Neuroanatomical Substrates of Wakefulness

Wakefulness is controlled by the ascending reticular activating system (ARAS) containing glutamatergic, cholinergic, aminergic, and hypocretinergic neurons (Chokroverty, 2003; Steriade and McCarley, 2005). Projections from the ARAS terminating in the thalamus and thalamocortical projections to widespread areas of the cerebral cortex produce cerebral cortical activation during wakefulness. Extrathalamic projections from the brainstem reticular neurons terminate in the posterior hypothalamus and the basal forebrain regions; the latter project to the cerebral cortex (basocortical projections) to maintain wakefulness (Fig. 68.12). In the 1930s, Bremer discovered evidence of an ascending arousal system necessary for cortical arousal when he demonstrated that transection of the brainstem at the midcollicular level (i.e., cerveau isolé), but not the spinomedullary junction (i.e., encéphale isolé), produced coma in anesthetized cats. Bremer hypothesized that the resulting reduction in “cerebral tone” following the cerveau isolé was due to interruption of ascending sensory inputs—that is, a passive “deafferentation theory” of sleep (Bremer, 1937).

Fig. 68.12 Ascending reticular activating system (ARAS); projections from the ARAS terminating in the thalamus, and thalamocortical projections to widespread areas of the cerebral cortex, inducing cerebral cortical activation during wakefulness.

All these pathways regulating the wakefulness system use the cholinergic, noradrenergic, dopaminergic, and histaminergic neurons (Fig. 68.13). The cholinergic neurons fire at the highest rate during wakefulness and REM sleep but decrease their rates of firing at the onset of NREM sleep. Wakefulness-promoting aminergic neurons include noradrenergic neurons in the locus ceruleus, serotonergic neurons in the dorsal raphe of the brainstem, histaminergic neurons in the tuberomammillary nucleus of the hypothalamus, and possibly also dopaminergic neurons in the ventral tegmental area, substantia nigra, and ventral periaqueductal area. After a period of uncertainty regarding the role of dopamine, it has recently been confirmed that the midbrain dopaminergic system (A8-A10), particularly the dopaminergic neurons in the ventral periaqueductal gray (vPAG), play an active role in maintaining wakefulness through their widespread reciprocal connections with sleep/wake regulatory systems of neurons (Fuller and Lu, 2009). Norepinephrine-containing locus ceruleus neurons show their highest firing rates during wakefulness, their lowest during REM sleep, and intermediate rates during NREM sleep. Pharmacological studies suggest that posterior hypothalamic histaminergic neurons also help maintain wakefulness.

Fig. 68.13 Neurochemistry of brainstem arousal centers. A, The ascending arousal system (ARAS) consists of noradrenergic neurons containing norepinephrine (NE) in the vicinity of the ventrolateral medulla and locus coeruleus (LC), cholinergic neurons (ACh) in the PPT/LDT nuclei, 5-HT serotoninergic neurons in the dorsal raphe nucleus (Raphe), dopaminergic neurons (DA) of the vPAG, and histaminergic neurons (His) of the TMN. Cortical arousal is generated through two systems: a dorsal route through the thalamus and a ventral route through the hypothalamus and basal forebrain (BF). The latter pathway receives contributions from the orexin (ORX) and MCH neurons of the lateral hypothalamic (LH) area as well as from GABA-ergic or cholinergic neurons of the BF. Note that all these ascending pathways traverse the region at the midbrain-diencephalic junction where von Economo observed that lesions caused hypersomnolence. B, Depiction of sleep-promoting circuitry in the anterior hypothalamus/preoptic area. The VLPO nucleus contains sleep-active cells that contain the inhibitory neurotransmitters, GABA and galanin (Gal). The VLPO (open circle) projects to all the main components of the ascending arousal system. Inhibition of the arousal system by the VLPO during sleep is critical for maintenance and consolidation of sleep. 5-HT, 5-Hydroxytryptamine; ARAS, ascending reticular activating system; GABA, γ-aminobutyric acid; LDT, laterodorsal tegmental; MCH, melanin-concentrating hormone; PPT, pedunculopontine tegmental; TMN, tuberomammillary nucleus; VLPO, ventrolateral preoptic; vPAG, ventral periaqueductal gray matter.

The excitatory amino acids, glutamate and aspartate, are intermingled within the ARAS and are present in many neurons projecting to the cerebral cortex, forebrain, and brainstem. These excitatory amino acids are maximally released during wakefulness. Recent discovery of hypothalamic hypocretin neurons and their widespread CNS projections have directed attention to the role of the hypocretin system in sleep/wake regulation. In 1998, deLecea and coauthors described two neuropeptides in the lateral hypothalamus and perifornical region that were termed hypocretin 1 and hypocretin 2. Independently in the same year, Sakurai and colleagues (1998) described two neuropeptides in the same region, which they named orexin A and orexin B (corresponding to hypocretin 1 and hypocretin 2, respectively). It was shown thereafter that these hypocretin systems have widespread ascending and descending projections to the locus ceruleus, dorsal raphe, ventral tegmental area, tuberomammillary nuclei of the posterior hypothalamus, laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei, ventrolateral preoptic (VLPO) neurons in the hypothalamus, basal forebrain, limbic system (hippocampus and amygdala), cerebral cortex, thalamus (intralaminar and midline nuclei), and autonomic neurons (nucleus tractus solitarius [NTS], dorsal vagal nuclei, and intermediolateral neurons of the spinal cord). Hypocretin systems promote wakefulness mainly through excitation of tuberomammillary histaminergic, locus ceruleus noradrenergic, and midline raphe serotonergic neurons as well as dopaminergic neurons. Reduced activity of hypocretin systems may be partly responsible for inducing sleepiness. These systems also suppress REM sleep through activation of the aminergic neurons (REM-off), which in turn inhibit REM-on neurons in the LDT/PPT nuclei. As shown in Fig. 68-13, brainstem arousal centers were identified and characterized, and support was later provided for the concept of sleep-promoting circuitry in the anterior hypothalamus/preoptic area. It was later in the mid-1990s that the identity of this sleep-promoting circuitry was revealed. In these investigations (see Fig. 68.13, B), it was demonstrated that the VLPO nucleus contains sleep-active cells that contain the inhibitory neurotransmitters, γ-aminobutyric acid (GABA) and galanin (Gal).

Neuroanatomical Substrates for REM Sleep

The existence of REM sleep–generating neurons in the pontine cat has been established by transection experiments (see Fig. 68.12) through different regions of the midbrain, pons, and medulla (McCarley, 2009). A transection at the junction of the pons and midbrain produced all the physiological findings compatible with REM sleep in the section caudal to that transection, whereas in the forebrain region rostral to the section, the recording showed no signs of REM sleep. After transection between pons and medulla, structures rostral to the section showed signs of REM sleep, but structures caudal to the section had no signs of REM sleep. After transection at the junction of the spinal cord and medulla, REM sleep signs were noted in the rostral brain areas. Finally, transection at the pontomesencephalic and pontomedullary junctions produced an isolated pons that showed all the signs of REM sleep. The pons is therefore sufficient and necessary to generate all the signs of REM sleep.

There are two main models to explain the mechanism of REM sleep. The earliest and most generally well known is the McCarley-Hobson reciprocal interaction model (Fig. 68.14) based on the reciprocal interaction of REM-on and REM-off neurons (McCarley, 2009). Neurons in the PPT and LDT nuclei in the pontomesencephalic region are cholinergic and are REM-on cells, which are responsible for REM sleep, showing highest firing rates at this stage. The REM-off cells are located in the locus ceruleus and dorsal raphe nuclei. These cells are aminergic neurons and are inactive during REM sleep. Histaminergic neurons in the tuberomammillary region of the posterior hypothalamus can also be considered REM-off cells. Thus, the cholinergic REM-on and aminergic REM-off cells are all located within the transections in the pons. LDT-PPT cholinergic neurons promote REM sleep through pontine reticular formation (PRF) effector neurons, which in turn send feedback loops to LDT-PPT neurons. Cholinergic neurons of the PPT and LDT projecting to the thalamus and basal forebrain regions, as well as to the PRF, are responsible for activation and generation of REM sleep. Aminergic cells seem to play a permissive role in the appearance of REM sleep state. In the latest modification of the reciprocal interaction model, McCarley suggested that in addition to cholinergic excitation of PRF, a reduction of GABA inhibition in the PRF also may play a role in REM sleep generation. For example, GABA levels in the PRF (as measured by microdialysis technique) are lowest during REM and intermediate between wakefulness and REM and NREM sleep. Also, injection of GABA antagonists (e.g., bicuculline) into rostral PRF produced REM sleep in cats and rats. There is evidence of GABA-ergic inhibition of locus ceruleus/dorsal raphe nuclei (REM-off neurons). The source of GABA-ergic neurons is probably both local (e.g., a subgroup of PRF GABA-ergic neurons) and distant (e.g., GABA-ergic neurons in the ventrolateral periaqueductal gray matter).

Fig. 68.14 Schematic diagram of McCarley-Hobson model of REM sleep mechanism. GABA, γ-Aminobutyric acid; LC/DR, locus ceruleus/dorsal raphe; LDT/PPT, laterodorsal tegmental/pedunculopontine tegmental nuclei.

(From Chokroverty, S., 2009. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, third ed. Saunders, Philadelphia, p. 438.)

Muscle hypotonia or atonia during REM sleep is thought to depend on inhibitory postsynaptic potentials generated by dorsal pontine interneurons sending descending axons. The pathway from the peri–locus ceruleus alpha region ventral to the locus ceruleus, to the lateral tegmental reticular tract, and then to the medial medullary region (e.g., nucleus magnocellularis and paramedianus) and the reticulospinal tract projecting to the anterior horn cells of the spinal cord controls REM sleep–induced muscle atonia. An experimental lesion in the peri–locus ceruleus alpha region and in the medial medullary region produced REM sleep without muscle atonia. In human REM behavior disorder, causing dream-enacting behavior associated with REM sleep without muscle atonia, it is thought that a structural or functional alteration of the pathway maintaining muscle atonia during REM sleep is most likely responsible.

In the model (Fig. 68.15) proposed by Lu and coworkers (2006), there is reciprocal interaction between GABA-ergic REM-off neurons in ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum and GABA-ergic REM-on neurons in the sublaterodorsal nucleus (SLD; corresponding to the dorsal subceruleus or peri–locus ceruleus alpha in cats) and a dorsal extension of the SLD termed the preceruleus (PC). These mutually inhibitory neuronal populations (SLD GABA-ergic REM-on and GABA-ergic REM-off neurons in the vlPAG- lateral pontine tegmentum) serve as a flip-flop switch. Ascending glutamatergic projections from PC neurons to medial septum are responsible for EEG hippocampal theta rhythm during REM sleep. Descending glutamatergic projections from ventral SLD directly to spinal interneurons, apparently without a relay in the medial medulla, inhibit spinal ventral horns by both glycerinergic and GABA-ergic mechanisms. Cholinergic and aminergic neurons play a modulatory role and are not part of the flip-flop switch. The question arises as to how two mutually inhibitory neuronal populations (e.g., GABA-ergic REM-on and GABA-ergic REM-off neurons) stabilize the flip-flop switch permitting NREM-REM cycling. It has been suggested that inhibitory external projections from extended ventrolateral preoptic neurons (eVLPO) and excitatory projections from hypocretinergic and aminergic neurons to the REM-off neurons stabilize the switch, permitting NREM-REM cycling. McCarley (2009) suggested that this model is based on C-fos labeling, only without electrophysiological recordings. Furthermore, this model does not address how REM sleep duration progressively increases with the progression of the night. A third promising model has recently been proposed by Luppi et al. (2011).

Fig. 68.15 Lu-Saper “flip-flop” model shown schematically to explain REM sleep mechanism. eVLPO, Extended region of ventrolateral preoptic nucleus; GABA, γ-aminobutyric acid; GLUT, glutamatergic neurons; GLYC, glycinergic neurons; LC-DRN, locus ceruleus and dorsal raphe nuclei; LDT-PPT, laterodorsal tegmental and pedunculopontine tegmental nuclei; LPT, lateral pontine tegmentum; PC, preceruleus; SLD, sublaterodorsal nucleus; VlPAG, ventrolateral periaqueductal gray.

(From Chokroverty, S., 2009. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, third ed. Saunders, Philadelphia, p. 439.)

Neuroanatomical Substrates of NREM Sleep

In the first quarter of the last century during the great epidemic of encephalitis lethargica, von Economo noted that patients with encephalitis lethargica who had excessive sleepiness had pathological alterations in the posterior hypothalamus, whereas those with severe insomnia had predominant lesions in the anterior hypothalamus. These findings immediately suggested the existence of sleep/wake centers in the hypothalamus. Sleep-promoting neurons are thought to reside in the VLPO area of the anterior hypothalamus as well as in the region of the NTS in the medulla. VLPO neurons consist of two subgroups, clustered and diffuse, depending on their distribution pattern. The tightly clustered neurons project to the tuberomammillary nuclei and promote NREM sleep, whereas diffusely distributed neurons project to the aminergic nuclei in the locus ceruleus and the dorsal raphe region of the brainstem, participating in REM sleep. The VLPO neurons fire actively during NREM sleep, and their lesion induces insomnia. The GABA-and galanin-containing VLPO neurons project to inhibit locus ceruleus, dorsal raphe, and tuberomammillary aminergic nuclei, which in turn inhibit VLPO neurons.

The contemporary theory for the mechanism of NREM sleep suggests a reciprocal interaction between two antagonistic neurons in the VLPO area of the anterior hypothalamus and wake-promoting neurons in the tuberomammillary nuclei of the posterior hypothalamus, basal forebrain, and mesopontine tegmentum (McCarley, 2009; Steriade and McCarley, 2005). Reciprocal interaction between sleep-promoting neurons in the region of the NTS and wake-promoting neurons within the ARAS of the brainstem independent of the reciprocal interaction of the neurons of the forebrain also plays a role in the generation of NREM sleep. The latter is the old reticular passive hypothesis, or the disfacilitation hypothesis, of sleep. In this model, sleep is said to result from a cascade of disfacilitation within the brainstem. The passive theory originated in the two classic preparations in cats by Bremer (1937), noted earlier in the chapter: cerveau isolé and encéphale isolé. Bremer found that in cerveau isolé (e.g., midcollicular transection), all specific sensory stimuli were withdrawn and the animals were somnolent, whereas in encéphale isolé (transection at C1 vertebral level disconnecting the entire brain from the spinal cord), these specific stimuli maintained activation of the brain and animals were awake. Moruzzi and Magoun postulated that withdrawal of generalized activation from ARAS is responsible for somnolence in cerveau isolé preparations, whereas activation of the midbrain reticular neurons causing direct excitation of the thalamocortical projections results in EEG desynchronizations and behavioral arousal. These observations support the later suggestion of Steriade and colleagues that at the onset of NREM sleep, there is a deafferentation of the brain due to blockage of afferent information, first at the thalamic level, causing the waking “open” brain to be converted to a “closed” brain owing to thalamocortical inhibition. This passive reticular theory, however, was challenged by the experiments of Batini and colleagues in 1959, producing the midpontine pretrigeminal section, which was only a few millimeters below the section that produced cerveau isolé. In this midpontine preparation, there were persistent EEG and behavioral signs of alertness, suggesting that structures located in the brainstem between cerveau isolé and midpontine pretrigeminal preparations are responsible for wakefulness. Thus an active inhibitory role of the lower brainstem hypnogenic neurons in the region of the NTS on the upper brainstem ARAS was clearly demonstrated by this preparation. Both active and passive theories partly explain the generation of NREM sleep, but the contemporary theory favors the activation of VLPO neurons and inhibition of posterior hypothalamic neurons containing histamine and hypocretin. Reduced activity of the hypocretin projections to the locus ceruleus noradrenergic, midline raphe serotonergic, mesopontine dopaminergic, and tuberomammillary hypothalamic histaminergic cells may also decrease the level of arousal, causing sleepiness.

The suprachiasmatic nuclei (SCN), the paired nuclei above the hypothalamus, function as the body clock to control circadian rhythm. The recent discovery of anatomical projections from SCN to lateral hypothalamic neurons containing hypocretin (wake-promoting) and anterior hypothalamic VLPO containing sleep-promoting neurons suggested that the SCN may also affect sleep regulation and homeostasis independent of circadian rhythm generation (Turek and Vitaterna, 2011). Finally, recent advances in neuroimaging studies, including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans, have been able to visualize dramatic changes in function in cortical and subcortical neuronal networks in different sleep states and stages, advancing our understanding of the functional neuroanatomy of sleep/wakefulness (Dang-Vu et al., 2007). PET scans have shown marked activation of the amygdala and the anterior cingulate region (part of the limbic system) during REM sleep, which is, of course, generated by brainstem neurons. In contrast, in NREM sleep, neuroimaging techniques have shown declining function in the thalamocortical circuits, including the association cortex of the frontoparietal and temporal lobes. Thus the brainstem, hypothalamic, and forebrain sleep/wake-promoting neurons modulate functions of widespread forebrain cortical areas, keeping in balance cortical and subcortical circuits to control sleep/wake regulation.

Many important questions regarding the mechanism of sleep remain unanswered. Why do VLPO neurons fire at sleep onset? What initiates the cascade of disfacilitation in brainstem wake-promoting neurons? What initiates activation of LDT neurons and PPT neurons at REM onset? What causes activation of wake-promoting neurons at sleep offset? What maintains NREM-REM sleep cycling?

The following speculative summary attempts to answer some of these questions. VLPO excitation at NREM sleep onset is initiated by adenosine (a sleep-promoting factor in the forebrain region, accumulated during prolonged wakefulness) and SCN, as well as by reciprocal inhibition of aminergic and orexin wake-promoting neurons; progressive inhibition of aminergic REM-off neurons, causing disinhibition of REM-on cholinergic neurons and initiating REM sleep; and simultaneous cascade of disfacilitation of the brainstem arousal system due to decreased environmental afferent stimuli, culminating in blockades at the thalamic level. Physiological facilitation (or disinhibition) after a certain period (perhaps determined in the case of sleep/wake regulation by the SCN regulatory neurons connected anatomically to sleep/wake neurons) will be followed by inhibition (or disfacilitation), and thus the cycle will begin again.

Marked impairment of the arousal and cognition systems may result in coma or severe sleepiness. The reversibility of this state of awareness differentiates sleep from coma. There are also physiological and metabolic differences between sleep and coma. Coma is a passive process (loss of function), whereas sleep is an active state resulting from physiological interactions of various systems in the brainstem and cerebral cortex. Metabolic depression of the cerebral cortex and brainstem characterizes coma and stupor, whereas in sleep, oxygen use and metabolic rhythm remain intact. By disrupting the arousal system or stimulating the sleep-promoting neurons, focal neurological lesions may also cause excessive sleepiness. For example, lesions of the brainstem, thalamus, hypothalamus, and periaqueductal region may produce excessive sleepiness, stupor, and coma. These regions may also affect REM-generating neurons in the pons and cause various REM sleep alterations, so lesions in these structures may cause symptomatic narcolepsy.

Performance and Productivity at Work and School

Impaired performance and reduced productivity at work for shift workers, reduced performance in class for school and college students, and impaired job performance in patients with narcolepsy, sleep apnea, circadian rhythm disorders, and chronic insomnia are well-known adverse effects of sleep deprivation and sleepiness. Sleepiness and associated morbidity are worse in night shift workers, older workers, and female shift workers.

Higher Cerebral Functions

Sleepiness interferes with higher cerebral functions, causing impairment of short-term memory, concentration, attention, cognition, and intellectual performance. Psychometric tests document increased reaction time in patients with excessive sleepiness. These individuals make increasing numbers of errors, and they need increasing time to reach the target in reaction time tests (Dinges, 1995). Sleepiness can also impair perceptual skills and new learning. Insufficient sleep and excessive sleepiness may cause irritability, anxiety, and depression. Learning disabilities and cognitive impairment due to impaired vigilance have also been described (Roth and Roehrs, 1996).

Quality of Life and Social Interaction

People complaining of EDS are often under severe psychological stress. They are often wrongly perceived as dull, lazy, and downright stupid. Excessive sleepiness may cause severe marital and social problems. Individuals with this problem have serious difficulty with interpersonal relationships.

Shift workers constitute approximately 20% to 25% of the work force in America (i.e., approximately 20 million people). A majority of them have difficulty with sleeping and sleepiness as a result of insufficient sleep and circadian dysrhythmia. Many of them have an impaired quality of life, marital discord, and gastrointestinal problems. Recent findings also show the positive effects of protecting sleep and preventing sleep deprivation. A study from 2010 in healthy elderly individuals older than 75 years of age who had no sleep complaints demonstrated that allowing more time to sleep (about 7.5 hours nightly) was associated with better maintenance of physical health–related quality of life and stability of medical illness burden over 30 months (Reynolds et al., 2010).

Morbidity and Mortality

Persistent daytime sleepiness causes individuals to have an increased likelihood of accidents. Estimates by the U.S. National Highway Traffic Safety Administration showed that approximately 56,000 police-reported crashes per year resulted from drivers who were “asleep at the wheel.” New York state police estimate that 30% of all fatal crashes along the New York State Thruway occur because the driver fell asleep at the wheel. Approximately 1 million crashes annually (one-sixth of all crashes) are thought to be produced by driver inattention or lapses. Sleep deprivation and fatigue make such lapses more likely to occur. Truck drivers are especially susceptible to fatigue-related crashes (Lyznicki et al., 1998). Many truckers drive during the night while they are sleepiest. Truckers also may have a high prevalence of sleep apnea. The U.S. Department of Transportation estimates that 200,000 automobile accidents each year may be related to sleepiness. Nearly one-third of all trucking accidents that are fatal to the driver are related to sleepiness and fatigue. A general population study by Hays and colleagues (1996) involving 3962 elderly individuals reported an increased mortality risk of 1.73 in those with EDS, defined by napping most of the time.

The presence of sleep disorders (see Primary Sleep Disorders Associated with Excessive Daytime Sleepiness, later) increases the risk of crashes. Individuals with untreated insomnia, sleep apnea, and narcolepsy, as well as shift workers, have more automobile crashes than other drivers (Costa de Silva et al., 1996). A 1991 Gallup Organization national survey found that individuals with chronic insomnia reported 2.5 times as many fatigue-related automobile accidents as those without insomnia. The same 1991 Gallup survey found serious morbidity associated with untreated sleep complaints, as well as impaired ability to concentrate and accomplish daily tasks, impaired memory, and interpersonal difficulties.

A 1994 telephone survey of drivers by the New York State Task Force estimated that approximately 25% reported that they had fallen asleep at the wheel at some time. Young male drivers are especially susceptible to crashes caused by falling asleep, as documented in a study in North Carolina in 1990, 1991, and 1992 (e.g., in 55% of the 4333 crashes, the drivers were predominantly male and age 25 or younger). In the October 1995 Gallup poll, 52% of all adults surveyed said that in the past year, they had driven a car or other vehicle while feeling drowsy; 31% of adults admitted dozing off while at the wheel of a car or other vehicle, and 4% reported having had an automobile accident because of tiredness during driving. A number of national and international catastrophes involving industrial operations, nuclear power plants, and all modes of transportation have been related to sleepiness and fatigue (Dinges, 1995). Some of the more infamous examples are the Exxon Valdez oil spill in Alaska; the nuclear disaster at Chernobyl in the former Soviet Union; the near-nuclear disaster at Three Mile Island in Pennsylvania; the gas leak disaster in Bhopal, India, resulting in 25,000 deaths; and the Challenger space shuttle disaster. In postgraduate medical training, new work hours schedules have been proposed by the Institute of Medicine (IOM) and were recently accepted by the Accreditation Council for Graduate Medical Education (ACGME, 2010) and scheduled to go into affect in July 2011.

Physiological Causes of Sleepiness

Sleep deprivation and sleepiness due to lifestyle and habits of going to sleep and waking up at irregular hours can be considered to result from disruption of the normal circadian and homeostatic physiology. Groups who are excessively sleepy because of lifestyle and inadequate sleep include young adults and elderly individuals, workers on irregular shifts, healthcare professionals (e.g., doctors, particularly the house staff, and nurses), firefighters, police officers, train drivers, pilots and flight attendants, commercial truck drivers, and those individuals with competitive drives to move ahead in life, sacrificing hours of sleep and accumulating sleep debt. Among young adults, high school and college students are particularly at risk for sleep deprivation and sleepiness. The reasons for excessive sleepiness in adolescents and young adults include both biological and psychosocial factors. Some of the causes for later bedtimes and sleep deprivation in these groups include social interactions with peers; homework in the evening; sports, employment, or other extracurricular activities; early wake-up times to start school; and academic obligations requiring additional school or college work at night. Biological factors may play a role but are not well studied. For example, teenagers may need extra hours of sleep. Also, the circadian timing system may change with sleep phase delay in teenagers. EDS associated with shift work has been described (see Primary Sleep Disorders Associated with Excessive Daytime Sleepiness, later).

Pathological Causes of Sleepiness

Neurological causes of excessive sleepiness may include tumors and vascular lesions affecting the ARAS and its projections to the posterior hypothalamus and thalamus, leading to daytime sleepiness. It should be noted that lesions of this system often cause coma rather than just sleepiness. Brain tumors (e.g., astrocytomas, suprasellar cysts, metastases, lymphomas and hamartomas affecting the posterior hypothalamus, pineal tumors, and astrocytomas of the upper brainstem) may produce excessive sleepiness. Prolonged hypersomnia may be associated with tumors in the region of the third ventricle. Symptomatic narcolepsy resulting from craniopharyngioma and other tumors of the hypothalamic and pituitary regions has been described. Cataplexy associated with sleepiness, sleep paralysis, and hypnagogic hallucinations has been described in patients with rostral brainstem gliomas with or without infiltration of the walls of the third ventricle. Narcolepsy-cataplexy also has been described in a human leukocyte antigen (HLA) DR2-negative patient with a pontine lesion documented by MRI.

Other neurological causes of EDS include bilateral paramedian thalamic and sometimes other cortical and subcortical infarcts (Bassetti and Valko, 2006), posttraumatic hypersomnolence, and multiple sclerosis (MS). Narcolepsy-cataplexy has been described in occasional patients with MS and arteriovenous malformations in the diencephalon (Clavelou et al., 1995).

Excessive daytime sleepiness has been described in association with encephalitis lethargica and other encephalitides, as well as with encephalopathies, including Wernicke encephalopathy. It was noted that the lesions of encephalitis lethargica described by Von Economo in the beginning of the last century, which severely affected the posterior hypothalamic region, were associated with the clinical manifestation of extreme somnolence. These lesions apparently interrupted the ascending arousal systems projecting to the posterior hypothalamus. Encephalitis lethargica is now extinct. Cerebral sarcoidosis involving the hypothalamus may cause symptomatic narcolepsy. Whipple disease of the nervous system involving the hypothalamus may occasionally cause hypersomnolence.

Cerebral trypanosomiasis, or African sleeping sickness, is transmitted to humans by tsetse flies: Trypanosoma gambiense causes Gambian or West African sleeping sickness, and Trypanosoma rhodesiense causes East African sleeping sickness.

Certain neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease (PD), and multisystem atrophy (MSA) also may cause EDS (Raggi and Ferri, 2010). The causes of EDS in AD include degeneration of the SCN, resulting in circadian dysrhythmia, associated sleep apnea-hypopnea, and periodic limb movements in sleep (PLMS). In PD, excessive sleepiness may be due to the associated PLMS, sleep apnea, and depression. EDS in MSA associated with cerebellar parkinsonism or parkinsonian-cerebellar syndrome and progressive autonomic deficit (Shy-Drager syndrome) may be caused by the frequent association with sleep-related respiratory dysrhythmias and possible degeneration of the reticular activating arousal systems (Chokroverty, 2009a).

Sleep disorders are being increasingly recognized as a feature of PD and other parkinsonian disorders. Although some studies have attributed the excessive daytime drowsiness and irresistible sleep episodes (sleep attacks) to antiparkinsonian medications (Ondo et al., 2001), sleep disturbances are also an integral part of PD (Arnulf et al., 2002). In one study of 303 patients with PD, 21% reported falling asleep while driving (Ondo et al., 2002). Several studies also reported a relatively high incidence (10%-20%) of symptoms of restless legs syndrome (RLS) in patients with PD (Hening et al., 2009; Krishnan et al., 2003; Ondo et al., 2002). There is also increasing awareness about the relationship between parkinsonian disorders and REM sleep behavior disorder (RBD), and RBD may be the presenting feature of PD, MSA, and other parkinsonian disorders (Boeve, 2010; Boeve et al., 2007; Postuma et al., 2010a; Raggi and Ferri, 2010).

These and other studies provide evidence supporting the notion that dopamine activity is normally influenced by circadian factors (Rye and Jankovic, 2002). For example, tyrosine hydroxylase levels fall several hours before waking, and their increase correlates with motor activity. The relationship between hypocretin and sleep disorders associated with PD is currently being explored (Baumann et al., 2005; Drouot et al., 2003; Fronczek et al., 2007; Overeem et al., 2002; Thannickal et al., 2007).

Myotonic dystrophy and other neuromuscular disorders may cause EDS due to associated sleep apnea-hypopnea syndrome and hypoventilation. In addition, in myotonic dystrophy, there may be involvement of the ARAS as part of the multisystem membrane effects noted in this disease.

Acute Insomnia

The category of adjustment insomnia (AASM, 2005) is the only class of acute insomnia resulting from an identifiable stressful situation. This lasts from a few days to a few weeks—3 months at most. Once the stressful event is removed and the patient adjusts to the event, the sleep disturbance resolves. Causes of acute insomnia are listed in Box 68.7.

Chronic Insomnia

Most cases of insomnia are chronic and comorbid with other conditions (Morin and Benca, 2009, 2011). Common comorbidities include psychiatric, medical, primary sleep-related (i.e., OSAS) or neurological disorders, or drug and alcohol abuse. Box 68.8 lists the causes of chronic insomnia. These comorbid insomnias were classified as secondary insomnia in the past, but this signifies causation; no definite evidence exists that these conditions are responsible for insomnia (National Institutes of Health, 2005).

In addition to short-term effects of disturbed sleep and inadequate daytime functioning, insomniacs report impaired work performance and productivity, reduced social and physical functioning, reduced overall quality of life, and a two- to fivefold increased risk for developing subsequent depression associated with significant suicidal behavior. There are also suggestions of increased mortality and morbidity from coronary artery disease, hypertension, obesity, and diabetes mellitus (Ayas et al., 2003a, 2003b; Knutsen and Turek, 2006). A recent longitudinal sleep laboratory follow-up study for 14 years, however, found increased mortality in men with chronic insomnia with objectively measured short sleep duration that could not be explained by comorbid type 2 diabetes mellitus or hypertension (Vgontzas et al., 2010).

Idiopathic and Psychophysiological Insomnia

The onset of idiopathic insomnia occurs in early childhood. Patients generally have lifelong difficulty with initiating or maintaining sleep, or both, resulting in poor daytime functioning. Diagnosis depends on the exclusion of concomitant comorbid medical, neurological, psychiatric, or psychological disturbances. Psychophysiological insomnia begins during young adulthood, and the symptoms may persist for decades. This is a chronic insomnia with increased tension or agitation that results from learned sleep-preventing associations. Patients are overconcerned and overfocused on sleep problems, but they do not have generalized anxiety or any other psychiatric disorders. Sometimes a family history exists. The development of conditioned responses incompatible with sleep is the predominant feature of psychophysiological insomnia. Insomnia is an event initiated by a stressor, but it persists even after that initial stress is gone. Factors contributing to negative conditioning and insomnia include excesses, low risk, fear and frustration about being unable to initiate and maintain sleep, and the identification of the bedroom as an arousal sign. Patients generally sleep poorly during PSG studies, although occasionally patients sleep better because they are removed from their usual sleep environment. Patients with psychophysiological insomnia confine anxiety to sleep-related issues, which differentiates them from patients with generalized anxiety disorders.

Paradoxical Insomnia

Paradoxical insomnia is a sleep state misperception characterized by subjective complaints of sleeplessness without objective evidence (e.g., PSG evidence of insomnia). Actigraphy (which measures sleep/wake activities) or PSG recording documents normal sleep patterns in such patients.

Inadequate Sleep Hygiene

Patients with inadequate sleep hygiene negate the good sleep measures that promote sleep. Such measures include avoidance of caffeinated beverages, alcohol, and tobacco in the evening; avoidance of intense mental activities and vigorous exercise close to bedtime; avoidance of daytime naps and excessive time spent in bed awake; and adherence to a regular sleep/wake schedule.

Insomnia commonly coexists or precedes the development of a number of psychiatric illnesses. Surveys have shown that individuals with insomnia are more likely to develop new psychiatric disorders, particularly major depression, within 6 to 12 months. Anxiety disorders, depression, and schizophrenia are some of the major psychiatric disorders associated with insomnia. Medical and neurological disorders comorbid with insomnia are listed in Boxes 68.9 and 68.10. RLS, periodic limb movement disorder (PLMD), and circadian rhythm disorders are some of the other causes of chronic insomnia. In some patients, insomnia may coexist with sleep apnea.

Physiological Profiles of Insomnias

Chronic insomniacs may suffer from a general disorder of hyperarousal due to a functional alteration in the anatomical substrates for sleep/wake states (e.g., hyperactivity of wake-promoting neurons or hypoactivity of sleep-generating neurons that is genetically determined). Evidence of hyperarousal is provided by the following observations in these patients (Morin and Benca, 2009, 2011):

Although the majority of published studies support hyperarousal in chronic insomnia, there are contradictory findings (Riemann et al., 2002; Stepanski et al., 2000; Varkevisser et al., 2005) casting doubt on the hyperarousal theory in all cases.

Mechanism of Insomnia in Neurological Diseases

Insomnia in neurological disorders may result from the following suggested mechanisms:

Genetics of Narcolepsy

Most cases of human narcolepsy are sporadic, but some are dominant. There is, however, a 10 to 40 times greater prevalence of narcolepsy in families than in the general population. For example, approximately 1 or 2 first-degree relatives of narcoleptic patients, compared with 0.02% to 0.18% in the general population, manifest the illness. Twin studies show that the majority of monozygotic twins are discordant, and only 25% to 31% are concordant, suggesting an influence of environmental factors in the etiology of narcolepsy. From 95% to 100% of white and Japanese patients carry the HLA. It has been established that HLA-DQB1*0602 is a marker for narcolepsy on chromosome 6 across all ethnic groups. However, cases of narcolepsy not carrying HLA-DR2 or HLA-DQ1 antigens have been reported. In addition, 12% to 38% of the general population carries the same HLA alleles, but narcolepsy is present in only 0.02% to 0.18% of the population; therefore, HLA-DQB1*0602 is neither necessary nor sufficient for susceptibility to narcolepsy.

Pathogenesis Of Narcolepsy-Cataplexy Syndrome

The most exciting recent development in sleep medicine is the pathogenetic role played by the recently discovered hypocretin (orexin) peptidergic systems in the lateral hypothalamus. Reports of mutation of the hypocretin receptor 2 gene (HCRTR2) in dogs (Lin et al., 1999) and pre-prohypocretin knockout mice (Chemelli et al., 1999) producing the phenotype of human narcolepsy brought narcolepsy research to the forefront of the molecular neurobiology field. Most cases of human narcolepsy and cataplexy have decreased hypocretin 1 in the cerebrospinal fluid (CSF) (Bourgin et al., 2008; Fronczek et al., 2009; Nishino, 2007). Hypocretins are noted to be depleted in narcoleptic brains at autopsy, as can be seen in Fig. 68.20 (Thannickal et al., 2000). In addition, mutation of the pre-prohypocretin gene has been identified in one child with severe narcolepsy (Peyron et al., 2000). Therefore, the contemporary theory for the pathogenesis of narcolepsy-cataplexy syndrome suggests that the condition results from a depletion (degeneration or autoimmune disorder) of the hypocretin neurons in the lateral and perifornical region of the hypothalamus, as can be appreciated in Fig. 68.21. Narcolepsy-cataplexy syndrome thus can be considered a hypocretin (orexin) deficiency syndrome. The possibility of an autoimmune disorder has been raised because of the association of narcolepsy with HLA-DQB1*0602 haplotype; however, all attempts to find evidence of autoimmune disorder in narcolepsy have so far failed (Overeem et al., 2008). There is no evidence of inflammatory processes or immune abnormalities, presence of classical autoantibodies, or an increase of oligoclonal bands in the CSF in these patients. Erythrocyte sedimentation rate, serum immunoglobulin levels, C-reactive protein, complement levels, and lymphocyte subset ratio are all found to be normal in these patients, pointing against an autoimmune disorder. On the other hand, increased levels of streptococcal antibodies in narcoleptic patients in some reports and evidence of gliosis in the lateral hypothalamus by Thannickal and colleagues (2000) indicate that further exploration for possible immune-related dysfunction in narcolepsy is needed. Finally, the presence of autoantibodies (patient serum binding to rat hypocretin neurons) in one out of nine narcolepsy-cataplexy patients keeps the autoimmune theory very much in the forefront (Knudsen et al., 2007).

Fig. 68.20 Hypocretin deficiency in human narcolepsy. The number of hypocretin neurons is severely depleted in patients with narcolepsy and cataplexy.

(Adapted from Thannickal, T., Moore, R., Nienhuis, R., et al., 2000. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469-474.)

Fig. 68.21 Hypocretin deficiency in human narcolepsy. Cerebrospinal fluid (CSF) hypocretin is shown on the left panel comparing patients with narcolepsy with those with other neurological conditions and with control patients. Right panel demonstrates lateral hypothalamic brain tissue staining in narcoleptic (A) versus control (B) patients. Studies show consistent reduction of CSF levels and brain tissue staining for hypocretin.

(From Nishino, S., Ripley, B., Overeem, S., et al., 2000. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39-40; and from Peyron, C., Faraco, J., Rogers, W., et al., 2000. A mutation in a case of early-onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6, 991-997. Courtesy Stanford Center for Narcolepsy.)

Clinical Manifestations of Narcolepsy

The onset of the disorder in most cases is in adolescents and young adults, with a peak incidence between ages 15 and 30. However, rare cases have been described in children younger than age 5 and adults older than age 50. The ICSD-2 (AASM, 2005) divides narcolepsy into three types: narcolepsy with cataplexy, narcolepsy without cataplexy, and secondary narcolepsy. The major clinical manifestations of narcolepsy include narcoleptic sleep attacks (100%), cataplexy (60%-70%), sleep paralysis (25%-50%), hypnagogic hallucinations (20%-40%), disturbed night sleep (70%-80%), and automatic behavior (20%-40%) (Nishino, 2007; Nishino and Mignot, 2011; Overeem et al., 2001) (Table 68.6).

Table 68.6 Clinical Features of Narcolepsy

BMI, Body mass index; REM, Rapid eye movement.

The classic narcoleptic sleep attack is an irresistible desire to fall asleep in inappropriate circumstances and at inappropriate places (e.g., while talking, driving, eating, playing, walking, running, working, sitting, listening to lectures, watching television or movies, during sexual intercourse, or when involved in boring or monotonous circumstances). These spells last for a few minutes to as long as 20 to 30 minutes, and the patient generally feels refreshed on waking. There are wide variations in frequency of attacks—anywhere from daily, weekly, monthly, or every few weeks to months. Attacks generally persist throughout the patient’s lifetime, although fluctuations and rare temporary remissions may occur. Patients often show a decline in performance at school and work and encounter psychosocial and socioeconomic difficulties as a result of sleep attacks and EDS.

Cataplexy is defined as a sudden loss of tone in all voluntary muscles with the exception of the respiratory and ocular muscles. The attacks are triggered by emotional factors such as laughter, rage, or anger more than 95% of the time. The attacks may be complete or partial and rarely are unilateral. Most commonly, patients momentarily have head nodding, sagging of the jaw, buckling of the knees, dropping of objects from the hands, dysarthria, or loss of voice, but sometimes they may slump or fall forward to the ground for a few seconds. The duration is usually a few seconds to a minute or two, and consciousness is retained completely during the attack. During brief cataplectic spells, neurological examination reveals flaccidity of the muscles and absence or markedly reduced muscle stretch reflexes. H reflex and F responses are decreased or absent. Generally, cataplectic spells occur months to years after the onset of sleep attacks, but occasionally cataplexy is the initial manifestation. It is a lifelong condition but is generally less severe and may even disappear in old age. Rarely, status cataplecticus occurs, particularly after withdrawal of anticataplectic medications. An EEG recording shows evidence of wakefulness during brief cataplectic spells, but if the attack lasts longer than 1 to 2 minutes, the EEG shows REM sleep.

Sleep paralysis occurs in approximately 25% to 50% of patients and is generally noted months to years after the onset of narcoleptic sleep attacks. The sudden apparent paralysis of one or both sides of the body or one limb occurs either during sleep onset (hypnagogic) or on awakening (hypnopompic) in the morning. The patient is unable to move or speak and is frightened, although he or she retains consciousness. The attacks last from a few minutes to 15 to 20 minutes.

Hypnagogic hallucinations are found in 20% to 40% of narcoleptic patients, hypnagogic hallucinations occur either at sleep onset or on awakening in the morning and generally appear months to years after the onset of sleep attacks. Hallucinations are most commonly vivid and visual (and often fear-inducing) but are sometimes auditory, vestibular, or somesthetic in nature. In 30% of patients, three of the four major manifestations of the narcoleptic tetrad (sleep attacks, cataplexy, sleep paralysis, and hypnagogic hallucinations) occur together, and in about 10% of cases, all four major features occur together.

Differential Diagnosis of Narcolepsy-Related Sleep Attacks

The most common conditions that should be differentiated from narcoleptic sleep attacks are illustrated in Box 68.11. Narcolepsy-related sleep attacks should be differentiated from other causes of EDS. These include sleep deprivation and insufficient sleep syndrome, OSAS, alcohol- and drug-related hypersomnolence, idiopathic hypersomnia (Aldrich, 1996), circadian rhythm sleep disorders, and other medical, neurological, and psychiatric disorders causing hypersomnolence. OSAS (see Sleep Apnea Syndrome, later) is the most common cause of EDS in patients referred to a sleep laboratory for evaluation. It is characterized by repeated episodes of obstructive and mixed apneas during NREM and REM sleep in overnight PSG recordings. These patients have prolonged daytime sleep episodes followed by fatigue and drowsiness on awakening, which contrasts with a fresh feeling in narcoleptic patients on awakening from brief sleep attacks. All patients with hypersomnolence can be excluded after careful history and physical examination and overnight PSG recording.

Idiopathic hypersomnia (see later discussion) closely resembles narcolepsy syndrome. In contrast to narcolepsy, the sleep episodes in idiopathic hypersomnia are prolonged, and the sleep is not refreshing. PSG recordings and MSLT scores do not show sleep-onset REM sleep but do show pathological sleepiness. There is no disturbance of REM-NREM organization on PSG recordings. Some patients with idiopathic hypersomnia may have a positive family history.

Differential Diagnosis of Cataplexy and Other Features of Narcolepsy

Cataplectic attacks may be mistaken for partial complex seizures, absence spells, atonic seizures, drop attacks, and syncope (Box 68.12). A partial complex seizure, however, is characterized by an altered state of consciousness, unlike cataplexy. In addition, patients with seizures may have generalized tonic-clonic movements, postictal confusion, and epileptiform discharges on EEG. Absence spells are characterized by staring with vacant expression lasting up to 30 seconds, with an altered state of alertness associated with characteristic 3-Hz spike-and-wave patterns in the EEG. Atonic seizures are accompanied by transient loss of consciousness and EEG evidence of slow spike-and-wave discharges or multiple spike-and-wave discharges.

Narcoleptic sleep paralysis should be differentiated from isolated physiological and familial sleep paralysis in which other manifestations of narcolepsy are absent. Automatic behavior should be differentiated from the automatisms observed in partial complex seizures and psychogenic fugue. History, physical examination, and EEG should be helpful in differentiating these conditions.

Symptomatic or secondary narcolepsy-cataplexy may be due to diencephalic and midbrain tumors, MS, strokes, cysts, vascular malformations, encephalitis, cerebral trauma, and paraneoplastic syndrome with anti-Ma2 antibodies and may present with narcoleptic-like sleep attacks and other manifestations (Nishino, 2007; Nishino and Mignot, 2011). Symptomatic narcolepsy associated with cataplexy may develop in children affected with Niemann-Pick disease type C.

Idiopathic Hypersomnia with or without Long Sleep Time

Idiopathic hypersomnia closely resembles narcolepsy syndrome (Billiard and Dauvilliers, 2001). This disorder is characterized by EDS (presumed CNS cause but not proven) that is associated with either normal (6 to 10 hours) or prolonged (>10 hours) nocturnal sleep documented by history, actigraphy, sleep logs, or PSG (AASM, 2005). The onset of the disease is generally around the same age as narcolepsy (15 to 30 years). The sleep pattern, however, is different from that of narcolepsy. The patient generally sleeps for hours, and the sleep is not refreshing. Because of EDS, the condition may be mistaken for sleep apnea. However, the patient does not give a history of cataplexy, snoring, or repeating awakenings throughout the night. Some patients may have automatic behavior with amnesia for the events. Physical examination uncovers no abnormal neurological findings. This disabling and lifelong condition should be differentiated from other causes of EDS (see Box 68.5). There is no clear association between idiopathic hypersomnia and HLA.

Sleep-Disordered Breathing Terminology

The spectrum of sleep-disordered breathing (SDB) includes a variety of breathing patterns based on analysis during overnight PSG recordings. Fig. 68.22 schematically shows some patterns of SDB. Apnea, or cessation of breathing, consists of three types: obstructive, central, and mixed.

Fig. 68.22 Schematic diagram showing different types of breathing patterns in neurological illnesses. A, Normal breathing pattern. B, Upper airway obstructive apnea. C, Central apnea. D, Mixed apnea (initial central followed by obstructive apnea). E, Paradoxical breathing. F, Cheyne-Stokes breathing. G, Cheyne-Stokes variant pattern. H, Inspiratory gasp. I, Dysrhythmic breathing. J, Biot breathing, a special type of ataxic breathing characterized by 2 to 3 breaths of nearly equal volume followed by long period of apnea. K, Ataxic breathing. L, Apneustic breathing.

(From Chokroverty, S., 2009. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, third ed. Saunders, Philadelphia, Fig. 29.6.)

Cessation of airflow with no respiratory effort defines central apnea, during which both diaphragmatic and intercostal muscle activities as well as gas exchange through the nose or mouth are absent (see Fig. 68.22). In contrast, during obstructive apnea, airflow stops while the effort continues (Fig. 68.23; see also Fig. 68.22). In mixed apnea, there is an initial cessation of airflow with no respiratory effort (central apnea) followed by a period of upper airway obstructive sleep apnea (see Fig. 68.22).

Fig. 68.23 A 120-second excerpt from an overnight polysomnographic (PSG) recording showing four recurrent episodes of upper airway apneas during stage 2 non–rapid eye movement (NREM) sleep. Note absence of airflow but continued effort and mild O₂ desaturation (Sao₂). Channels 1-4: Electroencephalogram (EEG; International electrode placement). Channels 6 and 7: Left and right electro-oculograms (LOC, ROC). Channel 8: Electromyography of chin (CHIN). Channel 9: Electrocardiogram (EKG). Channels 12 and 13: Left and right tibialis anterior electromyograms (LT. TIBIA; RT. TIBIA).

There are two separate rules for scoring hypopnea in the AASM Scoring Manual (Iber et al., 2007). The “recommended” rule requires a reduction of nasal pressure or the alternative airflow sensor signal by 30% or more of the baseline amplitude for at least 10 seconds accompanied by oxygen desaturation of 4% or more from the pre-event baseline. The “alternative” rule requires a reduction of the signal by 50% or more of the baseline for at least 10 seconds accompanied by oxygen desaturation of 3% or more, or the event is associated with an arousal within 3 seconds of the event. In both these rules, the amplitude reduction must be present for at least 90% of the event’s duration.

To be clinically significant, the number of apneas and hypopneas per hour of sleep (Apnea-Hypopnea Index, or AHI) must be at least 5. Most investigators, however, consider an AHI of 10 or more to be significant. An arousal is defined as either a transient return of alpha activities (8-13 Hz) or beta rhythms (>13 Hz) or a change from delta to theta activities in the EEG lasting from 3 to 14 seconds. Repeated arousals causing sleep fragmentation are important factors causing EDS.

Paradoxical breathing is characterized by movements of the thorax and abdomen in opposite directions, indicating increased upper airway resistance and upper airway obstruction (see Fig. 68.22). Cheyne-Stokes breathing is a type of periodic breathing characterized by cyclical changes in breathing with a crescendo-decrescendo sequence separated by central apneas or hypopneas (Fig. 68.24; see also Fig. 68.22). The Cheyne-Stokes variant pattern of breathing is distinguished by substitution of hypopnea for apnea.

Fig. 68.24 A 500-second excerpt showing the classic Cheyne-Stokes breathing (CSB) crescendo-decrescendo pattern from an overnight polysomnographic (PSG) recording of a 69-year-old man. The presence of CSB throughout most of the non–rapid eye movement (NREM) sleep (with marked decrement or absence during REM sleep) in this patient with a history of hypertension and excessive daytime sleepiness suggests incipient left ventricular failure. The PSG montage is similar to that in Fig. 68.23.

Dysrhythmic breathing is characterized by nonrhythmical respiration of irregular rate, rhythm, and amplitude that becomes worse during sleep. This type of breathing may result from an abnormality in the automatic respiratory pattern generator in the brainstem. Apneustic breathing is characterized by prolonged inspiration with an increase in the ratio of inspiratory to expiratory time. This type of breathing may result from a neurological lesion in the caudal pons disconnecting the apneustic center in the lower pons from the pneumotaxic center in the upper pons. Inspiratory gasp is characterized by short inspiratory time and a relatively prolonged expiration and has been noted in association with a lesion in the medulla. Ataxic breathing is characterized by clusters of cyclic breathing followed by recurrent periods of apnea (the apnea length is greater than the ventilatory phase). Biot breathing is a variant of ataxic breathing characterized by 2 to 3 breaths of nearly equal volume separated by long periods of apnea. Ataxic (including Biot) breathing is often noted in medullary lesions.

Hypoventilation refers to a reduction of alveolar ventilation accompanied by hypoxemia and hypercapnia without any apnea or hypopnea; it may be noted in patients with neuromuscular disorders and kyphoscoliosis and those with underlying lung or chest-wall abnormalities that impair gas exchange during wakefulness. During sleep hypoventilation, the partial pressure of arterial carbon dioxide (Paco₂) rises at least 10 mm above the supine awake values (Iber et al., 2007). Upper airway resistance syndrome (UARS) is characterized by repeated abnormal respiratory efforts during sleep without apnea, accompanied by recurrent arousals and EDS. The Respiratory Disturbance Index (RDI) includes all these abnormal breathing events, including respiratory effort–related arousals.

Epidemiology of Obstructive Sleep Apnea Syndrome

No study has been specifically designed to determine the incidence of OSAS in a previously healthy population. Based on a definition of at least five apneas or hypopneas per hour of sleep accompanied by EDS (Young et al., 1997), however, the prevalence of OSAS is 4% in men and 2% in women between the ages of 30 and 60. There is a strong association between OSAS and male gender, increasing age, and obesity. The condition is common in men older than 40, and among women, the incidence of OSAS is greater after menopause. Approximately 85% of patients with OSAS are men; obesity is present in about 70% of OSAS patients. There is an increased prevalence of OSAS in those with a thick neck and large abdomen. Men with a neck circumference measuring more than 17 inches and women with a neck measuring more than 16 inches are at risk for OSAS.

Race may be a factor, given that a high prevalence of SDB is noted in Pacific Islanders, Mexican Americans, and African Americans. There are also family aggregates of OSAS. Other factors with a high association are alcohol, smoking, and drug use. Other risk factors include nasal allergies or congestion, endocrine diseases (e.g., hypothyroidism, acromegaly), disorders with autonomic failure or those associated with craniofacial abnormalities (e.g., Marfan, Down, Pierre-Robin syndromes). Risk factors associated with OSAS are listed in Box 68.13.

Clinical Manifestations

The symptoms of OSAS can be divided into two groups (Flemons, 2002; Guilleminault and Zupancic, 2009): those occurring during sleep and those occurring during waking hours (Box 68.14). Nocturnal symptoms include habitual loud snoring, choking during sleep, cessation of breathing, and abnormal motor activities during sleep (e.g., jerking and shaking movements, confusional arousals, sleep walking), severe sleep disruption, gastroesophageal reflux causing heartburn, nocturnal enuresis (noted mostly in children), and profuse sweating at night. The daytime symptoms include EDS characterized by sleep attacks lasting 0.5 to 2 hours and occurring mostly when the patient is relaxing. The prolonged duration and the nonrefreshing nature of these sleep attacks in OSAS differentiate these from narcoleptic sleep attacks. Other daytime symptoms include impairment of memory and motor skills, irritability, morning headache in some patients, automatic behavior, retrograde amnesia, and hyperactivity (in children). Impotence in men is often associated with severe and long-standing OSAS. Physical examination may reveal obesity in approximately 70% of the cases, with increased body mass index and increased neck circumference, in addition to upper airway anatomical abnormalities causing reduction of the upper airway space (e.g., low-hanging soft palate, large edematous uvula, large tonsils and adenoids—especially in children—retrognathia, micrognathia). In severe cases, physical examination may reveal evidence of congestive heart failure, cardiac arrhythmias, hypertension, and polycythemia.

Consequences of Obstructive Sleep Apnea Syndrome

OSAS is associated with increased morbidity and mortality due to both short-term consequences (impairment of quality of life and increasing traffic- and work-related accidents), and long-term consequences from associated and comorbid conditions such as hypertension, heart failure, MI, cardiac arrhythmias, stroke due to both supratentorial and infratentorial infarctions, transient ischemic attacks, cognitive dysfunction, depression, and insomnia (Banno and Kryger, 2007; Flemons, 2002; Guilleminault and Zupancic, 2009; Marin et al., 2005; Somers et al., 2008). Several prospective longitudinal studies (Nieto et al., 2000; Peppard et al., 2000; Young et al., 1997) have shown a clear association between OSAS and systemic hypertension, which may be noted in approximately 45% of patients with OSAS. The factors that cause hypertension in OSAS include repeated hypoxemias during sleep at night, which cause increased sympathetic activity. OSAS is noted in about 30% of cases of essential hypertension. Several studies have shown improvement of hypertension or reduction of need for antihypertensive medications after effective treatment of OSAS with CPAP titration (Banno and Kryger, 2007; Faccenda et al., 2001; Hla et al., 2002; Pepperell et al., 2002). Pulmonary hypertension is also noted in approximately 15% to 20% of cases. Cardiac arrhythmias in the form of premature ventricular contractions, ventricular tachycardia, sinus pauses, and third-degree heart block as well as sudden cardiac death have been attributed to OSAS. Heart failure, mostly systolic heart failure but also diastolic heart failure (in which the studies are limited), is associated with both obstructive and central sleep apneas but more central sleep apneas, including Cheyne-Stokes breathing, than obstructive apneas (Arias et al., 2007; Javaheri, 2006; Javaheri and Somers, 2011; Somers et al., 2008). The presence of central apnea, including Cheyne-Stokes breathing, increases mortality in patients with heart failure. Cognitive dysfunction, which is noted in moderately severe to severe OSAS patients, shows improvement after satisfactory treatment with CPAP titration (Engelman et al., 2000). Recently, awareness about the presence of depression and insomnia in patients with OSAS has grown, but adequate studies have not been conducted to find the prevalence and impact of these conditions on OSAS (Aloia et al., 2005; Shepertycky et al., 2005). There has also been an increased association between OSAS and metabolic syndrome (a combination of hypertension, increased insulin resistance with type 2 diabetes, hypertriglyceridemia, and obesity) (Alam et al., 2007).

Pathogenesis of Obstructive Sleep Apnea Syndrome

Factors contributing to the pathogenesis of OSAS include local anatomical, neurological, and vascular factors, as well as familial predisposition (Banno and Kryger, 2007; Guilleminault and Zupancic, 2009). Collapse of the pharyngeal airway is the fundamental factor in OSA. During sleep, muscle tone decreases, including that of the upper airway dilator muscles which maintain upper airway patency. Decreased tone causes these muscles to relax, increasing upper airway resistance and narrowing the upper airway space. Defective upper airway reflexes may also play a role. Increasing familial occurrence of OSAS in some patients may be related to abnormal craniofacial features. In children, adenotonsilar enlargement and craniofacial dysostosis causing narrow upper airway space are important factors. Neurological factors include reduced medullary respiratory neuronal output as a result of abnormal ventilatory control. Other neurological factors include autonomic activation during sleep-related breathing events, contributing to development of hypertension and cardiac arrhythmias. Vascular factors contributing to the pathogenesis and long-term adverse consequences (Banno and Kryger, 2007; Javaheri and Somers, 2011) include increased endothelin 1 (a vasoconstrictor), reduced nitric oxide (a known vasodilator), and increased serum levels of vascular endothelial growth factor (glycoprotein responsible for vascular remodeling and atherosclerosis). It has been shown that after effective CPAP titration, these vascular abnormalities are reversed. Thus, a complex interaction of peripheral upper airway anatomical, central neural, vascular, and genetic factors contribute to the syndrome of upper airway OSAS.

Evaluation and Assessment

Evaluation and assessment are the same as for other sleep disorders. Particular attention should be paid to the detailed sleep history as well as the daytime history, and careful physical examination should be focused on specific associated and risk factors, specifically body mass index, cardiopulmonary examination, and an examination of the upper airways (neck circumference, airway size). The Mallampati classification is useful in evaluating patient airway size and gauging the possible risk for OSA (Fig. 68.25). Laboratory assessment and management are described later under Laboratory Assessment of Sleep Disorders.

Fig. 68.25 The Mallampati classification describes tongue size relative to oropharyngeal size. The test is conducted with the patient in the sitting position, the head held in a neutral position, the mouth wide open and relaxed, and the tongue protruding to the maximum. The subsequent classification is assigned based upon the pharyngeal structures that are visible. Class I = visualization of the soft palate, fauces, uvula, anterior and posterior pillars. Class II = visualization of the soft palate, fauces and uvula. Class III = visualization of the soft palate and the base of the uvula. Class IV = soft palate is not visible at all. If the patients phonates, this falsely improves the view. If the patient arches his or her tongue, the uvula is falsely obscured. The test was initially adapted to predict ease of intubation but can be used to predict the potential severity of obstructive sleep apnea.

(Modified from Mallampati, S.R., Gatt, S.P., Gugino, L.D., et al., 1985. A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anaesth Soc J 32, 429-434.)

Upper Airway Resistance Syndrome

Since UARS was described by Guilleminault and colleagues in 1993, there has been controversy about this entity. Some investigators have rejected it as a distinct clinical entity, whereas others have accepted it as such. One controversy concerns whether UARS can be considered as the initial stage, with progressive evolution into full-blown upper airway OSAS. In the only longitudinal study performed (in approximately 94 UARS subjects) by Guilleminault and colleagues (2006a), it was noted that about 5% of subjects had developed OSAS 4.5 years later. In the majority of patients with UARS, symptoms do not evolve into full-blown OSAS. Many patients have a multitude of symptoms of a somatic, psychiatric, or psychosomatic nature, whereas others are associated with attention-deficit hyperactivity disorder (ADHD), fibromyalgia, and chronic insomnia. UARS thus appears to be a heterogenous syndrome and could be part of a spectrum, with OSAS and obstructive hypoventilation at the far end of the spectrum and snoring at the other end. Some patients may fit with the spectrum, but the majority do not. Patients with UARS show subtle airflow limitations due to increased upper airway resistance, followed by repeated arousals during sleep at night. This subtle airflow limitation cannot be identified by the usual recording of respiration using an oronasal thermistor. Nasal pressure monitoring with a nasal cannula is more sensitive than use of a thermistor in detecting airflow limitation and increased upper airway resistance (Ayappa et al., 2000). Intraesophageal balloon recording, however, is the standard method for detecting upper airway resistance and reveals increasing efforts with increasing intraesophageal pressure leading to arousal but without any apnea or hypopnea (Fig. 68.26). These patients may or may not snore; they may have EDS and all its consequences, as seen in OSAS. Adult patients are more likely to complain of fatigue rather than sleepiness. Chronic insomnia is more commonly seen in UARS than in OSAS. UARS can sometimes be mistaken for chronic fatigue syndrome, fibromyalgia, ADHD, depression, and other psychiatric disorders. CPAP titration is widely used as the first line of therapy, but not all patients improve on CPAP. Recently it has been shown that cognitive behavioral therapy in addition to CPAP may be helpful for patients with chronic insomnia.

Fig. 68.26 Polysomnographic recording of a patient with upper airway resistance syndrome. Note that peak increase in effort (arrow) is associated with a small drop in peak flow and tidal volume, causing a transient arousal on the electroencephalogram. ECG, Electrocardiogram; EMG facial, facial muscle electromyogram; EOG, electro-oculogram (right and left); FLOW, pneumotachometer to quantify airflow; Pes, esophageal manometry to record esophageal pressure; RESPsum, respiratory effort; Sao₂, oxygen saturation.

(Reproduced with permission from Robinson, A., Guilleminault, C., 1999. Obstructive sleep apnea syndrome. In: Chokroverty, S. (Ed.), Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, second ed. Butterworth-Heinemann, Boston.)

Central Sleep Apnea Syndrome

Central sleep apnea syndrome includes primary or idiopathic CSA, CSA due to Cheyne-Stokes breathing pattern, CSA due to high altitude, CSA due to central neurological disorders (particularly brainstem dysfunction), and CSA due to drug or substance abuse (e.g., use of opiates) (AASM, 2005). Primary CSAS is rare, and the patient may present with EDS and frequent awakenings due to repeated episodes of central apnea followed by arousals. The patient may also present with insomnia. Cheyne-Stokes breathing is noted in patients with congestive heart failure (Javaheri, 2006; Javaheri and Somers, 2011) and sometimes in renal failure. The presence of Cheyne-Stokes breathing in cardiac failure increases mortality. Patients with primary CSA usually are normocapnic or hypocapnic, with a Paco₂ of 40 mm Hg or lower. The other important point of differentiation is that the cycle length (apnea plus ventilatory duration) is more than 45 seconds in Cheyne-Stokes breathing and less than 45 seconds in primary CSA (AASM, 2005).

Clinical Manifestations

RLS is the most common movement disorder but is uncommonly recognized and treated despite a lucid description of the entity in the middle of the last century (Hening et al., 2009). Even today, many physicians do not recognize the condition and mistake it for other superficially similar conditions. There is no single diagnostic test for RLS; therefore, the diagnosis rests entirely on clinical features and is based on the International Restless Legs Syndrome Study Group (IRLSSG) criteria first established in 1995 (Walters, 1995) and modified slightly in 2003 (Allen et al., 2003). These criteria include essential, supportive, and associated features, as listed in Box 68.15.

RLS is a lifelong sensory-motor neurological disorder (Earley, 2003) that often begins at a very young age but is mostly diagnosed in the middle or later years. Prevalence of RLS increases with age and plateaus for some unknown reason around age 85 to 90 (Allen et al., 2001; Earley, 2003; Earley et al., 2011). All four essential diagnostic criteria (see Box 68.15) are needed for establishing the diagnosis. The overall prevalence of RLS has been estimated at about 10% for all adult populations, particularly those in North American and European populations. Prevalence for the most severe cases is approximately 2.5% (Hening et al., 2004) but appears to be much less in some surveys from Asia (<1%-3%), suggesting possible ethnic and racial differences in RLS prevalence (Garcia-Borreguero et al., 2006). In most surveys, the prevalence is greater in women than in men, and the disease is gradually progressing. Family studies of RLS suggest an increased incidence (≈40%-50%) in first-degree relatives of idiopathic cases. A high concordance (83%) in monozygotic twins and complex segregation analysis suggest an autosomal dominant mode of inheritance (Hening et al., 2009). Linkage analysis documented significant linkage to at least six different chromosomes (12q, 14q, 9p, 2q, and 20p). Recent genome-wide association and linkage analysis have documented common variations in certain genomic regions, conferring more than 50% increase in risk to RLS-PLMS (Stefansson et al., 2007; Winkelmann et al., 2007). Four allelic variations in different genes have been identified on chromosomes 2p, 6p, 15q, and 12q.

The sensory manifestations of RLS include intense disagreeable feelings described as creeping, crawling, tingling, burning, aching, cramping, knifelike, or itching sensations. These creeping sensations occur mostly between the knees and ankles, causing an intense urge to move the limbs to relieve these feelings. Sometimes, similar symptoms occur in the arms or other parts of the body, particularly in advanced stages of the disease or when the patient develops augmentation (a hypermotor syndrome with symptoms occurring at least 2 hours earlier than the initial period, with intensification and spread to other body parts) resulting from long-standing dopaminergic medications (Allen et al., 2003; Garcia-Borreguero et al., 2007). Approximately 15% to 20% of patients complain of actual pain. Most of the movements, particularly in the early stages, are noted in the evening while the patients are resting in bed. In severe cases, however, movements may be noted in the daytime while subjects are sitting or lying down. At least 80% of RLS patients have PLMS, and many also have periodic limb movements in wakefulness. The condition may have a profound impact on sleep. Patients often seek medical attention for sleep disturbance—generally a problem of initiation, although difficulty maintaining sleep owing to associated PLMS can occur. Neurological examination is generally normal in the idiopathic form. As stated earlier, RLS often begins in childhood, but diagnosis of childhood RLS may be difficult based on the National Institutes of Health (NIH) consensus conference criteria established in 2002 (Allen et al., 2003). Some diagnostic criteria for childhood RLS have more recently been suggested. To make a correct diagnosis, RLS must be differentiated from conditions mimicking RLS (Box 68.16) or those associated (comorbid) with RLS (Chokroverty, 2009d) (Box 68.17 and 68.18). An important and often difficult condition to differentiate from RLS is akathisia (see Box 68.18).