- Clinical Findings
- Etiology
- Pathology
- Epidemiology
- Management & Treatment
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- Clinical Case Studies
- Study Questions
A 57-year-old professor at a medical school experienced numerous episodes of a sudden loss of muscle tone and an irresistible urge to sleep in the middle of the afternoon. The diagnosis was narcolepsy, which
The correct answer is B. You answered A.
Narcolepsy with cataplexy is caused by the loss of a chemical in the brain called hypocretin. Hypocretin acts on the alerting systems in the brain, keeping us awake and regulating sleep wake cycles. In narcolepsy, the cluster of cells that produce hypocretin—located in a region called the hypothalamus—is damaged or completely destroyed. Without hypocretin, the person has trouble staying awake, and also experiences disruptions in the normal sleep-wake cycles.
Currently there is no cure for narcolepsy, but medications and behavioral treatments can improve symptoms for people so they can lead normal, productive lives.
Narcolepsy is diagnosed by a physical exam, taking a medical history, as well as conducting sleep studies. If you do have narcolepsy, the most effective treatment is often a combination of medications and behavioral changes. People who are diagnosed with narcolepsy should seek counseling through educational networks and support groups. Getting a diagnosis of narcolepsy and managing the symptoms can be overwhelming and the disorder is not well understood by the general public. It helps to learn best practices and access support through others who have the disorder.
Narcolepsy occurs equally in men and women and is thought to affect roughly 1 in 2,000 people.1
Complications of Injecting Drug Use
- Local problems—Abscess (Figures 240-2
and 240-3; Abscess), cellulitis, septic thrombophlebitis, local induration, necrotizing fasciitis, gas gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (e.g., broken needle parts) in local areas.2A 32-year-old woman with type 1 diabetes developed large abscesses all over her body secondary to injection of cocaine and heroin. Her back shows the large scars remaining after the healing of these abscesses. (Courtesy of Richard P. Usatine, MD.)
- IDUs are at higher risk of getting methicillin-resistant Staphylococcus aureus(MRSA) skin infections that the patient may think are spider bites (Figure 240-4).
- Some IDUs give up trying to inject into their veins and put the cocaine directly into the skin. This causes local skin necrosis that produces round atrophic scars (Figure 240-5).
- IDUs are at risk for contracting systemic infections, including HIV and hepatitis B or hepatitis C.
- Injecting drug users are at risk of endocarditis, osteomyelitis (Figures 240-6and 240-7), and an abscess of the epidural region. These infections can lead to long hospitalizations for intravenous antibiotics. The endocarditis that occurs in IDUs involves the right-sided heart valves (see Chapter 50, Bacterial Endocarditis).2 They are also at risk of septic emboli to the lungs, group A β-hemolytic streptococcal septicemia, septic arthritis, and candidal and other fungal infections.
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A 29-year-old woman presents following an automobile accident in which she fell asleep at the wheel. She notes that she frequently falls asleep during the day and feels rested after these episodes.
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What are the considerations in the differential diagnosis?
Sleep deprivation, primary hypersomnia, narcolepsy, sleep apnea, substance abuse or withdrawal, hypothyroidism, and anemia are considerations.
In addition, she states that sometimes she awakens but is utterly “unable to move a muscle.” She states she has always been able to fall asleep quickly. She denies any use of drugs or medications. You excuse yourself to answer a page and find her asleep when you return to your office. On awakening she is startled at first but then seems to regain her orientation and asks, “What is wrong with me?”
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What is the likely diagnosis and what would be the expected electroencephalographic findings?
This patient has narcolepsy . The electroencephalogram (EEG) in a sleep study would likely show a decreased REM latency, meaning she rapidly progresses into REM sleep. This accounts for the restfulness these patients feel upon falling asleep.
Note: Patients with primary hypersomnia have a completely normal sleep architecture.
3
Which treatment is available for patients with narcolepsy?
A regimen of a regular schedule of forced naps during the day can be a successful treatment for some patients. In severe cases of narcolepsy, amphetamines such as methylphenidate (Ritalin) are also used in the treatment of narcolepsy. These agents cause the release of norepinephrine, dopamine, and serotonin, but all have some abuse potential. A newer agent, modafinil, has been added that has lower abuse liability. Modafinil appears to selectively decrease somnolence in narcoleptic patients; however, the mechanism of action is unknown.
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What are the stages of sleep and what happens physiologically in these stages?
Sleep is divided into non-REM (NREM) and REM sleep. NREM sleep is divided into four stages, each being a deeper sleep. The stages are further described as fast wave or slow wave sleep. The earliest two stages are fast wave sleep and stages 3 and 4 are termed slow wave sleep based on the EEG appearance of brain waves. REM refers to rapid conjugate eye movement. As a person falls asleep, he passes through stages 1 to 4 and then enters REM sleep the first time, normally after approximately 90 minutes. The first REM episode lasts typically less than 10 minutes, and then the person cycles through the stages again, with further REM episodes of about 15 to 40 minutes each.
Physiologically, during NREM sleep, a person's pulse, respiration rate, and blood pressure are decreased and show less minute-to-minute variation. Resting muscle tone is relaxed somewhat, and there are episodic body movements during NREM sleep. Males do not experience erection, and blood flow, including cerebral circulation, is somewhat lower. By contrast, REM sleep is characterized by higher pulse rate, respiratory rate, and blood pressure; EEG patterns are similar to those of one who is awake. REM sleep is also termed paradoxical sleep because of its similarities on EEG to a person who is awake. Men will experience partial or full erection. Additionally, a person in REM sleep experiences near total skeletal muscle paralysis, and movement is quite rare. Abstract and surreal dreams occur during this phase of sleep. Most REM sleep occurs in the last one third of the night.
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In Table 24-1 , cover the columns to the right, and for each stage of sleep listed in the left column, name the EEG appearance and describe the frequency and voltage of the waves seen:
Table 24-1
Electroencephalographic (EEG) Characteristics of Sleep Stages
State EEG Appearance Frequency Voltage
Awake β waves Random fast waves Low
Eyes closed α waves 8-12 cycles/sec Low
Stage 1 θ waves 3-7 cycles/sec Low
Stage 2 Sleep spindles
K complexes 12-14 cycles/sec
Slow, triphasic waves Low
High
Stage 3 δ waves 0.5-2.5 cycles/sec High
Stage 4
REM sleep β waves Random fast waves Low
REM, rapid eye movement.
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How do nightmares differ from night terrors?
Nightmares occur almost exclusively in REM sleep. Patients who experience nightmares are able to recall the events of these frightening events, which usually involve threat to life, security, or self-esteem. Upon awakening, the person rapidly becomes oriented. Night terrors occur in deep NREM sleep (stages 3 and 4). Often, the person wakes with a panicky scream. These patients are often unresponsive upon awakening, have amnesia for the episode, and show signs of autonomic arousal, such as tachycardia, tachypnea, and diaphoresis. Night terrors can be treated with benzodiazepines.
7
An 82-year-old woman complains that her sleep patterns have changed as she has aged. What changes in sleep are typical as people age?
Though this is somewhat controversial, for the purpose of boards you should assume that as people age, they experience a decrease in the amount of time in slow wave sleep (stages 3 and 4) and REM sleep. This typically results in a reduced need for time spent sleeping. Insomnia is common in the elderly population.
8
This woman had been given a benzodiazepine to assist her sleep, which improved for a while, but now she complains of poor sleep once more. Why have her sleep problems returned?
She is experiencing tolerance to the effects of her medication. Benzodiazepines may be used for short-term management of insomnia, especially when there is an identifiable precipitant, but not for long-term management, because tolerance and dependence may result. Reevaluation should follow a 7- to 10-day trial of a benzodiazepine, and other agents should be considered.
9
How do benzodiazepines manifest their pharmacologic effect?
Benzodiazepines are agonists of γ-aminobutyric acid (GABA) receptors, which are bound to chloride channels. GABA is the primary inhibitory neurotransmitter in the central nervous system (CNS). This CNS inhibition leads to decreased alertness, drowsiness, and less agitation.
10
Why would this be another reason benzodiazepines should be avoided in the elderly population?
The aged population has a markedly increased (about 25%) incidence of falls when given these types of medications, due to drowsiness and impaired balance. This effect would be especially concerning in this elderly postmenopausal woman, who may have underlying osteopenia or frank osteoporosis. Additionally, the geriatric population is more sensitive to this effect and should be started on a lower dose initially.
11
There are now a number of drugs other than benzodiazopines that also act on the γ-aminobutyric acid benzodiazepine receptor and that reach hypnotic effects with less tolerance and less daytime sedation. What are some examples of these?
Zaleplon, zolpidem, and eszopiclone are examples of these drugs.
Note: Sedating antidepressants such as trazodone and nefazodone (remember the zzzzzzzz group) may also be used.
12
When evaluating a person for sleep problems, perhaps the first and most important step is to make sure that the patient has good sleep hygiene. What does good sleep hygiene entail?
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No alcohol
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No caffeine or nicotine
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Regular exercise (but not too late in the day)
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Relaxing activity before bed (e.g., bath, reading)
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Only sleep and sex in the bedroom (no TV)
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No clockwatching
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No daytime naps
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No late meals
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Narcolepsy: daytime sleepiness, sleep attacks, decreased rapid eye movement (REM) latency, rested after sleep
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Primary hypersomnia: excessive somnolence (>1 month), normal sleep architecture
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Treatment for narcolepsy and primary hypersomnia: methylphenidate or modafinil
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Insomnia: difficulty initiating or maintaining sleep
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Nonbenzodiazopines acting at the benzodiazepine γ-aminobutyric acid (GABA) receptor may be the best treatment for insomnia because they allow for hypnotic effects with less tolerance and less daytime sedation.
Summary box: sleep disturbance
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A 20-year-old man presents for evaluation of excessive daytime somnolence. He is finding it increasingly difficult to stay awake during his classes. Recently, his grades have fallen because whenever he tries to read he finds himself drifting off. He finds that his alertness is best after exercising or brief naps of 10–30 minutes. Because of this, he states that he takes 5 or 10 “catnaps” daily. The sleepiness persists despite averaging 9 hours of sleep nightly. In addition to excessive somnolence, he reports occasional hallucinations that occur as he is falling asleep. He describes these occurrences as a voice calling his name as he drifts off. Perhaps once weekly, he awakens from sleep but is unable to move for a period of about 30 seconds. He has never had apparent loss of consciousness but states that whenever he is laughing, he feels heaviness in his neck and arms. Once he had to lean against a wall to keep from falling down. He undergoes an overnight sleep study and multiple sleep latency test. There is no sleep apnea. His mean sleep latency on five naps is 2.3 minutes. In three of the five naps, rapid eye movement sleep is present. Which of the following findings in this patient is most specific for the diagnosis of narcolepsy?
The correct answer is A. You answered C.
The answer is A. (Chap. 38) Narcolepsy is a sleep disorder characterized by excessive sleepiness with intrusion of rapid eye movement (REM) sleep into wakefulness. Narcolepsy affects ~1 in 4000 individuals in the United States with a genetic predisposition. Recent research has demonstrated that narcolepsy with cataplexy is associated with low or undetectable levels of the neurotransmitter hypocretin (orexin) in the cerebrospinal fluid. This neurotransmitter is released from a small number of neurons in the hypothalamus. Given the association of narcolepsy with the major histocompatibility complex (MHC) antigen HLA DQB1*0602, it is thought that narcolepsy is an autoimmune process that leads to destruction of the hypocretin-secreting neurons in the hypothalamus. The classic symptom tetrad of narcolepsy is: (1) cataplexy; (2) hypnagogic or hypnopompic hallucinations; (3) sleep paralysis; and (4) excessive daytime somnolence. Of these symptoms, cataplexy is the most specific for the diagnosis of narcolepsy. Cataplexy refers to the sudden loss of muscle tone in response to strong emotions. It most commonly occurs with laughter or surprise but may be associated with anger as well. Cataplexy can have a wide range of symptoms, from mild sagging of the jaw lasting for a few seconds to a complete loss of muscle tone lasting several minutes. During this time, individuals are aware of their surroundings and are not unconscious. This symptom is present in 76% of individuals diagnosed with narcolepsy and is the most specific finding for the diagnosis. Hypnagogic and hypnopompic hallucinations and sleep paralysis can occur from any cause of chronic sleep deprivation, including sleep apnea and chronic insufficient sleep. Excessive daytime somnolence is present in 100% of individuals with narcolepsy but is not specific for the diagnosis because this symptom may be present with any sleep disorder as well as with chronic insufficient sleep. The presence of two or more REM periods occurring during a daytime multiple sleep latency test is suggestive but not diagnostic of narcolepsy. Other disorders that may lead to presence of REM during short daytime nap periods include sleep apnea, sleep phase delay syndrome, and insufficient sleep.
A 75-year-old triathlete complains of gradually worsening vision over the past year. It seems to be involving near and far vision. The patient has never required corrective lenses and has no significant medical history other than diet-controlled hypertension. He takes no regular medications. Physical examination is normal except for bilateral visual acuity of 20/100. There are no focal visual field defects and no redness of the eyes or eyelids. Which of the following is the most likely diagnosis?
The correct answer is A. You answered A.
Age-related macular degeneration is a major cause of painless, gradual bilateral central visual loss. It occurs as nonexudative (dry) or exudative (wet) forms. Recent genetic data have shown an association with the alternative complement pathway gene for complement factor H. The mechanism link for that association is unknown. The nonexudative form is associated with retinal drusen that leads to retinal atrophy. Treatment with vitamin C, vitamin E, beta-carotene, and zinc may retard the visual loss. Exudative macular degeneration, which is less common, is caused by neovascular proliferation and leakage of choroidal blood vessels. Acute visual loss may occur because of bleeding. Exudative macular degeneration may be treated with intraocular injection of a vascular endothelial growth factor antagonist (bevacizumab or ranibizumab). Blepharitis is inflammation of the eyelids usually related to acne rosacea, seborrheic dermatitis, or staphylococcal infection. Diabetic retinopathy, now a leading cause of blindness in the United States, causes gradual bilateral visual loss in patients with long-standing diabetes. Retinal detachment is usually unilateral and causes visual loss and an afferent pupillary defect.
Mr. Jenson is a 40-year-old man with a congenital bicuspid aortic valve who you have been seeing for more than a decade. You obtain an echocardiogram every other year to follow the progression of his disease knowing that bicuspid valves often develop stenosis or regurgitation requiring replacement in middle age. Given his specific congenital abnormality, what other anatomic structure is important to follow on his biannual echocardiograms?
The correct answer is A. You answered A.
The answer is A. (Chap. 282) Bicuspid aortic valve is among the most common of congenital heart cardiac abnormalities. Valvular function is often normal in early life and thus may escape detection. Due to abnormal flow dynamics through the bicuspid aortic valve, the valve leaflets can become rigid and fibrosed, leading to either stenosis or regurgitation. However, pathology in patients with bicuspid aortic valve is not limited to the valve alone. The ascending aorta is often dilated, misnamed “poststenotic” dilatation; this is due to histologic abnormalities of the aortic media and may result in aortic dissection. It is important to screen specifically for aortopathy because dissection is a common cause of sudden death in these patients.