy, Parkinson’s disease, tumor Central sleep apnea Pons Apneustic, biots Multiple sclerosis, tumors, strokes Central sleep apnea Medulla Ataxic breathing Chiari malformations, multiple sclerosis, stroke, tumor Central sleep apnea, obstruc- tive sleep apnea Spinal cord At or above C3–5: no respiratory effort, C5–T8: potential impaired chest wall motion, difficulty with expiration and potential hypoventilation Multiple sclerosis, trauma, myelitis, syringomyelia, tumor Hypoventilation Peripheral nerve Respiratory cycle issues with severe sensory and motor neuropathies Guillain-Barré syndrome, porphyria, diabetes mellitus Central apnea, hypoventilation Neuromuscular junction Hypoventilation with fatigue Myasthenia gravis, Lambert-Eaton syndrome Obstructive sleep apnea, hypoventilation Muscle Hypoventilation with fatigue Myotonic dystrophy, Duchenne muscular dystrophy, polymyositis Hypoventilation Neurological Disorders 369 primarily active during inspiration receiving input from pulmonary vagal afferents. Many of these neurons excite lower motor cranial nerves that dilate the upper airway prior to excitation of the contralateral phrenic and intercostal neurons in the spinal cord. This coordinated output must occur in the correct timed sequence to permit the movement of air through a patent airway. Other neurons in this same group receive input from baroreceptors and cardiac receptors influencing several other respiratory-related reflexes (e.g., coughing, sneezing). The ventral respiratory group is located in the ventral lateral medulla from the top of the cervical cord to the level of the facial nerve. This group contains the BÖtzinger complex, the preBÖtzinger neurons, the rostral portion of nucleus ambiguous, and nucleus retroambigualis. The BÖtzinger complex contains neurons that are active during expiration and inhibit inspiration. The preBÖtzinger complex contains propriobulbar neurons that participate in generating the rhythm of respira- tion. The caudal portion of this group is primarily composed of expiratory neurons that project to intercostal, abdominal, and external sphincter motor neurons. Although these primary drivers form a rudimentary cycle, neurons in the ventral and midline medulla appear to have plasticity in response to intermittent hypox- emia to augment respiratory responses (3). Lesions in the medulla may produce ataxic breathing, agonal respiration or an absence of respiration. The pontine respiratory group adds another layer of control. This group is localized to the dorsal lateral pons and is important in stabilizing the respiratory pattern. These neurons are influenced by both inspiratory and expiratory inputs and help determine the length of inspiration and expiration (1). Typically, the destruction of these neurons lengthens the duration of inspiration. Lesions of the caudal pons may also produce apneustic respiration, and lesions in the mid- brain or posterior hypothalamus may produce hyperventilatory responses. These types of respiratory abnormalities may result from strokes, tumors or demyelin- ating plaques. The voluntary control over respiration primarily resides in the cerebral cortex and diencephalon. The cortex is responsible for initiating the intricate respi- ratory control involved in speech, eating, and singing. As an individual enters sleep, the cortical control over sleep is altered and may allow the emergence of SRBD. With cortical injury, patients may have prolonged posthyperventilatory apnea or Cheyne-Stokes respiration (CSR). The CSR may be more prominent or only present in sleep (4). The output to the lower respiratory neurons requires transmission of the respiratory effort through the spinal cord to the peripheral nerves. The spinal cord respiratory motor output is divided into two components. The phrenic nerves emerge from the upper cervical cord region (C3–5) to maintain diaphragmatic func- tion. The thoracic levels (T1–T12) innervate the intercostal muscles and the lower thoracic and upper lumbar levels (T6–L3) innervate the abdominal muscles. This division of labor adds a level of assurance of respiration despite the potential of spinal cord injury. The peripheral nerves must deliver the sensory and motor signals. These peripheral nerves are generally well-myelinated, relatively protected from trauma by bone and have limited lengths. These characteristics assure these nerves are less vulnerable to damage compared to most nerves supplying the limbs. In general, nerves with longer courses have greater opportunity to incur injury from trauma, toxins or demyelination, and thus are more likely to demonstrate dysfunction. This may not be true for some etiologies such as porphyrias, or inflammatory 370 Alattar and Vaughn polyradiculopathies, which can afflict more proximal nerves. Individuals with peripheral nerve disorders may demonstrate progressive nocturnal hypoventilation and respiratory failure requiring ventilatory assistance during the more severe por- tions of the disorder (5). In contrast, patients with multiple cranial neuropathies may also demonstrate features of upper airway obstruction. The neuromuscular junction may also be associated with respiratory dysfunc- tion. Respiratory muscles such as the diaphragm may require less depolarization to reach firing threshold and thus these muscles may not be the first affected by neuro- muscular dysfunction. The range of SRBDs affected by neuromuscular dysfunction is exemplified in myasthenia gravis (MG), as noted subsequently. At the level of the muscle, respiration depends upon adequate contraction of these muscles no matter the sleep–wake state. These lower respiratory muscles include slow-twitch muscle, which generally require the less amount of energy to contract and thus are generally more stable with fatigue (6). Some inherited muscle conditions such as Pompe’s disease (acid maltase deficiency) may primarily affect respiratory muscles causing hypoventilation. This hypoventilation may be more obvious in sleep. Overall, respiration during sleep offers a unique window to view the neuro- logical control over breathing. The entrance into each sleep state creates a change in the regulation over breathing and may allow the emergence of disordered breath- ing. This window may aid in the localization of neurological disease as well as bring insight into the potential causes of SRBD. We have included a table of typical breath- ing patterns and localization of neurological dysfunction (Table 1). As the reader reviews the variety of neurological disorders, the table may provide additional clarity to the secondary respiratory issues. SPECIFIC DISORDERS AND SLEEP APNEA Central Nervous System Disorders Alzheimer’s Disease Alzheimer’s disease is the classical tauopathy characterized by diffuse neuronal loss primarily in the cortex associated with the formation of neurofibrillary tangles and neuritic plaques. The incidence of SRBD in patients with Alzheimer’s disease is unclear. Some investigators have found an increase in SRBD, but in the more posi- tive of studies, the degree of sleep apnea is relatively small. In a cohort of 139 patients, Hoch found that the average apnea–hypopnea index (AHI) for patients with Alzheimer’s was 4.6 whereas the control group was 0.6 (7). This finding was in contrast to Smallwood’s findings, which showed that apnea index was not greater in elderly men with Alzheimer’s than healthy elderly men without sleep complaints (8). Despite the incidence, the question remains: does the apnea drive the neuropathol- ogy or does the dementia cause the breathing disturbance? Untreated sleep apnea has been linked to potential decline in neurocognitive function (9). Although this too has been under debate, some of this decline may be related to vascular issues (9). One component may be the potential link of genetic predisposition to cognitive decline. Apolipoprotein E (APOE) 4 alleles have been associated as a risk factor for the development of Alzheimer’s disease (10). This gene has also been linked to SRBD but to date the resulting cognitive issues have not been linked to APOE 4. Sleep-related respiratory disorders may have a daytime effect in patients with Alzheimer’s. Gehrman (11) found that institutionalized patients with OSA were more likely to have daytime agitation but not night-time agitation suggesting that the SRBD may have some influence on daytime behavior. Neurological Disorders 371 The diagnosis and treatment of SRBD in patients with Alzheimer’s disease can create some challenges. Early in the course of the dementia, most patients can easily adapt to the testing environment with extra instructions. Technologists and healthcare providers must be attuned to the patient’s limited ability to learn new skills and adapt to new settings. These same individuals must remain calm, take extra time to review the procedures, and incorporate multiple teaching aids to help the patient understand. Visual teaching aids along with verbal and written commu- nication may decrease the likelihood of confusion. For many of these patients, the laboratory personnel will find advantageous in having a family member or familiar caregiver in the testing environment to reinforce the communication. In more severely impaired individuals, patients may present significant challenges for electrode application. Making the environment calm with few stimuli may help. Sleep studies may show the patient has typical OSA or mixed apnea. This popula- tion is also at risk for CSR more commonly in Stage 1 and 2 sleeps but this pattern is uncommon in slow-wave sleep and rapid eye movement (REM) sleep. Patients with Alzheimer’s disease and sleep apnea generally accept the con- tinuous positive airway pressure (CPAP) therapy similar to the general population. Ayalon found that these patients used the device an average of 4.8 hours per night (12). The use of CPAP may improve daytime alertness and decrease irritable behavior. Some specific issues may arise in the treatment of this disorder. Individuals may not easily accept therapies such as CPAP or oral appliances thinking the ther- apy may harm them or that they are related to some other aspect of their health. Many of these individuals have memory difficulties and have periods of nocturnal confusion. In general, these individuals may have a better chance of adherence if a family member or caretaker is given the same information regarding the diagnosis and importance of therapy. The caretaker may also consider using some form of behavior modification to help the patient adjust to wearing the CPAP or oral appliance. These techniques may include notes or other messages in prominent and frequented areas, or serial verbal cues before bedtime reminding the patient to use the device. Many medications may influence the patient’s behavior and cognition: thus caregivers should be alert to medications given in the evening that may further confuse the patient. This is also true when considering surgery. These patients have some inherent risk with anesthesia, and will require close supervision following surgery. Most patients with early disease are able to tolerate surgery; this post- operative period is a frequent time for greater confusion and behavior change. Other Forms of Cognitive Impairment Lewy body dementia is also associated with cognitive decline and particular impair- ment of visual spatial tasks. These disorders are noted to have high prevalence of sleep-related complaints based on survey questionnaires, but no study has shown the prevalence of polysomnographic abnormalities in these patients (13). A case report suggests that individuals with autonomic features may have SRBD (14). Cheyne-Stokes breathing and OSA are common findings, but there is no clear link between this form of dementia and sleep apnea. In many of these individuals, treatment follows the same recommendations as those with Alzheimer’s disease. A subgroup of these individuals will have loss of REM sleep atonia and have periods of dream enactment, consistent with a diagnosis of REM sleep behavior disorder. This can become quite dangerous if the patient has a CPAP machine and uncontrolled nocturnal events. 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