Chapter 12

Sleep Dysfunction and Sleep-Disordered Breathing in Miscellaneous Neurological Disorders

Sudhansu Chokroverty, Sushanth Bhat and Federica Provini

The central nervous system (CNS) plays an important role in the regulation of sleep-wake cycles, and both the CNS and the peripheral nervous system play significant roles in the control of breathing in sleep. It is not therefore surprising that neurological disorders can have a profound impact on sleep and breathing.

Regulation of Sleep-Wake Cycles

Neuroanatomical substrates for wakefulness include the ascending reticular activating system terminating in the thalamus and extrathalamic regions of the basal forebrain. These ascending pathways project widely to the cerebral cortex to maintain wakefulness and a state of arousal. Major neurotransmitter pathways responsible for wakefulness include cholinergic neurons in the laterodorsal tegmentum (LDT) and pedunculopontine tegmentum (PPT), as well as the nucleus basalis of Meynert, noradrenergic neurons in the locus ceruleus (LC), serotonergic neurons in the dorsal raphe nucleus (DR), histaminergic posterior hypothalamic neurons, and the recently described neurons of the lateral hypothalamus and perifornical region that secrete orexin (also known as hypocretin). These hypocretinergic neurons have widespread ascending and descending projections throughout the CNS.

Generators of non–rapid eye movement (NREM) sleep are primarily located in the ventrolateral preoptic nucleus (VLPO) of the anterior hypothalamus, with a minor contribution from the nucleus tractus solitarius in the medulla. These neurons in the VLPO are γ-aminobutyric acid (GABA)ergic and galaninergic (both inhibitory neurotransmitters).

Rapid eye movement (REM) sleep is generated by neurons in the pons. The original McCarley-Hobson model for REM sleep generation mechanism by reciprocal interaction between REM-on (cholinergic LDT-PPT) neurons and REM-off (aminergic LC-DR) neurons was later superseded by the Lu-Saper and Luppi models. In the Lu-Saper model, REM-on GABAergic pontine neurons in the sublaterodorsal (SLD) nucleus (equivalent to peri-locus ceruleus alpha in cats and subceruleus in humans) and the REM-off GABAergic neurons in the ventrolateral periaqueductal gray (VLPAG) and lateral pontine region act as a flip-flop switch to generate REM-NREM cycles. In the Luppi model, REM-on SLD neurons are glutamatergic, whereas REM-off cells in VLPAG and the deep mesencephalic region are GABAergic. Dorsal SLD glutamatergic neurons project to the thalamus and cerebral cortex, causing electroencephalographic activation, and ventral SLD glutamatergic neurons are responsible for REM muscle atonia through both direct and indirect pathways via the ventromedial medulla, using glycinergic and GABAergic inhibitory projections to anterior horn cells of the spinal cord causing hyperpolarization.

Control of Breathing in Sleep and Wakefulness

The central respiratory neurons controlling respiration during sleep and wakefulness (metabolic or automatic system) are located in the medulla in the region of the nucleus tractus solitarius, nucleus ambiguus, and nucleus retroambigualis. The voluntary respiratory system is located in the cerebral cortex and projects partly to the metabolic system in the medulla but mostly descends to the upper cervical spinal cord where the metabolic and the voluntary systems are integrated. Therefore these anatomical locations make these structures controlling sleep-wakefulness and breathing highly vulnerable to the neurological lesions affecting the cortical and subcortical structures. Sleep-disordered breathing (SDB) therefore occurs in many central neurological disorders, as well as in peripheral neurological disorders such as polyneuropathies, neuromuscular junction disorders, and muscle diseases by causing weakness of the respiratory muscles. SDB has been described in many neurodegenerative disorders, “strokes,” other structural affections of the brainstem and upper cervical spinal cord, as well as in many neuromuscular diseases.

Sleep-Disordered Breathing and Other Sleep Dysfunction in Neurological Diseases

In this section of the atlas we are illustrating a few selected neurological disorders causing a variety of sleep dysfunction and SDB. SDB has been estimated to be present in 33% to 53% of Alzheimer’s disease (AD) patients (Fig. 12.1). Whether the prevalence of sleep apnea in AD patients is related to the advancing age of the patient and whether sleep apnea increases the severity of illness or more rapid progression of the disease remains to be determined. SDB causes cognitive impairment, and therefore it is most probable that the presence of SDB will adversely affect these demented patients, although there is some controversy about this. SDB (obstructive, central, and mixed apneas), as well as laryngeal stridor, may be more common in Parkinson’s disease (PD) patients than in age-matched controls. Those PD patients with autonomic dysfunction show increased incidence of SDB (Fig.12.2). Figure 12.3 schematically shows the spectrum of sleep dysfunction in PD. Multiple system atrophy (MSA), another degenerative disease of the autonomic and somatic neurons, initially presents with progressive autonomic failure followed by progressive somatic neurological manifestations affecting multiple systems. The term Shy-Drager syndrome is used to describe the condition in which autonomic failure is the predominant feature. The term striatonigral degeneration is used to describe the condition in which the predominant feature is parkinsonism, whereas sporadic olivopontocerebellar atrophy (OPCA) is used when cerebellar features are the predominant manifestations. A variety of sleep-related respiratory disturbances may occur, which include obstructive, central, and mixed apneas and hypopneas; dysrhythmic breathing; Cheyne-Stokes respiration; and nocturnal inspiratory stridor (Fig. 12.4). In addition to the sporadic OPCA, patients with dominant OPCA may also have central, upper airway obstructive, or mixed apneas, but these are less frequent and less intense in this condition than in MSA.

FIGURE 12.1 A case of Alzheimer’s dementia and sleep-disordered breathing.
Polysomnographic recording in a 75-year-old man in an advanced stage of Alzheimer’s disease with profound dementia, excessive daytime sleepiness, and severe nocturnal sleep disturbance. He had severe obstructive sleep apnea (apnea-hypopnea index 68/hr in general, O₂ saturation nadir of 77%) with several obstructive, central, and mixed apneas. This 90-second epoch shows first a mixed and then an obstructive apnea. Top four channels, Electroencephalographic recording with electrodes placed according to the 10-20 international electrode placement system; E1-M1 and E2-M1, electro-oculogram channels; ECG, electrocardiogram; CHIN1-CHIN2, mentalis electromyogram; HR, heart rate; RtTib, LtTib, right and left tibialis anterior electromyogram; OroNs, oronasal airflow; PFLOW; nasal pressure transducer recording; CHEST and ABD, effort belts; Sao₂, arterial oxygen saturation by finger oximetry. Also included is a snore channel.

FIGURE 12.2 A case of Parkinson’s disease and sleep-disordered breathing.
A 67-year-old man with history of loud snoring for several years, mild daytime sleepiness, and light-headedness on standing up in the last 2 to 3 months. His past medical history is significant for Parkinson’s disease diagnosed about 2 years ago (currently stage II Hoehn-Yahr scale) and hypertension. A prior sleep study performed approximately 3 years ago had diagnosed severe obstructive sleep apnea syndrome. He tried continuous positive airway pressure treatment unsuccessfully and has been using a dental appliance every night for the last 2 years, which has somewhat decreased his daytime sleepiness. A, Hypnogram shows sleep architectural changes with frequent stage shifts and awakenings resulting in a decreased sleep efficiency of 54%. Slow-wave sleep and rapid eye movement (REM) sleep are conspicuously lacking. Frequent respiratory events, particularly hypopneas, are recorded throughout the night associated with mild O₂ desaturation and arousals. The apnea-hypopnea index is moderately increased at 25/hr. The multiple sleep latency test shows a mean sleep latency of 1.75 minutes consistent with pathological sleepiness. Several sleep complaints, commonly sleep maintenance insomnia, hypersomnia, and parasomnias, particularly REM behavior disorder, are reported in Parkinson’s disease patients. Some patients may also have obstructive and central sleep apnea, but adequate studies have not been undertaken to see if apneas are part of the intrinsic disease process or related to aging. B, A 60-second excerpt from an overnight polysomnogram showing an obstructive sleep apnea in stage II non-REM sleep associated with mild O₂ desaturation and followed by an arousal. Top 10 channels, Electroencephalogram; L-EOG and R-EOG, left and right electro-oculograms; Chin EMG, electromyography of chin; LtTib, RtTib, left and right tibialis anterior electromyogram; PFLOW, nasal pressure transducer; oronasal thermistor; chest and abdomen effort channels; snore monitor; ECG, electrocardiography; Sao₂, oxygen saturation by finger oximetry; PLMS, periodic limb movements in sleep.

FIGURE 12.3 The spectrum of sleep dysfunction in Parkinson’s disease.
CHF, Congestive heart failure; COPD, chronic obstructive pulmonary disease; EDS, excessive daytime sleepiness; GERD, gastroesophageal reflux disease; PLMS, periodic limb movements in sleep; RBD, rapid eye movement sleep behavior disorder; RLS, restless legs syndrome; ST, sleep terror; SW, sleep walking.

FIGURE 12.4 A case of multiple systems atrophy (Shy-Drager syndrome) and sleep-disordered breathing.
Polysomnogram (PSG) recording in a 58-year-old patient with olivopontocerebellar atrophy presenting with ataxic gait, scanning dysarthria, nystagmus, marked finger-nose and heal-knee incoordination, and bilateral extensor plantar responses. Laboratory test results showed evidence of dysautonomia. PSG shows a portion of an episode of mixed apnea during stage II non-REM sleep. Top four channels, Electroencephalograms; EOGv, vertical electro-oculogram; MENT, mentalis; EMG, electromyography; SUBMENT, submentalis; Orb. oris, orbicularis oris; EGG, electroglossogram; INTRC, intercostal muscles; ABD PNEUMO, abdominal pneumogram. (From Chokroverty S, Sachdeo R, Masdeu J. Autonomic dysfunction and sleep apnea in olivopontocerebellar degeneration. Arch Neurol. 1984;41:509, with permission.)

In several multiple sclerosis patients, SDB abnormalities have been described, including predominant central sleep apnea and ataxic or Biot’s breathing (Fig. 12.5). SDB in such a condition may result from a demyelinating plaque involving the hypnogenic and respiratory neurons in the brainstem. In Arnold-Chiari malformation, particularly in type I malformation, several patients have been described with central and upper airway obstructive sleep apneas, as well as profound sleep hypoventilation (Fig. 12.6).