212 PART 2 Cardinal Manifestations and Presentation of Diseases

benefit when used intermittently but can produce tolerance and

anticholinergic side effects such as dry mouth and constipation,

which limit their use, particularly in the elderly.

Benzodiazepine receptor agonists (BzRAs) are an effective and

well-tolerated class of medications for insomnia. BzRAs bind to

the GABAA receptor and potentiate the postsynaptic response to

GABA. GABAA receptors are found throughout the brain, and

BzRAs may globally reduce neural activity and enhance the activity

of specific sleep-promoting GABAergic pathways. Classic BzRAs

include lorazepam, triazolam, and clonazepam, whereas newer

agents such as zolpidem and zaleplon have more selective affinity

for the α1

 subunit of the GABAA receptor.

Specific BzRAs are often chosen based on the desired duration

of action. The most commonly prescribed agents in this family are

zaleplon (5–20 mg), with a half-life of 1–2 h; zolpidem (5–10 mg)

and triazolam (0.125–0.25 mg), with half-lives of 2–4 h; eszopiclone

(1–3 mg), with a half-life of 5–8 h; and temazepam (15–30 mg),

with a half-life of 8–20 h. Generally, side effects are minimal when

the dose is kept low and the serum concentration is minimized during the waking hours (by using the shortest-acting effective agent).

For chronic insomnia, intermittent use is recommended, unless the

consequences of untreated insomnia outweigh concerns regarding

chronic use.

The heterocyclic antidepressants (trazodone, amitriptyline,2

 and

doxepin) are the most commonly prescribed alternatives to BzRAs due

to their lack of abuse potential and low cost. Trazodone (25–100 mg)

is used more commonly than the tricyclic antidepressants, because

it has a much shorter half-life (5–9 h) and less anticholinergic

activity.

The orexin receptor antagonists suvorexant (10–20 mg) and

lemborexant (5–10 mg) can also improve insomnia by blocking

the wake-promoting effects of the orexin neuropeptides. These

have long half-lives and can produce morning sedation, and as

they reduce orexin signaling, they can rarely produce hypnagogic

hallucinations and sleep paralysis (see narcolepsy section above).

Medications for insomnia are now among the most commonly

prescribed medications, but they should be used cautiously. All

sedatives increase the risk of injurious falls and confusion in the

elderly, and therefore if needed these medications should be used

at the lowest effective dose. Morning sedation can interfere with

driving and judgment, and when selecting a medication, one

should consider the duration of action. Benzodiazepines carry a

risk of addiction and abuse, especially in patients with a history of

alcohol or sedative abuse. In patients with depression, all sedatives

can worsen the depression. Like alcohol, some sleep-promoting

medications can worsen sleep apnea. Sedatives can also produce

complex behaviors during sleep, such as sleepwalking and sleep

eating, especially at higher doses.

2

Trazodone and amitriptyline have not been approved by the FDA for treating

insomnia.

■ RESTLESS LEGS SYNDROME

Patients with restless legs syndrome (RLS) report an irresistible urge

to move the legs. Many patients report a creepy-crawly or unpleasant

deep ache within the thighs or calves, and those with more severe RLS

may have discomfort in the arms as well. For most patients with RLS,

these dysesthesias and restlessness are much worse in the evening and

first half of the night. The symptoms appear with inactivity and can

make sitting still in an airplane or when watching a movie a miserable

experience. The sensations are temporarily relieved by movement,

stretching, or massage. This nocturnal discomfort usually interferes

with sleep, and patients may report daytime sleepiness as a consequence. RLS is very common, affecting 5–10% of adults, and is more

common in women and older adults.

A variety of factors can cause RLS. Iron deficiency is the most

common treatable cause, and iron replacement should be considered

if the ferritin level is <75 ng/mL. RLS can also occur with peripheral

neuropathies and uremia and can be worsened by pregnancy, caffeine,

alcohol, antidepressants, lithium, neuroleptics, and antihistamines.

Genetic factors contribute to RLS, and polymorphisms in a variety of

genes (BTBD9, MEIS1, MAP2K5/LBXCOR, and PTPRD) have been

linked to RLS, although as yet, the mechanism through which they

cause RLS remains unknown. Roughly one-third of patients (particularly those with an early age of onset) have multiple affected family

members.

RLS is treated by addressing the underlying cause such as iron

deficiency if present. Otherwise, treatment is symptomatic, and dopamine agonists or alpha-2-delta calcium channel ligands are used most

frequently. Agonists of dopamine D2/3 receptors such as pramipexole

(0.25–0.5 mg q7PM) or ropinirole (0.5–4 mg q7PM) are usually quite

effective, but about 25% of patients taking dopamine agonists develop

augmentation, a worsening of RLS such that symptoms begin earlier

in the day and can spread to other body regions. Other possible side

effects of dopamine agonists include nausea, morning sedation, and

increases in rewarding behaviors such as sex and gambling. Alpha2-delta calcium channel ligands such as gabapentin (300–600 mg

q7PM) and pregabalin (150–450 mg q7PM) can also be quite effective;

these are less likely to cause augmentation, and they can be especially

helpful in patients with concomitant pain, neuropathy, or anxiety.

Opioids and benzodiazepines may also be of therapeutic value. Most

patients with restless legs also experience PLMD, although the reverse

is not the case.

■ PERIODIC LIMB MOVEMENT DISORDER

PLMD involves rhythmic twitches of the legs that disrupt sleep. The

movements resemble a triple flexion reflex with extensions of the great

toe and dorsiflexion of the foot for 0.5–5.0 s, which recur every 20–40 s

during NREM sleep, in episodes lasting from minutes to hours. PLMD

is diagnosed by a polysomnogram that includes recordings of the

anterior tibialis and sometimes other muscles. The EEG shows that the

movements of PLMD frequently cause brief arousals that disrupt sleep

and can cause insomnia and daytime sleepiness. PLMD can be caused

by the same factors that cause RLS (see above), and the frequency of leg

movements improves with the same medications used for RLS, including dopamine agonists. Genetic studies identified polymorphisms

associated with both RLS and PLMD, suggesting that they may have a

common pathophysiology.

■ PARASOMNIAS

Parasomnias are abnormal behaviors or experiences that arise from

or occur during sleep. A variety of parasomnias can occur during

NREM sleep, from brief confusional arousals to sleepwalking and night

terrors. The presenting complaint is usually related to the behavior

itself, but the parasomnias can disturb sleep continuity or lead to mild

impairments in daytime alertness. Two main parasomnias occur in

REM sleep: REM sleep behavior disorder (RBD) and nightmares.

Sleepwalking (Somnambulism) Patients affected by this disorder carry out automatic motor activities that range from simple to

complex. Individuals may walk, urinate inappropriately, eat, exit the

house, or drive a car with minimal awareness. It may be difficult to

arouse the patient to wakefulness, and some individuals may respond

to attempted awakening with agitation or violence. In general, it is

safest to lead the patient back to bed, at which point he or she will

often fall back asleep. Sleepwalking arises from NREM stage N3 sleep,

usually in the first few hours of the night, and the EEG initially shows

the slow cortical activity of deep NREM sleep even when the patient

is moving about. Sleepwalking is most common in children and adolescents, when deep NREM sleep is most abundant. About 15% of

children have occasional sleepwalking, and it persists in about 1% of

adults. Episodes are usually isolated but may be recurrent in 1–6%

of patients. The cause is unknown, although it has a familial basis in

roughly one-third of cases. Sleepwalking can be worsened by stress,

alcohol, and insufficient sleep, which subsequently causes an increase

in deep NREM sleep. These should be addressed if present. Small studies have shown some efficacy of antidepressants and benzodiazepines;

213 Sleep Disorders CHAPTER 31

3

No medications have been approved by the FDA for the treatment of RBD.

relaxation techniques and hypnosis can also be helpful. Patients and

their families should improve home safety (e.g., replace glass doors,

remove low tables to avoid tripping) to minimize the chance of injury

if sleepwalking occurs.

Sleep Terrors This disorder occurs primarily in young children

during the first few hours of sleep during NREM stage N3 sleep. The

child often sits up during sleep and screams, exhibiting autonomic

arousal with sweating, tachycardia, large pupils, and hyperventilation.

The individual may be difficult to arouse and rarely recalls the episode

on awakening in the morning. Treatment usually consists of reassuring

parents that the condition is self-limited and benign, and like sleepwalking, it may improve by avoiding insufficient sleep.

Sleep Enuresis Bedwetting, like sleepwalking and night terrors,

is another parasomnia that occurs during sleep in the young. Before

age 5 or 6 years, nocturnal enuresis should be considered a normal

feature of development. The condition usually improves spontaneously

by puberty, persists in 1–3% of adolescents, and is rare in adulthood.

Treatment consists of bladder training exercises and behavioral therapy. Symptomatic pharmacotherapy is usually accomplished in adults

with desmopressin (0.2 mg qhs), oxybutynin chloride (5 mg qhs), or

imipramine (10–25 mg qhs). Important causes of nocturnal enuresis

in patients who were previously continent for 6–12 months include

urinary tract infections or malformations, cauda equina lesions, emotional disturbances, epilepsy, sleep apnea, and certain medications.

Sleep Bruxism Bruxism is an involuntary, forceful grinding of

teeth during sleep that affects 10–20% of the population. The patient is

usually unaware of the problem. The typical age of onset is 17–20 years,

and spontaneous remission usually occurs by age 40. In many cases,

the diagnosis is made during dental examination, damage is minor,

and no treatment is indicated. In more severe cases, treatment with a

mouth guard is necessary to prevent tooth injury. Stress management,

benzodiazepines, and biofeedback can be useful when bruxism is a

manifestation of psychological stress.

REM Sleep Behavior Disorder (RBD) RBD (Video 31-2) is

distinct from other parasomnias in that it occurs during REM sleep.

The patient or the bed partner usually reports agitated or violent

behavior during sleep, and upon awakening, the patient can often

report a dream that matches the accompanying movements. During

normal REM sleep, nearly all nonrespiratory skeletal muscles are

paralyzed, but in patients with RBD, dramatic limb movements such

as punching or kicking lasting seconds to minutes occur during REM

sleep, and it is not uncommon for the patient or the bed partner to be

injured.

The prevalence of RBD increases with age, afflicting about 2%

of adults aged >70, and is about twice as common in men. Within

12 years of disease onset, half of RBD patients develop a synucleinopathy such as Parkinson’s disease (Chap. 435) or dementia with Lewy

bodies (Chap. 434), or occasionally multiple system atrophy (Chap.

440), and over 90% develop a synucleinopathy by 25 years. RBD can

occur in patients taking antidepressants, and in some, these medications may unmask this early indicator of neurodegeneration. Synucleinopathies probably cause neuronal loss in brainstem regions that

regulate muscle paralysis during REM sleep, and loss of these neurons

permits movements to break through during REM sleep. RBD also

occurs in about 30% of patients with narcolepsy, but the underlying

cause is probably different, as they seem to be at no increased risk of a

neurodegenerative disorder.

Many patients with RBD have sustained improvement with

clonazepam (0.5–2.0 mg qhs).3

 Melatonin at doses up to 9 mg nightly

may also prevent attacks.

■ CIRCADIAN RHYTHM SLEEP DISORDERS

A subset of patients presenting with either insomnia or hypersomnia may have a disorder of sleep timing rather than sleep generation.

Disorders of sleep timing can be either organic (i.e., due to an abnormality of circadian pacemaker[s]) or environmental/behavioral (i.e.,

due to a disruption of environmental synchronizers). Effective therapies aim to entrain the circadian rhythm of sleep propensity to the

appropriate behavioral phase.

Delayed Sleep-Wake Phase Disorder DSWPD is characterized

by: (1) sleep onset and wake times persistently later than desired;

(2) actual sleep times at nearly the same clock hours daily; and (3) if

conducted at the habitual delayed sleep time, essentially normal sleep

on polysomnography (except for delayed sleep onset). About half of

patients with DSWPD exhibit an abnormally delayed endogenous

circadian phase, which can be assessed by measuring the onset of

secretion of melatonin in either the blood or saliva; this is best done

in a dimly lit environment as light suppresses melatonin secretion.

Dim-light melatonin onset (DLMO) in DSWPD patients occurs later

in the evening than normal, which is about 8:00–9:00 p.m. (i.e., about

1–2 h before habitual bedtime). Patients tend to be young adults. The

delayed circadian phase could be due to: (1) an abnormally long,

genetically determined intrinsic period of the endogenous circadian

pacemaker; (2) reduced phase-advancing capacity of the pacemaker;

(3) slower buildup of homeostatic sleep drive during wakefulness; or

(4) an irregular prior sleep-wake schedule, characterized by frequent

nights when the patient chooses to remain awake while exposed to

artificial light well past midnight (for personal, social, school, or

work reasons). In most cases, it is difficult to distinguish among these

factors, as patients with either a behaviorally induced or biologically

driven circadian phase delay may both exhibit a similar circadian phase

delay in DLMO, and both factors make it difficult to fall asleep at the

desired hour. Late onset of dim-light melatonin secretion can help distinguish DSWPD from other forms of sleep-onset insomnia. DSWPD

is a chronic condition that can persist for years and may not respond

to attempts to reestablish normal bedtime hours. Treatment methods

involving phototherapy with blue-enriched light during the morning

hours and/or melatonin administration in the evening hours show

promise in these patients, although the relapse rate is high.

Advanced Sleep-Wake Phase Disorder Advanced sleep-wake

phase disorder (ASWPD) is the converse of DSWPD. Most commonly,

this syndrome occurs in older people, 15% of whom report that they

cannot sleep past 5:00 a.m., with twice that number complaining that

they wake up too early at least several times per week. Patients with

ASWPD are sleepy during the evening hours, even in social settings.

Sleep-wake timing in ASWPD patients can interfere with a normal

social life. Patients with this circadian rhythm sleep disorder can be

distinguished from those who have early wakening due to insomnia

because ASWPD patients show early onset of dim-light melatonin

secretion.

In addition to age-related ASWPD, an early-onset familial variant of

this condition has also been reported. In two families in which ASWPD

was inherited in an autosomal dominant pattern, the syndrome was

due to missense mutations in a circadian clock component (in the

casein kinase binding domain of PER2 in one family, and in casein

kinase I delta in the other) that shortens the circadian period. Patients

with ASWPD may benefit from bright light and/or blue enriched phototherapy during the evening hours to reset the circadian pacemaker

to a later hour.

Non-24-h Sleep-Wake Rhythm Disorder Non-24-h sleepwake rhythm disorder (N24SWD) most commonly occurs when the

primary synchronizing input (i.e., the light-dark cycle) from the environment to the circadian pacemaker is lost (as occurs in many blind

people with no light perception), and the maximal phase-advancing

capacity of the circadian pacemaker in response to nonphotic cues

cannot accommodate the difference between the 24-h geophysical day

and the intrinsic period of the patient’s circadian pacemaker, resulting

in loss of entrainment to the 24-h day. The sleep of most blind patients

with N24SWD is restricted to the nighttime hours due to social or

occupational demands. Despite this regular sleep-wake schedule,

affected patients with N24SWD are nonetheless unable to maintain

214 PART 2 Cardinal Manifestations and Presentation of Diseases

a stable phase relationship between the output of the non-entrained

circadian pacemaker and the 24-h day. Therefore, most blind patients

present with intermittent bouts of insomnia. When the blind patient’s

endogenous circadian rhythms are out of phase with the local environment, nighttime insomnia coexists with excessive daytime sleepiness.

Conversely, when the endogenous circadian rhythms of those same

patients are in phase with the local environment, symptoms remit. The

interval between symptomatic phases may last several weeks to several

months in blind patients with N24SWD, depending on the period of

the underlying nonentrained rhythm and the 24-h day. Nightly lowdose (0.5 mg) melatonin administration may improve sleep and, in

some cases, induce synchronization of the circadian pacemaker. In

sighted patients, N24SWD can be caused by self-selected exposure to

artificial light that inadvertently entrains the circadian pacemaker to

a >24-h schedule, and these individuals present with an incremental

pattern of successive delays in sleep timing, progressing in and out of

phase with local time—a clinical presentation that is seldom seen in

blind patients with N24SWD.

Shift-Work Disorder More than 7 million workers in the United

States regularly work at night, either on a permanent or rotating schedule. Many more begin the commute to work or school between 4:00

a.m. and 7:00 a.m., requiring them to commute and then work during

a time of day that they would otherwise be asleep. In addition, each

week, millions of “day” workers and students elect to remain awake at

night or awaken very early in the morning to work or study to meet

work or school deadlines, drive long distances, compete in sporting

events, or participate in recreational activities. Such schedules can

result in both sleep loss and misalignment of circadian rhythms with

respect to the sleep-wake cycle.

The circadian timing system usually fails to adapt successfully to the

inverted schedules required by overnight work or the phase advance

required by early morning (4:00 a.m. to 7:00 a.m.) start times. This

leads to a misalignment between the desired work-rest schedule and

the output of the pacemaker, resulting in disturbed daytime sleep in

most such individuals. Excessive work hours (per day or per week),

insufficient time off between consecutive days of work or school,

and frequent travel across time zones may be contributing factors.

Sleep deficiency, increased length of time awake prior to work, and

misalignment of circadian phase impair alertness and performance,

increase reaction time, and increase risk of performance lapses, thereby

resulting in greater safety hazards among night workers and other

sleep-deprived individuals. Sleep disturbance nearly doubles the risk of

a fatal work accident. In addition, long-term night-shift workers have

higher rates of breast, colorectal, and prostate cancer and of cardiac,

gastrointestinal, metabolic, and reproductive disorders. The World

Health Organization has added night-shift work to its list of probable

carcinogens.

Sleep onset begins in local brain regions before gradually sweeping

over the entire brain as sensory thresholds rise and consciousness

is lost. A sleepy individual struggling to remain awake may attempt

to continue performing routine and familiar motor tasks during the

transition state between wakefulness and stage N1 sleep, while unable

to adequately process sensory input from the environment. Such sleeprelated attentional failures typically last only seconds but are known on

occasion to persist for longer durations. Motor vehicle operators who

fail to heed the warning signs of sleepiness are especially vulnerable

to sleep-related accidents, as sleep processes can slow reaction times,

induce automatic behavior, and intrude involuntarily upon the waking

brain, causing catastrophic consequences—including 6400 fatalities

and 50,000 debilitating injuries in the United States annually. For this

reason, an expert consensus panel has concluded that individuals who

have slept <2 h in the prior 24 h are unfit to drive a motor vehicle.

There is a significant increase in the risk of sleep-related, fatal-to-thedriver highway crashes in the early morning and late afternoon hours,

coincident with bimodal peaks in the daily rhythm of sleep tendency.

Physicians who work prolonged shifts, especially intermittent

overnight shifts, constitute another group of workers at greater risk

for accidents and other adverse consequences of lack of sleep and

misalignment of the circadian rhythm. Recurrent scheduling of

resident physicians to work shifts of ≥24 consecutive hours impairs

psychomotor performance to a degree that is comparable to alcohol

intoxication, doubles the risk of attentional failures among intensive care unit resident physicians working at night, and significantly

increases the risk of serious medical errors in intensive care units,

including a fivefold increase in the risk of serious diagnostic mistakes.

Some 20% of hospital resident physicians report making a fatiguerelated mistake that injured a patient, and 5% admit making a

fatigue-related mistake that resulted in the death of a patient. Moreover, working for >24 consecutive hours increases the risk of percutaneous injuries and more than doubles the risk of motor vehicle crashes

during the commute home. For these reasons, in 2008, the National

Academy of Medicine concluded that the practice of scheduling resident physicians to work for >16 consecutive hours without sleep is

hazardous for both resident physicians and their patients.

Of individuals scheduled to work at night or in the early morning

hours, 5–15% have much greater-than-average difficulties remaining

awake during night work and sleeping during the day; these individuals are diagnosed with chronic and severe shift-work disorder (SWD).

Patients with this disorder have a level of excessive sleepiness during

work at night or in the early morning and insomnia during day sleep

that the physician judges to be clinically significant; the condition is

associated with an increased risk of sleep-related accidents and with

some of the illnesses associated with night-shift work. Patients with

chronic and severe SWD are profoundly sleepy at work. In fact, their

sleep latencies during night work average just 2 min, comparable to

mean daytime sleep latency durations of patients with narcolepsy or

severe sleep apnea.

TREATMENT

Shift-Work Disorder

Caffeine is frequently used by night workers to promote wakefulness. However, it cannot forestall sleep indefinitely, and it does

not shield users from sleep-related performance lapses. Postural

changes, exercise, and strategic placement of nap opportunities can

sometimes temporarily reduce the risk of fatigue-related performance lapses. Properly timed exposure to blue-enriched light or

bright white light can directly enhance alertness and facilitate more

rapid adaptation to night-shift work.

Modafinil (200 mg) or armodafinil (150 mg) 30–60 min before

the start of an 8-h overnight shift is an effective treatment for

the excessive sleepiness during night work in patients with SWD.

Although treatment with modafinil or armodafinil significantly

improves performance and reduces sleep propensity and the risk

of lapses of attention during night work, affected patients remain

excessively sleepy.

Fatigue risk management programs for night-shift workers

should promote education about sleep, increase awareness of the

hazards associated with sleep deficiency and night work, and screen

for common sleep disorders. Work schedules should be designed

to minimize: (1) exposure to night work; (2) the frequency of shift

rotations; (3) the number of consecutive night shifts; and (4) the

duration of night shifts.

Jet Lag Disorder Each year, >60 million people fly from one

time zone to another, often resulting in excessive daytime sleepiness,

sleep-onset insomnia, and frequent arousals from sleep, particularly in

the latter half of the night. The syndrome is transient, typically lasting

2–14 d depending on the number of time zones crossed, the direction

of travel, and the traveler’s age and phase-shifting capacity. Travelers

who spend more time outdoors at their destination reportedly adapt

more quickly than those who remain in hotel or seminar rooms,

presumably due to brighter (outdoor) light exposure. Avoidance of

antecedent sleep loss or napping on the afternoon prior to overnight

travel can reduce the difficulties associated with extended wakefulness.

Laboratory studies suggest that low doses of melatonin can enhance

215 Disorders of the Eye CHAPTER 32

VIDEO 31-2 Typical aggressive movements in rapid eye movement (REM) sleep

behavior disorder. (Video courtesy of Dr. Carlos Schenck, University of Minnesota

Medical School.)

VIDEO 31-1 A typical episode of severe cataplexy. The patient is joking and

then falls to the ground with an abrupt loss of muscle tone. The electromyogram

recordings (four lower traces on the right) show reductions in muscle activity

during the period of paralysis. The electroencephalogram (top two traces) shows

wakefulness throughout the episode. (Video courtesy of Giuseppe Plazzi, University

of Bologna.)

sleep efficiency, but only if taken when endogenous melatonin concentrations are low (i.e., during the biologic daytime).

In addition to jet lag associated with travel across time zones, many

patients report a behavioral pattern that has been termed social jet lag,

in which bedtimes and wake times on weekends or days off occur 4–8 h

later than during the week. Such recurrent displacement of the timing

of the sleep-wake cycle is common in adolescents and young adults

and is associated with delayed circadian phase, sleep-onset insomnia, excessive daytime sleepiness, poorer academic performance, and

increased risk of both obesity and depressive symptoms.

■ MEDICAL IMPLICATIONS OF CIRCADIAN

RHYTHMICITY

Prominent circadian variations have been reported in the incidence

of acute myocardial infarction, sudden cardiac death, and stroke, the

leading causes of death in the United States. Platelet aggregability is

increased in the early morning hours, coincident with the peak incidence of these cardiovascular events. Recurrent circadian disruption

combined with chronic sleep deficiency, such as occurs during nightshift work, is associated with increased plasma glucose concentrations

after a meal due to inadequate pancreatic insulin secretion. Nightshift workers with elevated fasting glucose have an increased risk of

progressing to diabetes. Blood pressure of night workers with sleep

apnea is higher than that of day workers. A better understanding of the

possible role of circadian rhythmicity in the acute destabilization of a

chronic condition such as atherosclerotic disease could improve the

understanding of its pathophysiology.

Diagnostic and therapeutic procedures may also be affected by

the time of day at which data are collected. Examples include blood

pressure, body temperature, the dexamethasone suppression test, and

plasma cortisol levels. The timing of chemotherapy administration has

been reported to have an effect on the outcome of treatment. In addition, both the toxicity and effectiveness of drugs can vary with time of

day. For example, more than a fivefold difference has been observed

in mortality rates after administration of toxic agents to experimental

animals at different times of day. Anesthetic agents are particularly sensitive to time-of-day effects. Finally, the physician must be aware of the

public health risks associated with the ever-increasing demands made

by the 24/7 schedules in our round-the-clock society.

Acknowledgment

John W. Winkelman, MD, PhD, and Gary S. Richardson, MD, contributed to this chapter in prior editions, and some material from their work

has been retained here.

■ FURTHER READING

Cash RE et al: Association between sleep duration and ideal cardiovascular health among US adults, National Health and Nutrition

Examination Survey. Prev Chronic Dis 17:E43, 2020.

Chinoy ED et al: Unrestricted evening use of light-emitting tablet

computers delays self-selected bedtime and disrupts circadian timing

and alertness. Physiol Rep 6:e13692, 2018.

Fultz NE et al: Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science 366:628, 2019.

Holth JK et al: The sleep-wake cycle regulates brain interstitial fluid

tau in mice and CSF tau in humans. Science 363:880, 2019.

Landrigan CP et al: Effect on patient safety of a resident physician

schedule without 24-hour shifts. N Engl J Med 382:2514, 2020.

Lee ML et al: High risk of near-crash driving events following nightshift work. Proc Natl Acad Sci USA 113:176, 2016.

Lim AS et al: Sleep is related to neuron numbers in the ventrolateral

preoptic/intermediate nucleus in older adults with and without

Alzheimer’s disease. Brain 137:2847, 2014.

McAlpine CS et al: Sleep modulates haematopoiesis and protects

against atherosclerosis. Nature 566:383, 2019.

Riemann D et al: The neurobiology, investigation, and treatment of

chronic insomnia. Lancet Neurol 14:547, 2015.

Scammell TE: Narcolepsy. N Engl J Med 373:2654, 2015.

Scammell TE et al: Neural circuitry of wakefulness and sleep. Neuron

93:747, 2017.

Sletten TL et al: Efficacy of melatonin with behavioural sleep-wake

scheduling for delayed sleep-wake phase disorder: a double-blind,

randomised clinical trial. PLoS Med 15:e1002587, 2018.

Section 4 Disorders of Eyes, Ears, Nose,

and Throat

32 Disorders of the Eye

Jonathan C. Horton

THE HUMAN VISUAL SYSTEM

The visual system provides a supremely efficient means for the rapid

assimilation of information from the environment to aid in the guidance of behavior. The act of seeing begins with the capture of images

focused by the cornea and lens on a light-sensitive membrane in the

back of the eye called the retina. The retina is actually part of the brain,

banished to the periphery to serve as a transducer for the conversion

of patterns of light energy into neuronal signals. Light is absorbed by

pigment in two types of photoreceptors: rods and cones. In the human

retina, there are 100 million rods and 5 million cones. The rods operate in dim (scotopic) illumination. The cones function under daylight

(photopic) conditions. The cone system is specialized for color perception and high spatial resolution. The majority of cones are within the

macula, the portion of the retina that serves the central 10° of vision.

In the middle of the macula, a small pit termed the fovea, packed exclusively with cones, provides the best visual acuity.

Photoreceptors hyperpolarize in response to light, activating bipolar,

amacrine, and horizontal cells in the inner nuclear layer. After processing of photoreceptor responses by this complex retinal circuit, the flow

of sensory information ultimately converges on a final common pathway: the ganglion cells. These cells translate the visual image impinging

on the retina into a continuously varying barrage of action potentials

that propagates along the primary optic pathway to visual centers

within the brain. There are a million ganglion cells in each retina and

hence a million fibers in each optic nerve.

Ganglion cell axons sweep along the inner surface of the retina in

the nerve fiber layer, exit the eye at the optic disc, and travel through

the optic nerve, optic chiasm, and optic tract to reach targets in the

brain. The majority of fibers synapse on cells in the lateral geniculate

body, a thalamic relay station. Cells in the lateral geniculate body

project in turn to the primary visual cortex. This afferent retinogeniculocortical sensory pathway provides the neural substrate for visual

perception. Although the lateral geniculate body is the main target

of the retina, separate classes of ganglion cells project to other subcortical visual nuclei involved in different functions. Ganglion cells

that mediate pupillary constriction and circadian rhythms are light

sensitive owing to a novel visual pigment, melanopsin. Pupil responses

are mediated by input to the pretectal olivary nuclei in the midbrain.

The pretectal nuclei send their output to the Edinger-Westphal nuclei,

which in turn provide parasympathetic innervation to the iris sphincter via an interneuron in the ciliary ganglion. Circadian rhythms are

216 PART 2 Cardinal Manifestations and Presentation of Diseases

timed by a retinal projection to the suprachiasmatic nucleus. Visual

orientation and eye movements are served by retinal input to the superior colliculus. Gaze stabilization and optokinetic reflexes are governed

by a group of small retinal targets known collectively as the brainstem

accessory optic system.

The eyes must be rotated constantly within their orbits to place and

maintain targets of visual interest on the fovea. This activity, called

foveation, or looking, is governed by an elaborate efferent motor system. Each eye is moved by six extraocular muscles that are supplied by

cranial nerves from the oculomotor (III), trochlear (IV), and abducens

(VI) nuclei. Activity in these ocular motor nuclei is coordinated by

pontine and midbrain mechanisms for smooth pursuit, saccades, and

gaze stabilization during head and body movements. Large regions

of the frontal and parietooccipital cortex control these brainstem eye

movement centers by providing descending supranuclear input.

CLINICAL ASSESSMENT OF VISUAL

FUNCTION

■ REFRACTIVE STATE

In approaching a patient with reduced vision, the first step is to decide

whether refractive error is responsible. In emmetropia, parallel rays

from infinity are focused perfectly on the retina. Sadly, this condition

is enjoyed by only a minority of the population. In myopia, the globe

is too long, and light rays come to a focal point in front of the retina.

Near objects can be seen clearly, but distant objects require a diverging lens in front of the eye. In hyperopia, the globe is too short, and

hence, a converging lens is used to supplement the refractive power of

the eye. In astigmatism, the corneal surface is not perfectly spherical,

necessitating a cylindrical corrective lens. Most patients elect to wear

eyeglasses or contact lenses to neutralize refractive error. An alternative is to permanently alter the refractive properties of the cornea by

performing laser in situ keratomileusis (LASIK) or photorefractive

keratectomy (PRK).

With the onset of middle age, presbyopia develops as the lens within

the eye becomes unable to increase its refractive power to accommodate on near objects. To compensate for presbyopia, an emmetropic

patient must use reading glasses. A patient already wearing glasses for

distance correction usually switches to bifocals. The only exception is a

myopic patient, who may achieve clear vision at near simply by removing glasses containing the distance prescription.

Refractive errors usually develop slowly and remain stable after adolescence, except in unusual circumstances. For example, the acute onset

of diabetes mellitus can produce sudden myopia because of lens edema

induced by hyperglycemia. Testing vision through a pinhole aperture

is a useful way to screen quickly for refractive error. If visual acuity is

better through a pinhole than it is with the unaided eye, the patient

needs refraction to obtain best corrected visual acuity.

■ VISUAL ACUITY

The Snellen chart is used to test acuity at a distance of 6 m (20 ft). For

convenience, a scale version of the Snellen chart called the Rosenbaum

card is held at 36 cm (14 in.) from the patient (Fig. 32-1). All subjects

should be able to read the 6/6 m (20/20 ft) line with each eye using their

refractive correction, if any. Patients who need reading glasses because

of presbyopia must wear them for accurate testing with the Rosenbaum

card. If 6/6 (20/20) acuity is not present in each eye, the deficiency in

vision must be explained. If it is worse than 6/240 (20/800), acuity

should be recorded in terms of counting fingers, hand motions, light

perception, or no light perception. Legal blindness is defined by the

Internal Revenue Service as a best corrected acuity of 6/60 (20/200) or

less in the better eye or a binocular visual field subtending 20° or less.

Loss of vision in one eye only does not constitute legal blindness. For

driving, the laws vary by state, but most require a corrected acuity of

6/12 (20/40) in at least one eye for unrestricted privileges. Patients who

develop a homonymous hemianopia should not drive.

■ PUPILS

The pupils should be tested individually in dim light with the patient

fixating on a distant target. There is no need to check the near response

FIGURE 32-1 The Rosenbaum card is a miniature, scale version of the Snellen

chart for testing visual acuity at near. When the visual acuity is recorded, the

Snellen distance equivalent should bear a notation indicating that vision was tested

at near, not at 6 m (20 ft), or else the Jaeger number system should be used to report

the acuity. (Design Courtesy J.G. Rosenbaum MD.)

if the pupils respond briskly to light, because isolated loss of constriction (miosis) to accommodation does not occur. For this reason, the

ubiquitous abbreviation PERRLA (pupils equal, round, and reactive

to light and accommodation) implies a wasted effort with the last

step. However, it is important to test the near response if the light

response is poor or absent. Light-near dissociation occurs with neurosyphilis (Argyll Robertson pupil), with lesions of the dorsal midbrain

(Parinaud’s syndrome), and after aberrant regeneration (oculomotor

nerve palsy, Adie’s tonic pupil).

An eye with no light perception has no pupillary response to direct

light stimulation. If the retina or optic nerve is only partially injured,

the direct pupillary response will be weaker than the consensual pupillary response evoked by shining a light into the healthy fellow eye. A

relative afferent pupillary defect (Marcus Gunn pupil) is elicited with

the swinging flashlight test (Fig. 32-2). It is an extremely useful sign

in retrobulbar optic neuritis and other optic nerve diseases, in which

it may be the sole objective evidence for disease. In bilateral optic

neuropathy, no afferent pupil defect is present if the optic nerves are

affected equally.

Subtle inequality in pupil size, up to 0.5 mm, is a fairly common

finding in normal persons. The diagnosis of essential or physiologic

anisocoria is secure as long as the relative pupil asymmetry remains

constant as ambient lighting varies. Anisocoria that increases in dim

light indicates a sympathetic paresis of the iris dilator muscle. The triad

of miosis with ipsilateral ptosis and anhidrosis constitutes Horner’s

217 Disorders of the Eye CHAPTER 32

A

B

C

FIGURE 32-2 Demonstration of a relative afferent pupil defect (Marcus Gunn

pupil) in the left eye, done with the patient fixating on a distant target. A. With

dim background lighting, the pupils are equal and relatively large. B. Shining

a flashlight into the right eye evokes equal, strong constriction of both pupils. C.

Swinging the flashlight over to the damaged left eye causes dilation of both pupils,

although they remain smaller than in A. Swinging the flashlight back over to the

healthy right eye would result in symmetric constriction back to the appearance

shown in B. Note that the pupils always remain equal; the damage to the left retina/

optic nerve is revealed by weaker bilateral pupil constriction to a flashlight in the

left eye compared with the right eye. (From P Levatin: Arch Ophthalmol 62:768, 1959.

Copyright © 1959 American Medical Association. All rights reserved.)

syndrome, although anhidrosis is an inconstant feature. A drop of 1%

apraclonidine produces no effect on the normal pupil, but the miotic

pupil dilates because of denervation hypersensitivity. Brainstem stroke,

carotid dissection, and neoplasm impinging on the sympathetic chain

occasionally are identified as the cause of Horner’s syndrome, but most

cases are idiopathic.

Anisocoria that increases in bright light suggests a parasympathetic

palsy. The first concern is an oculomotor nerve paresis. This possibility

is excluded if the eye movements are full and the patient has no ptosis or

diplopia. Acute pupillary dilation (mydriasis) can result from damage

to the ciliary ganglion in the orbit. Common mechanisms are infection

(herpes zoster, influenza), trauma (blunt, penetrating, surgical), and

ischemia (diabetes, temporal arteritis). After denervation of the iris

sphincter, the pupil does not respond well to light, but the response to

near is often relatively intact. When the near stimulus is removed, the

pupil redilates very slowly compared with the normal pupil, hence the

term tonic pupil. In Adie’s syndrome, a tonic pupil is present, sometimes in conjunction with weak or absent tendon reflexes in the lower

extremities. This benign disorder, which occurs predominantly in

healthy young women, is assumed to represent a mild dysautonomia.

Tonic pupils are also associated with multiple system atrophy, segmental hypohidrosis, diabetes, and amyloidosis. Occasionally, a tonic pupil

is discovered incidentally in an otherwise completely normal, asymptomatic individual. The diagnosis is confirmed by placing a drop of

dilute (0.125%) pilocarpine into each eye. Denervation hypersensitivity

produces pupillary constriction in a tonic pupil, whereas the normal

pupil shows no response. Pharmacologic dilatation from accidental or

deliberate instillation of anticholinergic (atropine, scopolamine) drops

can produce pupillary mydriasis. Gardener’s pupil refers to mydriasis

induced by exposure to tropane alkaloids, contained in plants such as

deadly nightshade, jimsonweed, or angel’s trumpet. When an anticholinergic agent is responsible for pupil dilation, 1% pilocarpine causes

no constriction.

Both pupils are affected equally by systemic medications. They are

small with narcotic use (morphine, oxycodone) and large with anticholinergics (scopolamine). Parasympathetic agents (pilocarpine) used

to treat glaucoma produce miosis. In any patient with an unexplained

pupillary abnormality, a slit-lamp examination is helpful to exclude

surgical trauma to the iris, an occult foreign body, perforating injury,

intraocular inflammation, adhesions (synechia), angle-closure glaucoma, and iris sphincter rupture from blunt trauma.

■ EYE MOVEMENTS AND ALIGNMENT

Eye movements are tested by asking the patient, with both eyes open, to

pursue a small target such as a pen tip into the cardinal fields of gaze.

Normal ocular versions are smooth, symmetric, full, and maintained

in all directions without nystagmus. Saccades, or quick refixation eye

movements, are assessed by having the patient look back and forth

between two stationary targets. The eyes should move rapidly and

accurately in a single jump to their target. Ocular alignment can be

judged by holding a penlight directly in front of the patient at about

1 m. If the eyes are straight, the corneal light reflex will be centered

in the middle of each pupil. To test eye alignment more precisely, the

cover test is useful. The patient is instructed to look at a small fixation

target in the distance. One eye is occluded with a paddle or hand, while

the other eye is observed. If the viewing eye shifts position to take up

fixation on the target, it was misaligned. If it remains motionless, the

first eye is uncovered and the test is repeated on the second eye. If

neither eye moves, the eyes are aligned orthotropically. If the eyes are

orthotropic in primary gaze but the patient complains of diplopia, the

cover test should be performed with the head tilted or turned in whatever direction elicits diplopia. With practice, the examiner can detect

an ocular deviation (heterotropia) as small as 1–2° with the cover test.

In a patient with vertical diplopia, a small deviation can be difficult to

detect and easy to dismiss. The magnitude of the deviation can be measured by placing a prism in front of the misaligned eye to determine the

power required to neutralize the fixation shift evoked by covering the

other eye. Temporary press-on plastic Fresnel prisms, prism eyeglasses,

or eye muscle surgery can be used to restore binocular alignment.

■ STEREOPSIS

Stereoacuity is determined by presenting targets with retinal disparity

separately to each eye by using polarized images. The most popular

office tests measure a range of thresholds from 800 to 40 s of arc. Normal stereoacuity is 40 s of arc. If a patient achieves this level of stereoacuity, one is assured that the eyes are aligned orthotropically and that

vision is intact in each eye. Random dot stereograms have no monocular depth cues and provide an excellent screening test for strabismus.

■ COLOR VISION

The retina contains three classes of cones, with visual pigments of

differing peak spectral sensitivity: red (560 nm), green (530 nm), and

blue (430 nm). The red and green cone pigments are encoded on the X

chromosome, and the blue cone pigment on chromosome 7. Mutations

of the blue cone pigment are exceedingly rare. Mutations of the red

and green pigments cause congenital X-linked color blindness in 8% of

males. Affected individuals are not truly color blind; rather, they differ

218 PART 2 Cardinal Manifestations and Presentation of Diseases

from normal subjects in the way they perceive color and how they

combine primary monochromatic lights to match a particular color.

Anomalous trichromats have three cone types, but a mutation in one

cone pigment (usually red or green) causes a shift in peak spectral sensitivity, altering the proportion of primary colors required to achieve a

color match. Dichromats have only two cone types and therefore will

accept a color match based on only two primary colors. Anomalous trichromats and dichromats have 6/6 (20/20) visual acuity, but their hue

discrimination is impaired. Ishihara color plates can be used to detect

red-green color blindness. The test plates contain a hidden number

that is visible only to subjects with color confusion from red-green

color blindness. Because color blindness is almost exclusively X-linked,

it is worthwhile screening only male children.

The Ishihara plates often are used to detect acquired defects in color

vision, although they are intended as a screening test for congenital

color blindness. Acquired defects in color vision frequently result

from disease of the macula or optic nerve. For example, patients with

a history of optic neuritis often complain of color desaturation long

after their visual acuity has returned to normal. Color blindness also

can result from bilateral strokes involving the ventral portion of the

occipital lobe (cerebral achromatopsia). Such patients can perceive

only shades of gray and also may have difficulty recognizing faces

(prosopagnosia) (Chap. 30). Infarcts of the dominant occipital lobe

sometimes give rise to color anomia. Affected patients can discriminate

colors but cannot name them.

■ VISUAL FIELDS

Vision can be impaired by damage to the visual system anywhere from

the eyes to the occipital lobes. One can localize the site of the lesion

with considerable accuracy by mapping the visual field deficit by finger

confrontation and then correlating it with the topographic anatomy of

the visual pathway (Fig. 32-3). Quantitative visual field mapping is performed by computer-driven perimeters that present a target of variable

intensity at fixed positions in the visual field (Fig. 32-3A). By generating an automated printout of light thresholds, these static perimeters

provide a sensitive means of detecting scotomas in the visual field.

They are exceedingly useful for serial assessment of visual function in

chronic diseases such as glaucoma and pseudotumor cerebri.

The crux of visual field analysis is to decide whether a lesion is

before, at, or behind the optic chiasm. If a scotoma is confined to one

eye, it must be due to a lesion anterior to the chiasm, involving either

the optic nerve or the retina. Retinal lesions produce scotomas that

correspond optically to their location in the fundus. For example, a

superior-nasal retinal detachment results in an inferior-temporal field

cut. Damage to the macula causes a central scotoma (Fig. 32-3B).

Optic nerve disease produces characteristic patterns of visual field

loss. Glaucoma selectively destroys axons that enter the superotemporal or inferotemporal poles of the optic disc, resulting in arcuate scotomas shaped like a Turkish scimitar, which emanate from the blind spot

and curve around fixation to end flat against the horizontal meridian

(Fig. 32-3C). This type of field defect mirrors the arrangement of the

nerve fiber layer in the temporal retina. Arcuate or nerve fiber layer

scotomas also result from optic neuritis, ischemic optic neuropathy,

optic disc drusen, and branch retinal artery or vein occlusion.

Damage to the entire upper or lower pole of the optic disc causes an

altitudinal field cut that follows the horizontal meridian (Fig. 32-3D).

This pattern of visual field loss is typical of ischemic optic neuropathy

but also results from retinal vascular occlusion, advanced glaucoma,

and optic neuritis.

About half the fibers in the optic nerve originate from ganglion cells

serving the macula. Damage to papillomacular fibers causes a cecocentral scotoma that encompasses the blind spot and macula (Fig. 32-3E).

If the damage is irreversible, pallor eventually appears in the temporal

portion of the optic disc. Temporal pallor from a cecocentral scotoma

may develop in optic neuritis, nutritional optic neuropathy, toxic optic

neuropathy, Leber’s hereditary optic neuropathy, Kjer’s dominant optic

atrophy, and compressive optic neuropathy. It is worth mentioning that

the temporal side of the optic disc is slightly paler than the nasal side

in most normal individuals. Therefore, it sometimes can be difficult

to decide whether the temporal pallor visible on fundus examination

represents a pathologic change. Pallor of the nasal rim of the optic disc

is a less equivocal sign of optic atrophy.

At the optic chiasm, fibers from nasal ganglion cells decussate into

the contralateral optic tract. Crossed fibers are damaged more by

compression than are uncrossed fibers. As a result, mass lesions of the

sellar region cause a temporal hemianopia in each eye. Tumors anterior to the optic chiasm, such as meningiomas of the tuberculum sella,

produce a junctional scotoma characterized by an optic neuropathy in

one eye and a superior-temporal field cut in the other eye (Fig. 32-3G).

More symmetric compression of the optic chiasm by a pituitary adenoma (see Fig. 380-1), meningioma, craniopharyngioma, glioma, or

aneurysm results in a bitemporal hemianopia (Fig. 32-3H). The insidious development of a bitemporal hemianopia often goes unnoticed by

the patient and will escape detection by the physician unless each eye

is tested separately.

It is difficult to localize a postchiasmal lesion accurately, because

injury anywhere in the optic tract, lateral geniculate body, optic radiations, or visual cortex can produce a homonymous hemianopia (i.e.,

a temporal hemifield defect in the contralateral eye and a matching

nasal hemifield defect in the ipsilateral eye) (Fig. 32-3I). A unilateral

postchiasmal lesion leaves the visual acuity in each eye unaffected,

although the patient may read the letters on only the left or right half

of the eye chart. Lesions of the optic radiations tend to cause poorly

matched or incongruous field defects in each eye. Damage to the optic

radiations in the temporal lobe (Meyer’s loop) produces a superior

quadrantic homonymous hemianopia (Fig. 32-3J), whereas injury to

the optic radiations in the parietal lobe results in an inferior quadrantic homonymous hemianopia (Fig. 32-3K). Lesions of the primary

visual cortex give rise to dense, congruous hemianopic field defects.

Occlusion of the posterior cerebral artery supplying the occipital lobe

is a common cause of total homonymous hemianopia. Some patients

have macular sparing, because the central field representation at the

tip of the occipital lobe is supplied by collaterals from the middle cerebral artery (Fig. 32-3L). Destruction of both occipital lobes produces

cortical blindness. This condition can be distinguished from bilateral

prechiasmal visual loss by noting that the pupil responses and optic

fundi remain normal.

Partial recovery of homonymous hemianopia has been reported

through computer-based rehabilitation therapy. During daily training sessions, patients fixate a central target while visual stimuli are

presented within the blind region. The premise of vision restoration

programs is that extra stimulation can promote recovery of partially

damaged tissue located at the fringe of a cortical lesion. When fixation

is controlled rigorously, however, no improvement of the visual fields

can be demonstrated. No effective treatment exists for homonymous

hemianopia caused by permanent brain damage.

DISORDERS

■ RED OR PAINFUL EYE

Corneal Abrasions Corneal abrasions are seen best by placing a

drop of fluorescein in the eye and looking with the slit lamp, using a

cobalt-blue light. A penlight with a blue filter will suffice if a slit lamp

is not available. Damage to the corneal epithelium is revealed by yellow

fluorescence of the basement membrane exposed by loss of the overlying epithelium. It is important to check for foreign bodies. To search

the conjunctival fornices, the lower lid should be pulled down and the

upper lid everted. A foreign body can be removed with a moistened

cotton-tipped applicator after a drop of a topical anesthetic such as

proparacaine has been placed in the eye. Alternatively, it may be possible to flush the foreign body from the eye by irrigating copiously with

saline or artificial tears. If the corneal epithelium has been abraded,

antibiotic ointment and a patch may be applied to the eye. A drop of an

intermediate-acting cycloplegic such as cyclopentolate hydrochloride

1% helps reduce pain by relaxing the ciliary body. The eye should be

reexamined the next day. Minor abrasions may not require patching,

antibiotics, or cycloplegia.