Contrary to the popular belief that epilepsy is mainly a disease of youth, nearly 25% of new-onset seizures occur after age 65.^1,2 The incidence of epilepsy in this age group is almost twice the rate in children, and in people over age 80, it is triple the rate in children.³ As our population ages, the burden of “elderly-onset” epilepsy will rise.

See related editorial

A seizure diagnosis carries significant implications in older people, who are already vulnerable to cognitive decline, loss of functional independence, driving restrictions, and risk of falls. Newly diagnosed epilepsy further worsens quality of life.⁴

The causes and clinical manifestations of seizures and epilepsy in the elderly differ from those in younger people.⁵ Hence, it is often difficult to make a diagnosis with certainty from a wide range of differential diagnoses. Older people are also more likely to have comorbidities, further complicating the situation.

Managing seizures in the elderly is also challenging, as age-associated physiologic changes can affect the pharmacokinetics and pharmacodynamics of antiepileptic drugs. Diagnosing and managing elderly-onset epilepsy can be challenging for a family physician, an internist, a geriatrician, or even a neurologist.

In this review, we emphasize the common causes of new-onset epilepsy in the elderly and the assessment of the clinical clues that are essential for making an accurate diagnosis. We also review the pharmacology of antiepileptic drugs used in old age and highlight the need for psychological support for patients and caregivers.

RISING PREVALENCE IN THE ELDERLY

In US Medicare beneficiaries age 65 and older, the average annual incidence rate of epilepsy in 2001 to 2005 was 10.8 per 1,000.⁶ A large study in Finland revealed falling incidence rates of epilepsy in childhood and middle age and rising trends in the elderly.⁷

In the United States, the rates are higher in African Americans (18.7 per 1,000) and lower in Asian Americans and Native Americans (5.5 and 7.7 per 1,000) than in whites (10.2 per 1,000).⁶ Incidence rates are slightly higher for women than for men and increase with age in both sexes and all racial groups.

Acute symptomatic seizure is also common in older patients. The incidence of acute seizures in patients over age 60 was estimated at 50 to 100 per 100,000 per year in one study.⁷ The rate was considerably higher in men than in women. The study also found a 3.6% risk of experiencing an acute symptomatic seizure in an 80-year lifespan, which approaches that of developing epilepsy.⁸ The major causes of acute symptomatic seizure were traumatic brain injury, cerebrovascular disease, drug withdrawal, and central nervous system infection.

CAUSES OF NEW-ONSET EPILEPSY IN THE ELDERLY

The most common causes of new-onset epilepsy in the elderly include cerebrovascular disease, metabolic disturbances, dementia, traumatic brain injury, tumors, and drugs.^3,9–11

Cerebrovascular disease

In older adults, acute stroke is the most common cause, accounting for up to half of cases.^5,12

Seizures occur in 4.4% to 8.9% of acute cerebrovascular events.^13,14 The risk varies by stroke subtype, although all stroke subtypes, including transient ischemic attack, can be associated with seizure.¹⁵ For example, although 1% to 2% of patients experienced a seizure within 15 days of a transient ischemic attack or a lacunar infarct, this risk was 16.6% after an embolic stroke.¹⁵

Beyond this increased risk of “acute seizure” in the immediate poststroke period (usually defined as 1 week), the risk of epilepsy was also 20 times higher in the first year after a stroke.¹⁴ However, seizures tend to occur within the first 48 hours after the onset of ischemic stroke. In subarachnoid hemorrhage, seizures generally occur within hours.¹⁶

In a population-based study in Rochester, NY,¹⁷ epilepsy developed in two-thirds of patients with seizure related to acute stroke. Two factors that independently predicted the development of epilepsy were early seizure occurrence and recurrence of stroke.

Interestingly, the risk of stroke was three times higher in older patients who had new-onset seizure.¹⁸ Therefore, any elderly person with new-onset seizure should be assessed for cerebrovascular risk factors and treated accordingly for stroke prevention.

Metabolic disturbances

Acute metabolic disorders are common in elderly patients because of multiple comorbidities and polypharmacy. Hypoglycemia and hyponatremia need to be particularly considered in this population.¹⁹

Other well-documented metabolic causes of acute seizure, including nonketotic hyperglycemia, hypocalcemia, and uremic or hepatic encephalopathy, can all be considerations, albeit less specific to this age group.

Dementia

Primary neurodegenerative disorders associated with cognitive impairment, such as Alzheimer disease, are major risk factors for new-onset epilepsy in older patients.^3,5 Seizures occur in about 10% of Alzheimer patients.²⁰ Those who have brief periods of increased confusion may actually be experiencing unrecognized complex partial seizures.²¹

A case-control study discovered incidence rates of epilepsy almost 10 times higher in patients who had Alzheimer disease or vascular dementia than in nondemented patients.²² A prospective cohort study in patients with mild to moderate Alzheimer disease established that younger age, a greater degree of cognitive impairment, and a history of antipsychotic use were independent risk factors for new-onset seizures in the elderly.²³ Preexisting dementia also increases the risk of poststroke epilepsy.²⁴

Traumatic brain injury

The most common cause of brain trauma in the elderly is falls. Subdural hematoma, which can occur in the elderly with trivial trauma or sometimes even without it, needs to be considered. The risk of posttraumatic hemorrhage is especially relevant in patients taking anticoagulants.

Traumatic brain injury has a poorer prognosis in older people than in the young,²⁵ and it accounts for up to 20% of cases of epilepsy in the elderly.²⁶ Although no study has specifically addressed the longitudinal risk of epilepsy after traumatic brain injury in the elderly, a study in children and young adults revealed the risk was highest in the first year, with the increased risk persisting for more than 10 years.²⁷

Brain tumors

Between 10% and 30% of new-onset seizures in the elderly are associated with tumor, typically glioma, meningioma, and brain metastasis.^28,29 Seizures are usually associated more with primary than with secondary tumors, and more with low-grade tumors than high-grade ones.³⁰

Drug-induced

Drugs and drug withdrawal can contribute to up to 10% of acute symptomatic seizures in the geriatric population.^5,8,29 The elderly are susceptible to drug-induced seizure because of a higher prevalence of polypharmacy, impaired drug clearance, and heightened sensitivity to the proconvulsant side effects of medications.¹ A number of commonly used drugs have been implicated,³¹ including:

Antibiotics such as carbapenems and high-dose penicillin

Antihistamines such as desloratadine (Clarinex)

Pain medications such as tramadol (Ul-tram) and high-dose opiates

Neuromodulators

Antidepressants such as clomipramine (Anafranil), maprotiline (Ludiomil), amoxapine (Asendin), and bupropion (Wellbutrin).³²

Seizures also follow alcohol, benzodiazepine, and barbiturate withdrawal.³³

Other causes

Paraneoplastic limbic encephalitis is a rare cause of seizures in the elderly.³⁴ It can present with refractory seizures, confusion, and behavioral changes with or without a known concurrent neoplastic disease.

Posterior reversible leukoencephalopathy syndrome, another rare consideration, can particularly affect immunosuppressed elderly patients. This syndrome is characterized clinically by headache, confusion, seizures, vomiting, and visual disturbances with radiographic vasogenic edema.³⁵

CLINICAL PRESENTATION

The signs and symptoms of a seizure may be atypical in the elderly. Seizures more often have a picture of “epileptic amnesia,” with confusion, sleepiness, or clumsiness, rather than motor manifestations such as tonic stiffening or automatism.^36,37 Postictal states are also prolonged, particularly if there is underlying brain dysfunction.³⁸ All these features render the clinical seizure manifestations more subtle and, as such, more difficult for the uninitiated caregiver to identify.

Convulsive and nonconvulsive status epilepticus

Status epilepticus is defined as a single generalized seizure lasting more than 5 minutes or a series of seizures lasting longer than 30 minutes without the patient’s regaining consciousness.³⁹ The greatest increase in the incidence of status epilepticus occurs after age 60.⁴⁰ It is the first seizure in about 30% of new-onset seizures in the elderly.⁴¹

Mortality rates increase with age, anoxia, and duration of status epilepticus and are over 50% in patients age 80 and older.^40,42

Convulsive status epilepticus is most commonly caused by stroke.⁴⁰

Absence status epilepticus can occur in elderly patients as a late complication of idiopathic generalized epilepsy related to benzodiazepine withdrawal, alcohol intoxication, or initiation of psychotropic drugs.⁴²

Nonconvulsive status epilepticus manifests as altered mental status, psychosis, lethargy, or coma.^42–44 Occasionally, it presents as a more focal cognitive disturbance with aphasia or a neglect syndrome.^42,45 Electroencephalographic correlates of nonconvulsive status epilepticus include focal rhythmic discharges, often arising from frontal or temporal lobes, or generalized spike or sharp and slow-wave activity.⁴⁶ Its management is challenging because of delayed diagnosis or misdiagnosis. The risk of death is higher in patients with severely impaired mental status or acute complications.⁴⁷

Table 1 lists the typical seizure manifestations peculiar to the elderly.^37,48

Differential diagnosis of new-onset epilepsy in the elderly

New-onset epilepsy in elderly patients can be confused with syncope, transient ischemic attack, cardiac arrhythmia, metabolic disturbances, transient global amnesia, neurodegenerative disease, rapid-eye-movement sleep behavior disorder, psychogenic disorders, and other conditions (Table 2). If there is a high clinical suspicion of seizure, the patient should undergo electroencephalography (EEG) and be referred to a neurologist or epileptologist.

KEYS TO THE DIAGNOSIS

Clinical history

A reliable history and description of the event from an eyewitness or a video recording of the event are invaluable to the diagnosis of epileptic seizure. Signs and symptoms that suggest the diagnosis include aura, ictal pallor, urinary incontinence, tongue-biting, and motor symptoms, as well as postictal confusion, drowsiness, and speech disturbance.

Electroencephalography

EEG is the most useful diagnostic tool in epilepsy. However, an interictal EEG reading (ie, between epileptic attacks) in an elderly patient has limited utility, showing epileptiform activity in only about one-fourth of patients.⁴⁹ Nonspecific EEG abnormalities such as intermittent focal slowing are seen in many older people even without seizure.⁵⁰ Also, normal findings on outpatient EEG do not rule out epilepsy, as EEG is normal in about one-third of patients with epilepsy, irrespective of age.^1,49 Activation procedures such as hyperventilation and photic stimulation add little to the diagnosis in the elderly.⁴⁹

On the other hand, video-EEG monitoring is an excellent tool for evaluating possible epilepsy, as it allows accurate assessment of brain electrical activity during the events in question. Moreover, studies of video-EEG recording of seizures in elderly patients demonstrated epileptiform discharges on EEG in 76% of clinical ictal events.⁵⁰

Therefore, routine EEG is a useful screening tool, and inpatient video-EEG monitoring is the gold standard to characterize events of concern and distinguish between epileptic and nonepileptic or psychogenic seizures.

Other diagnostic studies

Brain imaging, preferably magnetic resonance imaging with contrast, should be done in every patient with possible epilepsy due to stroke, traumatic brain injury, or other structural brain disease.⁵¹

Electrocardiography helps exclude cardiac causes such as arrhythmia.

Blood testing. Metabolically provoked seizure can be distinguished by blood analysis for electrolytes, blood urea nitrogen, creatinine, glucose, calcium, magnesium, liver enzymes, and drug levels (eg, ethanol). A complete blood cell count with differential and platelets should also be done in anticipation of starting antiepileptic drug therapy.

Lumbar puncture for cell count, protein, glucose, stains, and cultures should be performed whenever meningitis or encephalitis is suspected.

A sleep study with concurrent video-EEG monitoring may be required to distinguish epileptic seizures from sleep disorders.

Neuropsychological testing may help account for the degree of cognitive impairment present.

Risk factors for stroke should be assessed in every elderly person who has new-onset seizures, because the risk of stroke is high.¹⁷

Figure 1 shows the workup for an elderly patient with suspected new-onset epilepsy.

TREATING EPILEPSY IN THE ELDERLY

Therapeutic challenges

Age-associated changes in drug absorption, protein binding, and distribution in body compartments require adjustments in drug selection and dosage. The causes and manifestations of these changes are typically multifactorial, mainly related to altered metabolism, declining plasma albumin concentrations, and increasing competition for protein binding by concomitantly used drugs.

The differences in the pharmacokinetics and pharmacodynamics of antiepileptic drugs depend on the patient’s physical status, relevant comorbidities, and concomitant medications.⁵² Renal and hepatic function may decline in an elderly patient; accordingly, precaution is needed in the prescribing and dosing of antiepileptic drugs.

Adverse effects from seizure medications are twice as common in elderly patients compared with younger patients. Ataxia, tremor, visual disturbance, and sedation are the most common.¹ Antiepileptic drugs are also harmful to bone; induced abnormalities in bone metabolism include hypocalcemia, hypophosphatemia, decreased levels of active vitamin D metabolites, and hyperparathyroidism.⁵³

Elderly patients tend to take multiple drugs, and some drugs can lower the seizure threshold, particularly antidepressants, anti-psychotics, and antibiotics.³² The herbal remedy ginkgo biloba can also precipitate seizure in this population.⁵⁴

Antiepileptic drugs such as phenobarbital, primidone (Mysoline), phenytoin (Dilantin), and carbamazepine (Tegretol) can be broad-spectrum enzyme-inducers, increasing the metabolism of many drugs, including warfarin (Coumadin), cytotoxic agents, statins, cardiac antiarrhythmics, antihypertensives, corticosteroids, and other immunosuppressants.⁵⁵ For example, carbamazepine can alter the metabolism of several hepatically metabolized drugs and cause significant hyponatremia. This is problematic in patients already taking sodium-depleting antihypertensives. Age-related cognitive decline can worsen the situation, often leading to misdiagnosis or patient noncompliance.

Table 3 profiles the interactions of commonly used antiepileptic drugs.

The ideal pharmacotherapy

No single drug is ideal for elderly patients with new-onset epilepsy. The choice mostly depends on the type of seizure and the patient’s comorbidities. The ideal antiepileptic drug would have minimal enzyme interaction, little protein binding, linear kinetics, a long half-life, a good safety profile, and a high therapeutic index. The goal of management should be to maintain the patient’s normal lifestyle with complete control of seizures and with minimal side effects.

The only randomized controlled trial in new-onset geriatric epilepsy concluded that gabapentin (Neurontin) and lamotrigine (Lamictal) should be the initial therapy in such patients.⁵⁶ Trials indicate extended-release carbamazepine or levetiracetam (Keppra) can also be tried.⁵⁷

The prescribing strategy includes lower initial dose, slower titration, and a lower target dose than for younger patients. Intense monitoring of dosing and drug levels is necessary to avoid toxicity. If the first drug is not tolerated well, another should be substituted. If seizures persist despite increasing dosage, a drug with a different mechanism of action should be tried.⁵⁸ A patient with drug-resistant epilepsy (failure to respond to two adequate and appropriate antiepileptic drug trials⁵⁹) should be referred to an epilepsy surgical center for reevaluation and consideration of epilepsy surgery.

Patient and caregiver support is an essential component of management. New-onset epilepsy in the elderly has a significant effect on quality of life, more so if the patient is already cognitively impaired. It erodes self-confidence, survival becomes difficult, and the condition is worse for patients who live alone. Driving restrictions further limit independence and increase isolation. Hence, psychological support programs can significantly boost the self-esteem and morale of such patients and their caregivers.

SPECIAL CONSIDERATION: EPILEPSY IN THE NURSING HOME

Certain points apply to the growing proportion of elderly who reside in nursing homes:

• Several studies in the United States and in Europe^60–62 suggest that this subgroup is at higher risk of polypharmacy and more likely to be treated with older antiepileptic drugs.
• Only a minority of these patients (as low as 42% in one study⁶⁰) received adequate monitoring of antiepileptic drug levels.
• The clinical characteristics and epileptic etiologies of these patients are less well defined.

Together, these observations highlight a particularly vulnerable population, at risk for medication toxicity as well as for undertreatment.

OUR KNOWLEDGE IS STILL GROWING

New-onset epilepsy, although common in the elderly, is difficult to diagnose because of its atypical presentation, concomitant cognitive impairment, and nonspecific abnormalities in routine investigations. But knowledge of its common causes and differential diagnoses makes the task easier. A high suspicion warrants referral to a neurologist or epileptologist.

Challenges to the management of seizures in the elderly include deranged physiologic processes, multiple comorbidities, and polypharmacy. No single drug is ideal for antiepileptic therapy in the elderly; the choice of drug is usually dictated by seizure type, comorbidities, and tolerance level. The treatment regimen in the elderly is more conservative, and the target dosage is lower than for younger adults. Emotional support of patient and caregivers should be an important aspect of management.

Our knowledge about new-onset epilepsy in the elderly is still growing, and future research should explore its diagnosis, treatment strategies, and care-delivery models.

Contrary to the popular belief that epilepsy is mainly a disease of youth, nearly 25% of new-onset seizures occur after age 65.^1,2 The incidence of epilepsy in this age group is almost twice the rate in children, and in people over age 80, it is triple the rate in children.³ As our population ages, the burden of “elderly-onset” epilepsy will rise.

See related editorial

A seizure diagnosis carries significant implications in older people, who are already vulnerable to cognitive decline, loss of functional independence, driving restrictions, and risk of falls. Newly diagnosed epilepsy further worsens quality of life.⁴

The causes and clinical manifestations of seizures and epilepsy in the elderly differ from those in younger people.⁵ Hence, it is often difficult to make a diagnosis with certainty from a wide range of differential diagnoses. Older people are also more likely to have comorbidities, further complicating the situation.

Managing seizures in the elderly is also challenging, as age-associated physiologic changes can affect the pharmacokinetics and pharmacodynamics of antiepileptic drugs. Diagnosing and managing elderly-onset epilepsy can be challenging for a family physician, an internist, a geriatrician, or even a neurologist.

In this review, we emphasize the common causes of new-onset epilepsy in the elderly and the assessment of the clinical clues that are essential for making an accurate diagnosis. We also review the pharmacology of antiepileptic drugs used in old age and highlight the need for psychological support for patients and caregivers.

RISING PREVALENCE IN THE ELDERLY

In US Medicare beneficiaries age 65 and older, the average annual incidence rate of epilepsy in 2001 to 2005 was 10.8 per 1,000.⁶ A large study in Finland revealed falling incidence rates of epilepsy in childhood and middle age and rising trends in the elderly.⁷

In the United States, the rates are higher in African Americans (18.7 per 1,000) and lower in Asian Americans and Native Americans (5.5 and 7.7 per 1,000) than in whites (10.2 per 1,000).⁶ Incidence rates are slightly higher for women than for men and increase with age in both sexes and all racial groups.

Acute symptomatic seizure is also common in older patients. The incidence of acute seizures in patients over age 60 was estimated at 50 to 100 per 100,000 per year in one study.⁷ The rate was considerably higher in men than in women. The study also found a 3.6% risk of experiencing an acute symptomatic seizure in an 80-year lifespan, which approaches that of developing epilepsy.⁸ The major causes of acute symptomatic seizure were traumatic brain injury, cerebrovascular disease, drug withdrawal, and central nervous system infection.

CAUSES OF NEW-ONSET EPILEPSY IN THE ELDERLY

The most common causes of new-onset epilepsy in the elderly include cerebrovascular disease, metabolic disturbances, dementia, traumatic brain injury, tumors, and drugs.^3,9–11

Cerebrovascular disease

In older adults, acute stroke is the most common cause, accounting for up to half of cases.^5,12

Seizures occur in 4.4% to 8.9% of acute cerebrovascular events.^13,14 The risk varies by stroke subtype, although all stroke subtypes, including transient ischemic attack, can be associated with seizure.¹⁵ For example, although 1% to 2% of patients experienced a seizure within 15 days of a transient ischemic attack or a lacunar infarct, this risk was 16.6% after an embolic stroke.¹⁵

Beyond this increased risk of “acute seizure” in the immediate poststroke period (usually defined as 1 week), the risk of epilepsy was also 20 times higher in the first year after a stroke.¹⁴ However, seizures tend to occur within the first 48 hours after the onset of ischemic stroke. In subarachnoid hemorrhage, seizures generally occur within hours.¹⁶

In a population-based study in Rochester, NY,¹⁷ epilepsy developed in two-thirds of patients with seizure related to acute stroke. Two factors that independently predicted the development of epilepsy were early seizure occurrence and recurrence of stroke.

Interestingly, the risk of stroke was three times higher in older patients who had new-onset seizure.¹⁸ Therefore, any elderly person with new-onset seizure should be assessed for cerebrovascular risk factors and treated accordingly for stroke prevention.

Metabolic disturbances

Acute metabolic disorders are common in elderly patients because of multiple comorbidities and polypharmacy. Hypoglycemia and hyponatremia need to be particularly considered in this population.¹⁹

Other well-documented metabolic causes of acute seizure, including nonketotic hyperglycemia, hypocalcemia, and uremic or hepatic encephalopathy, can all be considerations, albeit less specific to this age group.

Dementia

Primary neurodegenerative disorders associated with cognitive impairment, such as Alzheimer disease, are major risk factors for new-onset epilepsy in older patients.^3,5 Seizures occur in about 10% of Alzheimer patients.²⁰ Those who have brief periods of increased confusion may actually be experiencing unrecognized complex partial seizures.²¹

A case-control study discovered incidence rates of epilepsy almost 10 times higher in patients who had Alzheimer disease or vascular dementia than in nondemented patients.²² A prospective cohort study in patients with mild to moderate Alzheimer disease established that younger age, a greater degree of cognitive impairment, and a history of antipsychotic use were independent risk factors for new-onset seizures in the elderly.²³ Preexisting dementia also increases the risk of poststroke epilepsy.²⁴

Traumatic brain injury

The most common cause of brain trauma in the elderly is falls. Subdural hematoma, which can occur in the elderly with trivial trauma or sometimes even without it, needs to be considered. The risk of posttraumatic hemorrhage is especially relevant in patients taking anticoagulants.

Traumatic brain injury has a poorer prognosis in older people than in the young,²⁵ and it accounts for up to 20% of cases of epilepsy in the elderly.²⁶ Although no study has specifically addressed the longitudinal risk of epilepsy after traumatic brain injury in the elderly, a study in children and young adults revealed the risk was highest in the first year, with the increased risk persisting for more than 10 years.²⁷

Brain tumors

Between 10% and 30% of new-onset seizures in the elderly are associated with tumor, typically glioma, meningioma, and brain metastasis.^28,29 Seizures are usually associated more with primary than with secondary tumors, and more with low-grade tumors than high-grade ones.³⁰

Drug-induced

Drugs and drug withdrawal can contribute to up to 10% of acute symptomatic seizures in the geriatric population.^5,8,29 The elderly are susceptible to drug-induced seizure because of a higher prevalence of polypharmacy, impaired drug clearance, and heightened sensitivity to the proconvulsant side effects of medications.¹ A number of commonly used drugs have been implicated,³¹ including:

Antibiotics such as carbapenems and high-dose penicillin

Antihistamines such as desloratadine (Clarinex)

Pain medications such as tramadol (Ul-tram) and high-dose opiates

Neuromodulators

Antidepressants such as clomipramine (Anafranil), maprotiline (Ludiomil), amoxapine (Asendin), and bupropion (Wellbutrin).³²

Seizures also follow alcohol, benzodiazepine, and barbiturate withdrawal.³³

Other causes

Paraneoplastic limbic encephalitis is a rare cause of seizures in the elderly.³⁴ It can present with refractory seizures, confusion, and behavioral changes with or without a known concurrent neoplastic disease.

Posterior reversible leukoencephalopathy syndrome, another rare consideration, can particularly affect immunosuppressed elderly patients. This syndrome is characterized clinically by headache, confusion, seizures, vomiting, and visual disturbances with radiographic vasogenic edema.³⁵

CLINICAL PRESENTATION

The signs and symptoms of a seizure may be atypical in the elderly. Seizures more often have a picture of “epileptic amnesia,” with confusion, sleepiness, or clumsiness, rather than motor manifestations such as tonic stiffening or automatism.^36,37 Postictal states are also prolonged, particularly if there is underlying brain dysfunction.³⁸ All these features render the clinical seizure manifestations more subtle and, as such, more difficult for the uninitiated caregiver to identify.

Convulsive and nonconvulsive status epilepticus

Status epilepticus is defined as a single generalized seizure lasting more than 5 minutes or a series of seizures lasting longer than 30 minutes without the patient’s regaining consciousness.³⁹ The greatest increase in the incidence of status epilepticus occurs after age 60.⁴⁰ It is the first seizure in about 30% of new-onset seizures in the elderly.⁴¹

Mortality rates increase with age, anoxia, and duration of status epilepticus and are over 50% in patients age 80 and older.^40,42

Convulsive status epilepticus is most commonly caused by stroke.⁴⁰

Absence status epilepticus can occur in elderly patients as a late complication of idiopathic generalized epilepsy related to benzodiazepine withdrawal, alcohol intoxication, or initiation of psychotropic drugs.⁴²

Nonconvulsive status epilepticus manifests as altered mental status, psychosis, lethargy, or coma.^42–44 Occasionally, it presents as a more focal cognitive disturbance with aphasia or a neglect syndrome.^42,45 Electroencephalographic correlates of nonconvulsive status epilepticus include focal rhythmic discharges, often arising from frontal or temporal lobes, or generalized spike or sharp and slow-wave activity.⁴⁶ Its management is challenging because of delayed diagnosis or misdiagnosis. The risk of death is higher in patients with severely impaired mental status or acute complications.⁴⁷

Table 1 lists the typical seizure manifestations peculiar to the elderly.^37,48

Differential diagnosis of new-onset epilepsy in the elderly

New-onset epilepsy in elderly patients can be confused with syncope, transient ischemic attack, cardiac arrhythmia, metabolic disturbances, transient global amnesia, neurodegenerative disease, rapid-eye-movement sleep behavior disorder, psychogenic disorders, and other conditions (Table 2). If there is a high clinical suspicion of seizure, the patient should undergo electroencephalography (EEG) and be referred to a neurologist or epileptologist.

KEYS TO THE DIAGNOSIS

Clinical history

A reliable history and description of the event from an eyewitness or a video recording of the event are invaluable to the diagnosis of epileptic seizure. Signs and symptoms that suggest the diagnosis include aura, ictal pallor, urinary incontinence, tongue-biting, and motor symptoms, as well as postictal confusion, drowsiness, and speech disturbance.

Electroencephalography

EEG is the most useful diagnostic tool in epilepsy. However, an interictal EEG reading (ie, between epileptic attacks) in an elderly patient has limited utility, showing epileptiform activity in only about one-fourth of patients.⁴⁹ Nonspecific EEG abnormalities such as intermittent focal slowing are seen in many older people even without seizure.⁵⁰ Also, normal findings on outpatient EEG do not rule out epilepsy, as EEG is normal in about one-third of patients with epilepsy, irrespective of age.^1,49 Activation procedures such as hyperventilation and photic stimulation add little to the diagnosis in the elderly.⁴⁹

On the other hand, video-EEG monitoring is an excellent tool for evaluating possible epilepsy, as it allows accurate assessment of brain electrical activity during the events in question. Moreover, studies of video-EEG recording of seizures in elderly patients demonstrated epileptiform discharges on EEG in 76% of clinical ictal events.⁵⁰

Therefore, routine EEG is a useful screening tool, and inpatient video-EEG monitoring is the gold standard to characterize events of concern and distinguish between epileptic and nonepileptic or psychogenic seizures.

Other diagnostic studies

Brain imaging, preferably magnetic resonance imaging with contrast, should be done in every patient with possible epilepsy due to stroke, traumatic brain injury, or other structural brain disease.⁵¹

Electrocardiography helps exclude cardiac causes such as arrhythmia.

Blood testing. Metabolically provoked seizure can be distinguished by blood analysis for electrolytes, blood urea nitrogen, creatinine, glucose, calcium, magnesium, liver enzymes, and drug levels (eg, ethanol). A complete blood cell count with differential and platelets should also be done in anticipation of starting antiepileptic drug therapy.

Lumbar puncture for cell count, protein, glucose, stains, and cultures should be performed whenever meningitis or encephalitis is suspected.

A sleep study with concurrent video-EEG monitoring may be required to distinguish epileptic seizures from sleep disorders.

Neuropsychological testing may help account for the degree of cognitive impairment present.

Risk factors for stroke should be assessed in every elderly person who has new-onset seizures, because the risk of stroke is high.¹⁷

Figure 1 shows the workup for an elderly patient with suspected new-onset epilepsy.

TREATING EPILEPSY IN THE ELDERLY

Therapeutic challenges

Age-associated changes in drug absorption, protein binding, and distribution in body compartments require adjustments in drug selection and dosage. The causes and manifestations of these changes are typically multifactorial, mainly related to altered metabolism, declining plasma albumin concentrations, and increasing competition for protein binding by concomitantly used drugs.

The differences in the pharmacokinetics and pharmacodynamics of antiepileptic drugs depend on the patient’s physical status, relevant comorbidities, and concomitant medications.⁵² Renal and hepatic function may decline in an elderly patient; accordingly, precaution is needed in the prescribing and dosing of antiepileptic drugs.

Adverse effects from seizure medications are twice as common in elderly patients compared with younger patients. Ataxia, tremor, visual disturbance, and sedation are the most common.¹ Antiepileptic drugs are also harmful to bone; induced abnormalities in bone metabolism include hypocalcemia, hypophosphatemia, decreased levels of active vitamin D metabolites, and hyperparathyroidism.⁵³

Elderly patients tend to take multiple drugs, and some drugs can lower the seizure threshold, particularly antidepressants, anti-psychotics, and antibiotics.³² The herbal remedy ginkgo biloba can also precipitate seizure in this population.⁵⁴

Antiepileptic drugs such as phenobarbital, primidone (Mysoline), phenytoin (Dilantin), and carbamazepine (Tegretol) can be broad-spectrum enzyme-inducers, increasing the metabolism of many drugs, including warfarin (Coumadin), cytotoxic agents, statins, cardiac antiarrhythmics, antihypertensives, corticosteroids, and other immunosuppressants.⁵⁵ For example, carbamazepine can alter the metabolism of several hepatically metabolized drugs and cause significant hyponatremia. This is problematic in patients already taking sodium-depleting antihypertensives. Age-related cognitive decline can worsen the situation, often leading to misdiagnosis or patient noncompliance.

Table 3 profiles the interactions of commonly used antiepileptic drugs.

The ideal pharmacotherapy

No single drug is ideal for elderly patients with new-onset epilepsy. The choice mostly depends on the type of seizure and the patient’s comorbidities. The ideal antiepileptic drug would have minimal enzyme interaction, little protein binding, linear kinetics, a long half-life, a good safety profile, and a high therapeutic index. The goal of management should be to maintain the patient’s normal lifestyle with complete control of seizures and with minimal side effects.

The only randomized controlled trial in new-onset geriatric epilepsy concluded that gabapentin (Neurontin) and lamotrigine (Lamictal) should be the initial therapy in such patients.⁵⁶ Trials indicate extended-release carbamazepine or levetiracetam (Keppra) can also be tried.⁵⁷

The prescribing strategy includes lower initial dose, slower titration, and a lower target dose than for younger patients. Intense monitoring of dosing and drug levels is necessary to avoid toxicity. If the first drug is not tolerated well, another should be substituted. If seizures persist despite increasing dosage, a drug with a different mechanism of action should be tried.⁵⁸ A patient with drug-resistant epilepsy (failure to respond to two adequate and appropriate antiepileptic drug trials⁵⁹) should be referred to an epilepsy surgical center for reevaluation and consideration of epilepsy surgery.

Patient and caregiver support is an essential component of management. New-onset epilepsy in the elderly has a significant effect on quality of life, more so if the patient is already cognitively impaired. It erodes self-confidence, survival becomes difficult, and the condition is worse for patients who live alone. Driving restrictions further limit independence and increase isolation. Hence, psychological support programs can significantly boost the self-esteem and morale of such patients and their caregivers.

SPECIAL CONSIDERATION: EPILEPSY IN THE NURSING HOME

Certain points apply to the growing proportion of elderly who reside in nursing homes:

• Several studies in the United States and in Europe^60–62 suggest that this subgroup is at higher risk of polypharmacy and more likely to be treated with older antiepileptic drugs.
• Only a minority of these patients (as low as 42% in one study⁶⁰) received adequate monitoring of antiepileptic drug levels.
• The clinical characteristics and epileptic etiologies of these patients are less well defined.

Together, these observations highlight a particularly vulnerable population, at risk for medication toxicity as well as for undertreatment.

OUR KNOWLEDGE IS STILL GROWING

New-onset epilepsy, although common in the elderly, is difficult to diagnose because of its atypical presentation, concomitant cognitive impairment, and nonspecific abnormalities in routine investigations. But knowledge of its common causes and differential diagnoses makes the task easier. A high suspicion warrants referral to a neurologist or epileptologist.

Challenges to the management of seizures in the elderly include deranged physiologic processes, multiple comorbidities, and polypharmacy. No single drug is ideal for antiepileptic therapy in the elderly; the choice of drug is usually dictated by seizure type, comorbidities, and tolerance level. The treatment regimen in the elderly is more conservative, and the target dosage is lower than for younger adults. Emotional support of patient and caregivers should be an important aspect of management.

Our knowledge about new-onset epilepsy in the elderly is still growing, and future research should explore its diagnosis, treatment strategies, and care-delivery models.

Contrary to the popular belief that epilepsy is mainly a disease of youth, nearly 25% of new-onset seizures occur after age 65.^1,2 The incidence of epilepsy in this age group is almost twice the rate in children, and in people over age 80, it is triple the rate in children.³ As our population ages, the burden of “elderly-onset” epilepsy will rise.

See related editorial

A seizure diagnosis carries significant implications in older people, who are already vulnerable to cognitive decline, loss of functional independence, driving restrictions, and risk of falls. Newly diagnosed epilepsy further worsens quality of life.⁴

The causes and clinical manifestations of seizures and epilepsy in the elderly differ from those in younger people.⁵ Hence, it is often difficult to make a diagnosis with certainty from a wide range of differential diagnoses. Older people are also more likely to have comorbidities, further complicating the situation.

Managing seizures in the elderly is also challenging, as age-associated physiologic changes can affect the pharmacokinetics and pharmacodynamics of antiepileptic drugs. Diagnosing and managing elderly-onset epilepsy can be challenging for a family physician, an internist, a geriatrician, or even a neurologist.

In this review, we emphasize the common causes of new-onset epilepsy in the elderly and the assessment of the clinical clues that are essential for making an accurate diagnosis. We also review the pharmacology of antiepileptic drugs used in old age and highlight the need for psychological support for patients and caregivers.

RISING PREVALENCE IN THE ELDERLY

In US Medicare beneficiaries age 65 and older, the average annual incidence rate of epilepsy in 2001 to 2005 was 10.8 per 1,000.⁶ A large study in Finland revealed falling incidence rates of epilepsy in childhood and middle age and rising trends in the elderly.⁷

In the United States, the rates are higher in African Americans (18.7 per 1,000) and lower in Asian Americans and Native Americans (5.5 and 7.7 per 1,000) than in whites (10.2 per 1,000).⁶ Incidence rates are slightly higher for women than for men and increase with age in both sexes and all racial groups.

Acute symptomatic seizure is also common in older patients. The incidence of acute seizures in patients over age 60 was estimated at 50 to 100 per 100,000 per year in one study.⁷ The rate was considerably higher in men than in women. The study also found a 3.6% risk of experiencing an acute symptomatic seizure in an 80-year lifespan, which approaches that of developing epilepsy.⁸ The major causes of acute symptomatic seizure were traumatic brain injury, cerebrovascular disease, drug withdrawal, and central nervous system infection.

CAUSES OF NEW-ONSET EPILEPSY IN THE ELDERLY

The most common causes of new-onset epilepsy in the elderly include cerebrovascular disease, metabolic disturbances, dementia, traumatic brain injury, tumors, and drugs.^3,9–11

Cerebrovascular disease

In older adults, acute stroke is the most common cause, accounting for up to half of cases.^5,12

Seizures occur in 4.4% to 8.9% of acute cerebrovascular events.^13,14 The risk varies by stroke subtype, although all stroke subtypes, including transient ischemic attack, can be associated with seizure.¹⁵ For example, although 1% to 2% of patients experienced a seizure within 15 days of a transient ischemic attack or a lacunar infarct, this risk was 16.6% after an embolic stroke.¹⁵

Beyond this increased risk of “acute seizure” in the immediate poststroke period (usually defined as 1 week), the risk of epilepsy was also 20 times higher in the first year after a stroke.¹⁴ However, seizures tend to occur within the first 48 hours after the onset of ischemic stroke. In subarachnoid hemorrhage, seizures generally occur within hours.¹⁶

In a population-based study in Rochester, NY,¹⁷ epilepsy developed in two-thirds of patients with seizure related to acute stroke. Two factors that independently predicted the development of epilepsy were early seizure occurrence and recurrence of stroke.

Interestingly, the risk of stroke was three times higher in older patients who had new-onset seizure.¹⁸ Therefore, any elderly person with new-onset seizure should be assessed for cerebrovascular risk factors and treated accordingly for stroke prevention.

Metabolic disturbances

Acute metabolic disorders are common in elderly patients because of multiple comorbidities and polypharmacy. Hypoglycemia and hyponatremia need to be particularly considered in this population.¹⁹

Other well-documented metabolic causes of acute seizure, including nonketotic hyperglycemia, hypocalcemia, and uremic or hepatic encephalopathy, can all be considerations, albeit less specific to this age group.

Dementia

Primary neurodegenerative disorders associated with cognitive impairment, such as Alzheimer disease, are major risk factors for new-onset epilepsy in older patients.^3,5 Seizures occur in about 10% of Alzheimer patients.²⁰ Those who have brief periods of increased confusion may actually be experiencing unrecognized complex partial seizures.²¹

A case-control study discovered incidence rates of epilepsy almost 10 times higher in patients who had Alzheimer disease or vascular dementia than in nondemented patients.²² A prospective cohort study in patients with mild to moderate Alzheimer disease established that younger age, a greater degree of cognitive impairment, and a history of antipsychotic use were independent risk factors for new-onset seizures in the elderly.²³ Preexisting dementia also increases the risk of poststroke epilepsy.²⁴

Traumatic brain injury

The most common cause of brain trauma in the elderly is falls. Subdural hematoma, which can occur in the elderly with trivial trauma or sometimes even without it, needs to be considered. The risk of posttraumatic hemorrhage is especially relevant in patients taking anticoagulants.

Traumatic brain injury has a poorer prognosis in older people than in the young,²⁵ and it accounts for up to 20% of cases of epilepsy in the elderly.²⁶ Although no study has specifically addressed the longitudinal risk of epilepsy after traumatic brain injury in the elderly, a study in children and young adults revealed the risk was highest in the first year, with the increased risk persisting for more than 10 years.²⁷

Brain tumors

Between 10% and 30% of new-onset seizures in the elderly are associated with tumor, typically glioma, meningioma, and brain metastasis.^28,29 Seizures are usually associated more with primary than with secondary tumors, and more with low-grade tumors than high-grade ones.³⁰

Drug-induced

Drugs and drug withdrawal can contribute to up to 10% of acute symptomatic seizures in the geriatric population.^5,8,29 The elderly are susceptible to drug-induced seizure because of a higher prevalence of polypharmacy, impaired drug clearance, and heightened sensitivity to the proconvulsant side effects of medications.¹ A number of commonly used drugs have been implicated,³¹ including:

Antibiotics such as carbapenems and high-dose penicillin

Antihistamines such as desloratadine (Clarinex)

Pain medications such as tramadol (Ul-tram) and high-dose opiates

Neuromodulators

Antidepressants such as clomipramine (Anafranil), maprotiline (Ludiomil), amoxapine (Asendin), and bupropion (Wellbutrin).³²

Seizures also follow alcohol, benzodiazepine, and barbiturate withdrawal.³³

Other causes

Paraneoplastic limbic encephalitis is a rare cause of seizures in the elderly.³⁴ It can present with refractory seizures, confusion, and behavioral changes with or without a known concurrent neoplastic disease.

Posterior reversible leukoencephalopathy syndrome, another rare consideration, can particularly affect immunosuppressed elderly patients. This syndrome is characterized clinically by headache, confusion, seizures, vomiting, and visual disturbances with radiographic vasogenic edema.³⁵

CLINICAL PRESENTATION

The signs and symptoms of a seizure may be atypical in the elderly. Seizures more often have a picture of “epileptic amnesia,” with confusion, sleepiness, or clumsiness, rather than motor manifestations such as tonic stiffening or automatism.^36,37 Postictal states are also prolonged, particularly if there is underlying brain dysfunction.³⁸ All these features render the clinical seizure manifestations more subtle and, as such, more difficult for the uninitiated caregiver to identify.

Convulsive and nonconvulsive status epilepticus

Status epilepticus is defined as a single generalized seizure lasting more than 5 minutes or a series of seizures lasting longer than 30 minutes without the patient’s regaining consciousness.³⁹ The greatest increase in the incidence of status epilepticus occurs after age 60.⁴⁰ It is the first seizure in about 30% of new-onset seizures in the elderly.⁴¹

Mortality rates increase with age, anoxia, and duration of status epilepticus and are over 50% in patients age 80 and older.^40,42

Convulsive status epilepticus is most commonly caused by stroke.⁴⁰

Absence status epilepticus can occur in elderly patients as a late complication of idiopathic generalized epilepsy related to benzodiazepine withdrawal, alcohol intoxication, or initiation of psychotropic drugs.⁴²

Nonconvulsive status epilepticus manifests as altered mental status, psychosis, lethargy, or coma.^42–44 Occasionally, it presents as a more focal cognitive disturbance with aphasia or a neglect syndrome.^42,45 Electroencephalographic correlates of nonconvulsive status epilepticus include focal rhythmic discharges, often arising from frontal or temporal lobes, or generalized spike or sharp and slow-wave activity.⁴⁶ Its management is challenging because of delayed diagnosis or misdiagnosis. The risk of death is higher in patients with severely impaired mental status or acute complications.⁴⁷

Table 1 lists the typical seizure manifestations peculiar to the elderly.^37,48

Differential diagnosis of new-onset epilepsy in the elderly

New-onset epilepsy in elderly patients can be confused with syncope, transient ischemic attack, cardiac arrhythmia, metabolic disturbances, transient global amnesia, neurodegenerative disease, rapid-eye-movement sleep behavior disorder, psychogenic disorders, and other conditions (Table 2). If there is a high clinical suspicion of seizure, the patient should undergo electroencephalography (EEG) and be referred to a neurologist or epileptologist.

KEYS TO THE DIAGNOSIS

Clinical history

A reliable history and description of the event from an eyewitness or a video recording of the event are invaluable to the diagnosis of epileptic seizure. Signs and symptoms that suggest the diagnosis include aura, ictal pallor, urinary incontinence, tongue-biting, and motor symptoms, as well as postictal confusion, drowsiness, and speech disturbance.

Electroencephalography

EEG is the most useful diagnostic tool in epilepsy. However, an interictal EEG reading (ie, between epileptic attacks) in an elderly patient has limited utility, showing epileptiform activity in only about one-fourth of patients.⁴⁹ Nonspecific EEG abnormalities such as intermittent focal slowing are seen in many older people even without seizure.⁵⁰ Also, normal findings on outpatient EEG do not rule out epilepsy, as EEG is normal in about one-third of patients with epilepsy, irrespective of age.^1,49 Activation procedures such as hyperventilation and photic stimulation add little to the diagnosis in the elderly.⁴⁹

On the other hand, video-EEG monitoring is an excellent tool for evaluating possible epilepsy, as it allows accurate assessment of brain electrical activity during the events in question. Moreover, studies of video-EEG recording of seizures in elderly patients demonstrated epileptiform discharges on EEG in 76% of clinical ictal events.⁵⁰

Therefore, routine EEG is a useful screening tool, and inpatient video-EEG monitoring is the gold standard to characterize events of concern and distinguish between epileptic and nonepileptic or psychogenic seizures.

Other diagnostic studies

Brain imaging, preferably magnetic resonance imaging with contrast, should be done in every patient with possible epilepsy due to stroke, traumatic brain injury, or other structural brain disease.⁵¹

Electrocardiography helps exclude cardiac causes such as arrhythmia.

Blood testing. Metabolically provoked seizure can be distinguished by blood analysis for electrolytes, blood urea nitrogen, creatinine, glucose, calcium, magnesium, liver enzymes, and drug levels (eg, ethanol). A complete blood cell count with differential and platelets should also be done in anticipation of starting antiepileptic drug therapy.

Lumbar puncture for cell count, protein, glucose, stains, and cultures should be performed whenever meningitis or encephalitis is suspected.

A sleep study with concurrent video-EEG monitoring may be required to distinguish epileptic seizures from sleep disorders.

Neuropsychological testing may help account for the degree of cognitive impairment present.

Risk factors for stroke should be assessed in every elderly person who has new-onset seizures, because the risk of stroke is high.¹⁷

Figure 1 shows the workup for an elderly patient with suspected new-onset epilepsy.

TREATING EPILEPSY IN THE ELDERLY

Therapeutic challenges

Age-associated changes in drug absorption, protein binding, and distribution in body compartments require adjustments in drug selection and dosage. The causes and manifestations of these changes are typically multifactorial, mainly related to altered metabolism, declining plasma albumin concentrations, and increasing competition for protein binding by concomitantly used drugs.

The differences in the pharmacokinetics and pharmacodynamics of antiepileptic drugs depend on the patient’s physical status, relevant comorbidities, and concomitant medications.⁵² Renal and hepatic function may decline in an elderly patient; accordingly, precaution is needed in the prescribing and dosing of antiepileptic drugs.

Adverse effects from seizure medications are twice as common in elderly patients compared with younger patients. Ataxia, tremor, visual disturbance, and sedation are the most common.¹ Antiepileptic drugs are also harmful to bone; induced abnormalities in bone metabolism include hypocalcemia, hypophosphatemia, decreased levels of active vitamin D metabolites, and hyperparathyroidism.⁵³

Elderly patients tend to take multiple drugs, and some drugs can lower the seizure threshold, particularly antidepressants, anti-psychotics, and antibiotics.³² The herbal remedy ginkgo biloba can also precipitate seizure in this population.⁵⁴

Antiepileptic drugs such as phenobarbital, primidone (Mysoline), phenytoin (Dilantin), and carbamazepine (Tegretol) can be broad-spectrum enzyme-inducers, increasing the metabolism of many drugs, including warfarin (Coumadin), cytotoxic agents, statins, cardiac antiarrhythmics, antihypertensives, corticosteroids, and other immunosuppressants.⁵⁵ For example, carbamazepine can alter the metabolism of several hepatically metabolized drugs and cause significant hyponatremia. This is problematic in patients already taking sodium-depleting antihypertensives. Age-related cognitive decline can worsen the situation, often leading to misdiagnosis or patient noncompliance.

Table 3 profiles the interactions of commonly used antiepileptic drugs.

The ideal pharmacotherapy

No single drug is ideal for elderly patients with new-onset epilepsy. The choice mostly depends on the type of seizure and the patient’s comorbidities. The ideal antiepileptic drug would have minimal enzyme interaction, little protein binding, linear kinetics, a long half-life, a good safety profile, and a high therapeutic index. The goal of management should be to maintain the patient’s normal lifestyle with complete control of seizures and with minimal side effects.

The only randomized controlled trial in new-onset geriatric epilepsy concluded that gabapentin (Neurontin) and lamotrigine (Lamictal) should be the initial therapy in such patients.⁵⁶ Trials indicate extended-release carbamazepine or levetiracetam (Keppra) can also be tried.⁵⁷

The prescribing strategy includes lower initial dose, slower titration, and a lower target dose than for younger patients. Intense monitoring of dosing and drug levels is necessary to avoid toxicity. If the first drug is not tolerated well, another should be substituted. If seizures persist despite increasing dosage, a drug with a different mechanism of action should be tried.⁵⁸ A patient with drug-resistant epilepsy (failure to respond to two adequate and appropriate antiepileptic drug trials⁵⁹) should be referred to an epilepsy surgical center for reevaluation and consideration of epilepsy surgery.

Patient and caregiver support is an essential component of management. New-onset epilepsy in the elderly has a significant effect on quality of life, more so if the patient is already cognitively impaired. It erodes self-confidence, survival becomes difficult, and the condition is worse for patients who live alone. Driving restrictions further limit independence and increase isolation. Hence, psychological support programs can significantly boost the self-esteem and morale of such patients and their caregivers.

SPECIAL CONSIDERATION: EPILEPSY IN THE NURSING HOME

Certain points apply to the growing proportion of elderly who reside in nursing homes:

• Several studies in the United States and in Europe^60–62 suggest that this subgroup is at higher risk of polypharmacy and more likely to be treated with older antiepileptic drugs.
• Only a minority of these patients (as low as 42% in one study⁶⁰) received adequate monitoring of antiepileptic drug levels.
• The clinical characteristics and epileptic etiologies of these patients are less well defined.

Together, these observations highlight a particularly vulnerable population, at risk for medication toxicity as well as for undertreatment.

OUR KNOWLEDGE IS STILL GROWING

New-onset epilepsy, although common in the elderly, is difficult to diagnose because of its atypical presentation, concomitant cognitive impairment, and nonspecific abnormalities in routine investigations. But knowledge of its common causes and differential diagnoses makes the task easier. A high suspicion warrants referral to a neurologist or epileptologist.

Challenges to the management of seizures in the elderly include deranged physiologic processes, multiple comorbidities, and polypharmacy. No single drug is ideal for antiepileptic therapy in the elderly; the choice of drug is usually dictated by seizure type, comorbidities, and tolerance level. The treatment regimen in the elderly is more conservative, and the target dosage is lower than for younger adults. Emotional support of patient and caregivers should be an important aspect of management.

Our knowledge about new-onset epilepsy in the elderly is still growing, and future research should explore its diagnosis, treatment strategies, and care-delivery models.

As Drs. ghosh and jehi discuss in this issue of the Journal,¹ physicians face many challenges when caring for elderly patients who have epileptic seizures.

See related article

Owing to the graying of America and higher rates of incidence and prevalence of epilepsy in older patients than in younger ones, the number of patients with epilepsy will climb steeply in the coming years. Among patients in nursing homes, the numbers are much higher (an incidence of up to 16 per 1,000 per year and a prevalence of 60 per 1,000) than in community-dwelling elderly.^2,3

DOES THE PATIENT HAVE EPILEPSY?

The first concern is to make the correct diagnosis. Epilepsy is defined as a condition of the central nervous system predisposing to seizures. Younger patients need to have two unprovoked seizures for epilepsy to be diagnosed. However, a recent modification in the definition allows epilepsy to be diagnosed after a single seizure in a person who has a condition of the central nervous system known to significantly increase the risk of additional seizures.⁴

CONSIDERATIONS IN TREATMENT

When treating any patient, one size does not fit all, and this is especially true with elderly patients, in whom treatment should be based on health status. Many elderly patients with epilepsy have age-related comorbidities, and one would treat epilepsy differently in patients who are otherwise healthy than in those who are frail or have multiple comorbidities.⁵ Elderly people who live in their own homes have different needs from those who reside in a nursing home.

These patients have social and psychological problems as well as medical ones. For example, the loss of driving privileges can be a major concern with epilepsy patients; it is often emotionally devastating, in addition to greatly limiting independence.

Comorbidities, seizures, and treatment share a complex and tangled relationship. To decide on the appropriate therapy, a physician needs to evaluate the effects that antiepileptic drugs and central nervous system disorders can have on mood, cognition, and neurologic function. In addition, it is imperative to consider the possible pharmacokinetic and pharmacodynamic interactions of antiepileptic drugs with the many drugs used to treat other conditions.

Should treatment be started?

Antiepileptic drugs can cause side effects, and an elderly person who has had a single seizure may never have another one. On the other hand, given that seizures can pose higher risks to the elderly and lead to injuries that can be more devastating than in the young, preventing recurrent seizures may be very appropriate. Lack of studies of this issue means that there is no evidence to support either decision.

Which antiepileptic drug should be used?

Things to consider when selecting an antiepileptic drug include efficacy, tolerability, pharmacokinetic properties, adverse effects, use of other drugs that interact with these drugs, and compliance.

Pharmacokinetics can be affected by age-related changes in the function of the gastrointestinal tract, kidneys, and liver and in protein binding. However, contrary to common perception, hepatic metabolism in healthy elderly people may not change significantly with advancing age. Ahn et al⁶ gave radiolabeled phenytoin (Dilantin) intravenously to patients with epilepsy and found that its clearance changed only slightly with age.

Antiepileptic drugs can interact with other drugs, herbal remedies, and food. Physicians need to know about the metabolic pathways of these drugs and other substances to make appropriate decisions about treatment. Interactions between antipsychotic and antiepileptic drugs are particularly worrisome because they involve both pharmacokinetic and pharmacodynamic mechanisms. Certain antiepileptic drugs can also induce (ie, increase) the hepatic metabolism of certain other drugs. Other drugs may lower the threshold for seizures.

Is the patient’s drug level stable?

We assume that if a drug is taken on a regular schedule at the same dose, its serum concentration will remain relatively stable (at a “steady state”). And in younger adults, antiepileptic drug concentrations vary relatively little over time, by about 20% in compliant patients.⁷ This was assumed to be true for elderly patients as well.

However, Birnbaum et al⁸ found that phenytoin levels fluctuated as much as two- to threefold in serial measurements in nursing home residents, even though the dose or formulation had not been changed and the patients were not taking any interfering medication. Yet some of the patients had very stable levels. The authors observed similar variations in levels of carbamazepine (Tegretol) and valproic acid (Depakote).⁹

The reasons for this variability are not known but may involve age-related changes in the gut.

RESEARCH NEEDED

Epilepsy is increasing in elderly people. Yet little basic or clinical research has been done to clarify the mechanisms or to determine the best treatment in terms of quality of life. Lacking appropriate animal models, basic research has been slow. For example, we do not know if the mechanisms leading to seizures after strokes differ from those leading to seizures in people with Alzheimer disease. Thus, it is not possible to choose an antiepileptic drug on the basis of its mechanism of action.

Many elderly patients who have epilepsy also have conditions that may alter the pharmacokinetic and pharmacodynamic properties of antiepileptic drugs, and data from younger people may be misleading.

Given the magnitude of the problem, we need to make a concerted effort to answer these questions with additional research.¹⁰ Meanwhile, the treatment of elderly patients with epilepsy is more of an art than a science.

As Drs. ghosh and jehi discuss in this issue of the Journal,¹ physicians face many challenges when caring for elderly patients who have epileptic seizures.

See related article

Owing to the graying of America and higher rates of incidence and prevalence of epilepsy in older patients than in younger ones, the number of patients with epilepsy will climb steeply in the coming years. Among patients in nursing homes, the numbers are much higher (an incidence of up to 16 per 1,000 per year and a prevalence of 60 per 1,000) than in community-dwelling elderly.^2,3

DOES THE PATIENT HAVE EPILEPSY?

The first concern is to make the correct diagnosis. Epilepsy is defined as a condition of the central nervous system predisposing to seizures. Younger patients need to have two unprovoked seizures for epilepsy to be diagnosed. However, a recent modification in the definition allows epilepsy to be diagnosed after a single seizure in a person who has a condition of the central nervous system known to significantly increase the risk of additional seizures.⁴

CONSIDERATIONS IN TREATMENT

When treating any patient, one size does not fit all, and this is especially true with elderly patients, in whom treatment should be based on health status. Many elderly patients with epilepsy have age-related comorbidities, and one would treat epilepsy differently in patients who are otherwise healthy than in those who are frail or have multiple comorbidities.⁵ Elderly people who live in their own homes have different needs from those who reside in a nursing home.

These patients have social and psychological problems as well as medical ones. For example, the loss of driving privileges can be a major concern with epilepsy patients; it is often emotionally devastating, in addition to greatly limiting independence.

Comorbidities, seizures, and treatment share a complex and tangled relationship. To decide on the appropriate therapy, a physician needs to evaluate the effects that antiepileptic drugs and central nervous system disorders can have on mood, cognition, and neurologic function. In addition, it is imperative to consider the possible pharmacokinetic and pharmacodynamic interactions of antiepileptic drugs with the many drugs used to treat other conditions.

Should treatment be started?

Antiepileptic drugs can cause side effects, and an elderly person who has had a single seizure may never have another one. On the other hand, given that seizures can pose higher risks to the elderly and lead to injuries that can be more devastating than in the young, preventing recurrent seizures may be very appropriate. Lack of studies of this issue means that there is no evidence to support either decision.

Which antiepileptic drug should be used?

Things to consider when selecting an antiepileptic drug include efficacy, tolerability, pharmacokinetic properties, adverse effects, use of other drugs that interact with these drugs, and compliance.

Pharmacokinetics can be affected by age-related changes in the function of the gastrointestinal tract, kidneys, and liver and in protein binding. However, contrary to common perception, hepatic metabolism in healthy elderly people may not change significantly with advancing age. Ahn et al⁶ gave radiolabeled phenytoin (Dilantin) intravenously to patients with epilepsy and found that its clearance changed only slightly with age.

Antiepileptic drugs can interact with other drugs, herbal remedies, and food. Physicians need to know about the metabolic pathways of these drugs and other substances to make appropriate decisions about treatment. Interactions between antipsychotic and antiepileptic drugs are particularly worrisome because they involve both pharmacokinetic and pharmacodynamic mechanisms. Certain antiepileptic drugs can also induce (ie, increase) the hepatic metabolism of certain other drugs. Other drugs may lower the threshold for seizures.

Is the patient’s drug level stable?

We assume that if a drug is taken on a regular schedule at the same dose, its serum concentration will remain relatively stable (at a “steady state”). And in younger adults, antiepileptic drug concentrations vary relatively little over time, by about 20% in compliant patients.⁷ This was assumed to be true for elderly patients as well.

However, Birnbaum et al⁸ found that phenytoin levels fluctuated as much as two- to threefold in serial measurements in nursing home residents, even though the dose or formulation had not been changed and the patients were not taking any interfering medication. Yet some of the patients had very stable levels. The authors observed similar variations in levels of carbamazepine (Tegretol) and valproic acid (Depakote).⁹

The reasons for this variability are not known but may involve age-related changes in the gut.

RESEARCH NEEDED

Epilepsy is increasing in elderly people. Yet little basic or clinical research has been done to clarify the mechanisms or to determine the best treatment in terms of quality of life. Lacking appropriate animal models, basic research has been slow. For example, we do not know if the mechanisms leading to seizures after strokes differ from those leading to seizures in people with Alzheimer disease. Thus, it is not possible to choose an antiepileptic drug on the basis of its mechanism of action.

Many elderly patients who have epilepsy also have conditions that may alter the pharmacokinetic and pharmacodynamic properties of antiepileptic drugs, and data from younger people may be misleading.

Given the magnitude of the problem, we need to make a concerted effort to answer these questions with additional research.¹⁰ Meanwhile, the treatment of elderly patients with epilepsy is more of an art than a science.

As Drs. ghosh and jehi discuss in this issue of the Journal,¹ physicians face many challenges when caring for elderly patients who have epileptic seizures.

See related article

Owing to the graying of America and higher rates of incidence and prevalence of epilepsy in older patients than in younger ones, the number of patients with epilepsy will climb steeply in the coming years. Among patients in nursing homes, the numbers are much higher (an incidence of up to 16 per 1,000 per year and a prevalence of 60 per 1,000) than in community-dwelling elderly.^2,3

DOES THE PATIENT HAVE EPILEPSY?

The first concern is to make the correct diagnosis. Epilepsy is defined as a condition of the central nervous system predisposing to seizures. Younger patients need to have two unprovoked seizures for epilepsy to be diagnosed. However, a recent modification in the definition allows epilepsy to be diagnosed after a single seizure in a person who has a condition of the central nervous system known to significantly increase the risk of additional seizures.⁴

CONSIDERATIONS IN TREATMENT

When treating any patient, one size does not fit all, and this is especially true with elderly patients, in whom treatment should be based on health status. Many elderly patients with epilepsy have age-related comorbidities, and one would treat epilepsy differently in patients who are otherwise healthy than in those who are frail or have multiple comorbidities.⁵ Elderly people who live in their own homes have different needs from those who reside in a nursing home.

These patients have social and psychological problems as well as medical ones. For example, the loss of driving privileges can be a major concern with epilepsy patients; it is often emotionally devastating, in addition to greatly limiting independence.

Comorbidities, seizures, and treatment share a complex and tangled relationship. To decide on the appropriate therapy, a physician needs to evaluate the effects that antiepileptic drugs and central nervous system disorders can have on mood, cognition, and neurologic function. In addition, it is imperative to consider the possible pharmacokinetic and pharmacodynamic interactions of antiepileptic drugs with the many drugs used to treat other conditions.

Should treatment be started?

Antiepileptic drugs can cause side effects, and an elderly person who has had a single seizure may never have another one. On the other hand, given that seizures can pose higher risks to the elderly and lead to injuries that can be more devastating than in the young, preventing recurrent seizures may be very appropriate. Lack of studies of this issue means that there is no evidence to support either decision.

Which antiepileptic drug should be used?

Things to consider when selecting an antiepileptic drug include efficacy, tolerability, pharmacokinetic properties, adverse effects, use of other drugs that interact with these drugs, and compliance.

Pharmacokinetics can be affected by age-related changes in the function of the gastrointestinal tract, kidneys, and liver and in protein binding. However, contrary to common perception, hepatic metabolism in healthy elderly people may not change significantly with advancing age. Ahn et al⁶ gave radiolabeled phenytoin (Dilantin) intravenously to patients with epilepsy and found that its clearance changed only slightly with age.

Antiepileptic drugs can interact with other drugs, herbal remedies, and food. Physicians need to know about the metabolic pathways of these drugs and other substances to make appropriate decisions about treatment. Interactions between antipsychotic and antiepileptic drugs are particularly worrisome because they involve both pharmacokinetic and pharmacodynamic mechanisms. Certain antiepileptic drugs can also induce (ie, increase) the hepatic metabolism of certain other drugs. Other drugs may lower the threshold for seizures.

Is the patient’s drug level stable?

We assume that if a drug is taken on a regular schedule at the same dose, its serum concentration will remain relatively stable (at a “steady state”). And in younger adults, antiepileptic drug concentrations vary relatively little over time, by about 20% in compliant patients.⁷ This was assumed to be true for elderly patients as well.

However, Birnbaum et al⁸ found that phenytoin levels fluctuated as much as two- to threefold in serial measurements in nursing home residents, even though the dose or formulation had not been changed and the patients were not taking any interfering medication. Yet some of the patients had very stable levels. The authors observed similar variations in levels of carbamazepine (Tegretol) and valproic acid (Depakote).⁹

The reasons for this variability are not known but may involve age-related changes in the gut.

RESEARCH NEEDED

Epilepsy is increasing in elderly people. Yet little basic or clinical research has been done to clarify the mechanisms or to determine the best treatment in terms of quality of life. Lacking appropriate animal models, basic research has been slow. For example, we do not know if the mechanisms leading to seizures after strokes differ from those leading to seizures in people with Alzheimer disease. Thus, it is not possible to choose an antiepileptic drug on the basis of its mechanism of action.

Many elderly patients who have epilepsy also have conditions that may alter the pharmacokinetic and pharmacodynamic properties of antiepileptic drugs, and data from younger people may be misleading.

Given the magnitude of the problem, we need to make a concerted effort to answer these questions with additional research.¹⁰ Meanwhile, the treatment of elderly patients with epilepsy is more of an art than a science.

When a 78-year-old man underwent magnetic resonance imaging of the lumbar spine because of back pain, the scan revealed a mass in the right lung. He had no respiratory symptoms but had a 40-pack-year smoking history. Physical examination and routine blood tests were unremarkable.

Radiography (Figure 1) showed a large rounded opacity in the right lower lobe. The patient’s age, smoking history, and imaging findings raised concern for lung cancer, so computed tomography (CT) was performed (Figure 2).

DIAGNOSIS: PULMONARY HAMARTOMA

The findings of a well-circumscribed solitary pulmonary nodule or mass containing areas of fat, either as focal islands or more generally distributed, and chondroid “popcorn” calcification are virtually pathognomonic for pulmonary hamartoma.^1,2 Unfortunately, although this pattern of calcification is strongly diagnostic, it is present in only a minority of cases of hamartoma.

Pulmonary hamartoma is the most common benign tumor of the lung, accounting for approximately 75% of benign neoplasms and 6% to 8% of all focal lung parenchymal masses.³

Like hamartoma elsewhere in the body, pulmonary hamartoma consists of disorganized overgrowth and aberrant arrangement of normal tissues, including cartilage (which may calcify), smooth muscle, epithelium, and fibrostroma. Pulmonary hamartoma is twice as common in men as in women, and it has a peak incidence in the seventh decade of life.⁴

Although size ranged from 0.2 to 6 cm in a large case series,⁴ hamartomas are usually less than 2.5 cm in diameter. As noted in Figure 1, our patient’s lesion was 5 cm.

Pulmonary hamartomas grow slowly and are often asymptomatic, although up to 39% of patients may have symptoms such as cough, dyspnea, and chest tightness.⁵ The nonspecific nature of these symptoms makes it difficult to be certain that they are caused by the hamartoma; in many cases, they are likely to be coincidental. Lesions tend to occur in the periphery of the lobe and do not favor a particular lobe. Endobronchial lesions can occur but are uncommon.

The internal heterogeneous elements are difficult to see on radiography; CT is usually required to further characterize the lesion and to exclude more sinister differential diagnoses. In some cases the characteristic features of fat and calcification are absent, making a certain diagnosis difficult or impossible radiologically; in such cases, biopsy or resection may be required.

Hamartomas usually do not take up fluorodeoxyglucose avidly on positron-emission tomography CT. However, nuclear medicine studies such as this are superfluous if the classic features are present on CT.

FOLLOW-UP AND TREATMENT

Given the benign nature, slow growth, and usually incidental detection of pulmonary hamartoma in patients without symptoms, no follow-up imaging or treatment is usually required. In the few cases in which symptoms are attributable to the lesion, the lesion can be resected.⁵ Resection is also an option when the patient is very anxious about the mass, or when imaging studies do not provide a clear diagnosis and tissue needs to be obtained for study.

Because patients often present to different institutions during their lifetime, it is important to counsel them about the natural history of pulmonary hamartomas. Giving them a copy of their imaging may help avoid unnecessary repetition.

When a 78-year-old man underwent magnetic resonance imaging of the lumbar spine because of back pain, the scan revealed a mass in the right lung. He had no respiratory symptoms but had a 40-pack-year smoking history. Physical examination and routine blood tests were unremarkable.

Radiography (Figure 1) showed a large rounded opacity in the right lower lobe. The patient’s age, smoking history, and imaging findings raised concern for lung cancer, so computed tomography (CT) was performed (Figure 2).

DIAGNOSIS: PULMONARY HAMARTOMA

The findings of a well-circumscribed solitary pulmonary nodule or mass containing areas of fat, either as focal islands or more generally distributed, and chondroid “popcorn” calcification are virtually pathognomonic for pulmonary hamartoma.^1,2 Unfortunately, although this pattern of calcification is strongly diagnostic, it is present in only a minority of cases of hamartoma.

Pulmonary hamartoma is the most common benign tumor of the lung, accounting for approximately 75% of benign neoplasms and 6% to 8% of all focal lung parenchymal masses.³

Like hamartoma elsewhere in the body, pulmonary hamartoma consists of disorganized overgrowth and aberrant arrangement of normal tissues, including cartilage (which may calcify), smooth muscle, epithelium, and fibrostroma. Pulmonary hamartoma is twice as common in men as in women, and it has a peak incidence in the seventh decade of life.⁴

Although size ranged from 0.2 to 6 cm in a large case series,⁴ hamartomas are usually less than 2.5 cm in diameter. As noted in Figure 1, our patient’s lesion was 5 cm.

Pulmonary hamartomas grow slowly and are often asymptomatic, although up to 39% of patients may have symptoms such as cough, dyspnea, and chest tightness.⁵ The nonspecific nature of these symptoms makes it difficult to be certain that they are caused by the hamartoma; in many cases, they are likely to be coincidental. Lesions tend to occur in the periphery of the lobe and do not favor a particular lobe. Endobronchial lesions can occur but are uncommon.

The internal heterogeneous elements are difficult to see on radiography; CT is usually required to further characterize the lesion and to exclude more sinister differential diagnoses. In some cases the characteristic features of fat and calcification are absent, making a certain diagnosis difficult or impossible radiologically; in such cases, biopsy or resection may be required.

Hamartomas usually do not take up fluorodeoxyglucose avidly on positron-emission tomography CT. However, nuclear medicine studies such as this are superfluous if the classic features are present on CT.

FOLLOW-UP AND TREATMENT

Given the benign nature, slow growth, and usually incidental detection of pulmonary hamartoma in patients without symptoms, no follow-up imaging or treatment is usually required. In the few cases in which symptoms are attributable to the lesion, the lesion can be resected.⁵ Resection is also an option when the patient is very anxious about the mass, or when imaging studies do not provide a clear diagnosis and tissue needs to be obtained for study.

Because patients often present to different institutions during their lifetime, it is important to counsel them about the natural history of pulmonary hamartomas. Giving them a copy of their imaging may help avoid unnecessary repetition.

When a 78-year-old man underwent magnetic resonance imaging of the lumbar spine because of back pain, the scan revealed a mass in the right lung. He had no respiratory symptoms but had a 40-pack-year smoking history. Physical examination and routine blood tests were unremarkable.

Radiography (Figure 1) showed a large rounded opacity in the right lower lobe. The patient’s age, smoking history, and imaging findings raised concern for lung cancer, so computed tomography (CT) was performed (Figure 2).

DIAGNOSIS: PULMONARY HAMARTOMA

The findings of a well-circumscribed solitary pulmonary nodule or mass containing areas of fat, either as focal islands or more generally distributed, and chondroid “popcorn” calcification are virtually pathognomonic for pulmonary hamartoma.^1,2 Unfortunately, although this pattern of calcification is strongly diagnostic, it is present in only a minority of cases of hamartoma.

Pulmonary hamartoma is the most common benign tumor of the lung, accounting for approximately 75% of benign neoplasms and 6% to 8% of all focal lung parenchymal masses.³

Like hamartoma elsewhere in the body, pulmonary hamartoma consists of disorganized overgrowth and aberrant arrangement of normal tissues, including cartilage (which may calcify), smooth muscle, epithelium, and fibrostroma. Pulmonary hamartoma is twice as common in men as in women, and it has a peak incidence in the seventh decade of life.⁴

Although size ranged from 0.2 to 6 cm in a large case series,⁴ hamartomas are usually less than 2.5 cm in diameter. As noted in Figure 1, our patient’s lesion was 5 cm.

Pulmonary hamartomas grow slowly and are often asymptomatic, although up to 39% of patients may have symptoms such as cough, dyspnea, and chest tightness.⁵ The nonspecific nature of these symptoms makes it difficult to be certain that they are caused by the hamartoma; in many cases, they are likely to be coincidental. Lesions tend to occur in the periphery of the lobe and do not favor a particular lobe. Endobronchial lesions can occur but are uncommon.

The internal heterogeneous elements are difficult to see on radiography; CT is usually required to further characterize the lesion and to exclude more sinister differential diagnoses. In some cases the characteristic features of fat and calcification are absent, making a certain diagnosis difficult or impossible radiologically; in such cases, biopsy or resection may be required.

Hamartomas usually do not take up fluorodeoxyglucose avidly on positron-emission tomography CT. However, nuclear medicine studies such as this are superfluous if the classic features are present on CT.

FOLLOW-UP AND TREATMENT

Given the benign nature, slow growth, and usually incidental detection of pulmonary hamartoma in patients without symptoms, no follow-up imaging or treatment is usually required. In the few cases in which symptoms are attributable to the lesion, the lesion can be resected.⁵ Resection is also an option when the patient is very anxious about the mass, or when imaging studies do not provide a clear diagnosis and tissue needs to be obtained for study.

Because patients often present to different institutions during their lifetime, it is important to counsel them about the natural history of pulmonary hamartomas. Giving them a copy of their imaging may help avoid unnecessary repetition.

A 30-year-old man presented with progressive dyspnea and dry cough, which had developed over the last 6 months. His oxygen saturation was 88% on room air, and he had diffuse bilateral crackles on auscultation. Imaging showed a mixture of diffuse airspace and interstitial abnormalities (Figure 1).

He underwent bronchoscopy. The bronchoalveolar lavage fluid had a turbid appearance that gradually cleared with successive aliquots. Transbronchial biopsy studies confirmed the diagnosis of pulmonary alveolar proteinosis (Figure 2). Sequential whole-lung lavage recovered significant amounts of thick, proteinaceous effluent that slowly cleared. After the procedure, the patient’s symptoms, oxygen saturation, and chest radiographic appearance (Figure 3) improved markedly, with no recurrence at 1 year of follow-up.

ALVEOLAR PROTEINOSIS

Pulmonary alveolar proteinosis is a rare disease characterized by the accumulation of lipoproteinaceous material in the alveolar space secondary to alveolar macrophage dysfunction. The condition can be congenital, secondary, or acquired. Patients typically present with progressive exertional dyspnea, nonproductive cough, variable restrictive ventilatory defects, and diffusion limitation on pulmonary function testing.

Plain chest radiographs usually resemble those seen in pulmonary edema but without features of heart failure, ie, cardiomegaly, Kerley B lines, and effusion.

A “crazy-paving” pattern on computed tomography—a combination of geographic ground-glass appearance and interseptal thickening—suggests alveolar proteinosis, but is not specific for it. Other differential diagnoses for the crazy-paving pattern include Pneumocystis jirovecii infection, invasive mucinous adenocarcinoma, cardiogenic pulmonary edema, alveolar hemorrhage, sarcoidosis, cryptogenic organizing pneumonia, exogenous lipoid pneumonia, drug-induced lung disease, acute radiation pneumonitis, and nonspecific interstitial pneumonia.¹

Laboratory testing is not very helpful in the diagnosis, although the serum lactate dehydrogenase level may be mildly elevated. Circulating antibodies to granulocyte macrophage colony-stimulating factor may support the diagnosis, but they are only present in the acquired form. Communication with a research laboratory is usually needed to test for these antibodies.

The bronchoalveolar lavage fluid typically has an opaque, milky, or muddy appearance. The diagnosis is confirmed by demonstration of alveolar filling with material that is periodic acid-Schiff-positive and that is amorphous, eosinophilic, and granular.

Whole-lung lavage² is the physical removal of surfactant by repeated flooding of the lungs with warmed saline, done under general anesthesia with single-lung ventilation. It remains the standard of care and is indicated in patients with the confirmed diagnosis and one of the following: severe dyspnea, resting hypoxemia (Pao₂ < 60 mm Hg at sea level), alveolar-arterial gradient > 40 mm Hg, or a shunt fraction of more than 10%. Successful bronchoscopic lavage has also been reported.³

Other treatments include granulocyte-macrophage colony-stimulating factor, rituximab (Rituxan, an anti-CD20 monoclonal antibody), plasmapheresis, and lung transplantation. Systemic corticosteroids are usually ineffective unless indicated for secondary types of alveolar proteinosis.

Inhalation rather than subcutaneous administration of granulocyte-macrophage colony-stimulating factor seems preferred as it ensures a high concentration in the target organ, avoids systemic complications (injection-site edema, erythema, neutropenia, malaise, and shortness of breath) and achieves lower levels of autoantibodies in bronchoalveolar lavage fluid, which correlates with disease activity.

Data are sparse as to the recurrence of autoimmune pulmonary alveolar proteinosis after whole-lung lavage, yet about 40% of patients require a repeat procedure within 18 months. Recurrence has also been reported after double-lung transplantation.⁴

Adjuvant therapy with rituximab or, to a lesser extent, with inhaled granulocyte-macrophage colony-stimulating factor has recently been shown to diminish the need for repeated lavage.⁵ These treatments can also be used when whole-lung lavage cannot be performed or proves to be ineffective.⁵

Acknowledgment: I would like to thank Dr. Kamelia Velikova for providing the pathology image.

A 30-year-old man presented with progressive dyspnea and dry cough, which had developed over the last 6 months. His oxygen saturation was 88% on room air, and he had diffuse bilateral crackles on auscultation. Imaging showed a mixture of diffuse airspace and interstitial abnormalities (Figure 1).

He underwent bronchoscopy. The bronchoalveolar lavage fluid had a turbid appearance that gradually cleared with successive aliquots. Transbronchial biopsy studies confirmed the diagnosis of pulmonary alveolar proteinosis (Figure 2). Sequential whole-lung lavage recovered significant amounts of thick, proteinaceous effluent that slowly cleared. After the procedure, the patient’s symptoms, oxygen saturation, and chest radiographic appearance (Figure 3) improved markedly, with no recurrence at 1 year of follow-up.

ALVEOLAR PROTEINOSIS

Pulmonary alveolar proteinosis is a rare disease characterized by the accumulation of lipoproteinaceous material in the alveolar space secondary to alveolar macrophage dysfunction. The condition can be congenital, secondary, or acquired. Patients typically present with progressive exertional dyspnea, nonproductive cough, variable restrictive ventilatory defects, and diffusion limitation on pulmonary function testing.

Plain chest radiographs usually resemble those seen in pulmonary edema but without features of heart failure, ie, cardiomegaly, Kerley B lines, and effusion.

A “crazy-paving” pattern on computed tomography—a combination of geographic ground-glass appearance and interseptal thickening—suggests alveolar proteinosis, but is not specific for it. Other differential diagnoses for the crazy-paving pattern include Pneumocystis jirovecii infection, invasive mucinous adenocarcinoma, cardiogenic pulmonary edema, alveolar hemorrhage, sarcoidosis, cryptogenic organizing pneumonia, exogenous lipoid pneumonia, drug-induced lung disease, acute radiation pneumonitis, and nonspecific interstitial pneumonia.¹

Laboratory testing is not very helpful in the diagnosis, although the serum lactate dehydrogenase level may be mildly elevated. Circulating antibodies to granulocyte macrophage colony-stimulating factor may support the diagnosis, but they are only present in the acquired form. Communication with a research laboratory is usually needed to test for these antibodies.

The bronchoalveolar lavage fluid typically has an opaque, milky, or muddy appearance. The diagnosis is confirmed by demonstration of alveolar filling with material that is periodic acid-Schiff-positive and that is amorphous, eosinophilic, and granular.

Whole-lung lavage² is the physical removal of surfactant by repeated flooding of the lungs with warmed saline, done under general anesthesia with single-lung ventilation. It remains the standard of care and is indicated in patients with the confirmed diagnosis and one of the following: severe dyspnea, resting hypoxemia (Pao₂ < 60 mm Hg at sea level), alveolar-arterial gradient > 40 mm Hg, or a shunt fraction of more than 10%. Successful bronchoscopic lavage has also been reported.³

Other treatments include granulocyte-macrophage colony-stimulating factor, rituximab (Rituxan, an anti-CD20 monoclonal antibody), plasmapheresis, and lung transplantation. Systemic corticosteroids are usually ineffective unless indicated for secondary types of alveolar proteinosis.

Inhalation rather than subcutaneous administration of granulocyte-macrophage colony-stimulating factor seems preferred as it ensures a high concentration in the target organ, avoids systemic complications (injection-site edema, erythema, neutropenia, malaise, and shortness of breath) and achieves lower levels of autoantibodies in bronchoalveolar lavage fluid, which correlates with disease activity.

Data are sparse as to the recurrence of autoimmune pulmonary alveolar proteinosis after whole-lung lavage, yet about 40% of patients require a repeat procedure within 18 months. Recurrence has also been reported after double-lung transplantation.⁴

Adjuvant therapy with rituximab or, to a lesser extent, with inhaled granulocyte-macrophage colony-stimulating factor has recently been shown to diminish the need for repeated lavage.⁵ These treatments can also be used when whole-lung lavage cannot be performed or proves to be ineffective.⁵

Acknowledgment: I would like to thank Dr. Kamelia Velikova for providing the pathology image.

A 30-year-old man presented with progressive dyspnea and dry cough, which had developed over the last 6 months. His oxygen saturation was 88% on room air, and he had diffuse bilateral crackles on auscultation. Imaging showed a mixture of diffuse airspace and interstitial abnormalities (Figure 1).

He underwent bronchoscopy. The bronchoalveolar lavage fluid had a turbid appearance that gradually cleared with successive aliquots. Transbronchial biopsy studies confirmed the diagnosis of pulmonary alveolar proteinosis (Figure 2). Sequential whole-lung lavage recovered significant amounts of thick, proteinaceous effluent that slowly cleared. After the procedure, the patient’s symptoms, oxygen saturation, and chest radiographic appearance (Figure 3) improved markedly, with no recurrence at 1 year of follow-up.

ALVEOLAR PROTEINOSIS

Pulmonary alveolar proteinosis is a rare disease characterized by the accumulation of lipoproteinaceous material in the alveolar space secondary to alveolar macrophage dysfunction. The condition can be congenital, secondary, or acquired. Patients typically present with progressive exertional dyspnea, nonproductive cough, variable restrictive ventilatory defects, and diffusion limitation on pulmonary function testing.

Plain chest radiographs usually resemble those seen in pulmonary edema but without features of heart failure, ie, cardiomegaly, Kerley B lines, and effusion.

A “crazy-paving” pattern on computed tomography—a combination of geographic ground-glass appearance and interseptal thickening—suggests alveolar proteinosis, but is not specific for it. Other differential diagnoses for the crazy-paving pattern include Pneumocystis jirovecii infection, invasive mucinous adenocarcinoma, cardiogenic pulmonary edema, alveolar hemorrhage, sarcoidosis, cryptogenic organizing pneumonia, exogenous lipoid pneumonia, drug-induced lung disease, acute radiation pneumonitis, and nonspecific interstitial pneumonia.¹

Laboratory testing is not very helpful in the diagnosis, although the serum lactate dehydrogenase level may be mildly elevated. Circulating antibodies to granulocyte macrophage colony-stimulating factor may support the diagnosis, but they are only present in the acquired form. Communication with a research laboratory is usually needed to test for these antibodies.

The bronchoalveolar lavage fluid typically has an opaque, milky, or muddy appearance. The diagnosis is confirmed by demonstration of alveolar filling with material that is periodic acid-Schiff-positive and that is amorphous, eosinophilic, and granular.

Whole-lung lavage² is the physical removal of surfactant by repeated flooding of the lungs with warmed saline, done under general anesthesia with single-lung ventilation. It remains the standard of care and is indicated in patients with the confirmed diagnosis and one of the following: severe dyspnea, resting hypoxemia (Pao₂ < 60 mm Hg at sea level), alveolar-arterial gradient > 40 mm Hg, or a shunt fraction of more than 10%. Successful bronchoscopic lavage has also been reported.³

Other treatments include granulocyte-macrophage colony-stimulating factor, rituximab (Rituxan, an anti-CD20 monoclonal antibody), plasmapheresis, and lung transplantation. Systemic corticosteroids are usually ineffective unless indicated for secondary types of alveolar proteinosis.

Inhalation rather than subcutaneous administration of granulocyte-macrophage colony-stimulating factor seems preferred as it ensures a high concentration in the target organ, avoids systemic complications (injection-site edema, erythema, neutropenia, malaise, and shortness of breath) and achieves lower levels of autoantibodies in bronchoalveolar lavage fluid, which correlates with disease activity.

Data are sparse as to the recurrence of autoimmune pulmonary alveolar proteinosis after whole-lung lavage, yet about 40% of patients require a repeat procedure within 18 months. Recurrence has also been reported after double-lung transplantation.⁴

Adjuvant therapy with rituximab or, to a lesser extent, with inhaled granulocyte-macrophage colony-stimulating factor has recently been shown to diminish the need for repeated lavage.⁵ These treatments can also be used when whole-lung lavage cannot be performed or proves to be ineffective.⁵

Acknowledgment: I would like to thank Dr. Kamelia Velikova for providing the pathology image.

A 38-year-old man is evaluated in an urgent care center for back pain. He is a high school mathematics teacher who reports the insidious onset of low back pain 3 weeks ago. Over the last week the pain has become constant, is worsened by movement, and does not respond to naproxen. He has no history of trauma, malignancy, fever, weight loss, or bladder or bowel symptoms. He does not use intravenous drugs. On examination, he appears uncomfortable and stiff, protecting his back against motion. He has intact sensation, strength, and reflexes. The straight-leg-raising maneuver reproduces his lower back pain but does not cause radicular pain. Should I now order an imaging study such as spinal radiography, computed tomography, or magnetic resonance imaging to direct therapy?

IMAGING STUDIES ARE UNLIKELY TO HELP

This man with acute, nonspecific low back pain does not need spinal imaging. Imaging—ie, spine radiography, computed tomography, or magnetic resonance imaging—is unlikely to be helpful in a patient with nonspecific low back pain and may expose him unnecessarily to radiation and the anxiety of findings that are clinically insignificant.

Imaging studies are often ordered inappropriately as part of the evaluation of back pain in patients such as this. In 2008, the total national cost of treating spine (neck and back) problems was estimated to be $86 billion, representing 9% of total health care costs, which is close to the estimated $89 billion per year spent on cancer care.¹

Spine imaging should be considered only in patients who have a “red flag” such as advanced age, history of trauma, history of cancer, and prolonged corticosteroid use, all of which have been associated with an increased probability (from 9% to 33%) of either spinal fracture or malignancy.² Other red flags include duration longer than 6 weeks, fever, weight loss, and progressive neurologic findings on examination. This patient has none of these.

GUIDELINES AND CHOOSING WISELY

High-quality guidelines from different groups recommend against spine imaging in patients with low back pain.^3–6 These guidelines vary slightly in their patient populations and definitions of uncomplicated low back pain.

The American College of Radiology⁴ and the American College of Occupational and Environmental Medicine⁶ recommend against imaging for patients with both nonspecific and radicular low back pain in the first 6 weeks as long as no red flags are present.

The National Institute for Health and Clinical Excellence³ and, jointly, the American College of Physicians and American Pain Society (ACP/APS)⁵ recommend against imaging for patients with nonspecific low back pain in both the acute and chronic settings. Nonspecific low back pain is defined as pain without signs of a serious underlying condition (eg, cancer, infection, cauda equina syndrome), spinal stenosis or radiculopathy, or another specific spinal cause (eg, vertebral compression fracture, ankylosing spondylitis).

In addition, imaging in patients with nonspecific low back pain is one of the top five practices that should be questioned by physicians and patients, according to the American Board of Internal Medicine Foundation in its Choosing Wisely campaign (www.choosingwisely.org).

HARMS ASSOCIATED WITH SPINE IMAGING

Several guidelines cite radiation exposure as a potential harmful consequence of spinal imaging by plain radiography and computed tomography. The American College of Radiology guideline⁴ estimates that the radiation exposure of plain lumbar radiography or lumbar computed tomography ranges between 1 and 10 mSv (3 mSv is the annual amount of ambient radiation in the United States), placing both studies in the medium-range category for relative radiation exposure. The ACP/APS guideline⁵ states that radiation exposure from imaging is a reason to dissuade clinicians from routine use.

Although lumbar magnetic resonance imaging does not carry the risk of radiation exposure, it may result in harm by detecting clinically insignificant abnormalities in more than 30% of patients.⁷ These incidental findings increase with age and may lead to additional and possibly unnecessary testing and invasive treatments. The American College of Occupational and Environmental Medicine guideline⁶ also cites the high prevalence of abnormal findings on plain radiography, magnetic resonance imaging, and other diagnostic tests that are unrelated to symptoms.

CLINICAL BOTTOM LINE

On the basis of current data, the patient described at the beginning of this article should not undergo spine imaging; the results are unlikely to affect his medical management and improve his clinical outcome, and imaging carries a small risk of harm.

A practical approach would be to treat his pain with simple analgesia (a different nonsteroidal anti-inflammatory drug or acetaminophen), address his functional challenges, and reassure him that his chance of having a serious underlying cause of back pain is low (< 1%). He should be told to expect significant improvement in his symptoms within 30 days, be encouraged to stay active, and should be offered patient-focused self-help resources.

The recommendation to conservatively manage patients at low risk without imaging is consistent among all four guidelines. Imaging can be considered for a small subset of patients at high risk with red-flag indications. Potential harms associated with routine imaging of all patients with low back pain include radiation exposure and the high rate of clinically insignificant abnormalities that may lead to unnecessary and invasive interventions that increase expense, patient risk, and anxiety without improving outcomes.

A 38-year-old man is evaluated in an urgent care center for back pain. He is a high school mathematics teacher who reports the insidious onset of low back pain 3 weeks ago. Over the last week the pain has become constant, is worsened by movement, and does not respond to naproxen. He has no history of trauma, malignancy, fever, weight loss, or bladder or bowel symptoms. He does not use intravenous drugs. On examination, he appears uncomfortable and stiff, protecting his back against motion. He has intact sensation, strength, and reflexes. The straight-leg-raising maneuver reproduces his lower back pain but does not cause radicular pain. Should I now order an imaging study such as spinal radiography, computed tomography, or magnetic resonance imaging to direct therapy?

IMAGING STUDIES ARE UNLIKELY TO HELP

This man with acute, nonspecific low back pain does not need spinal imaging. Imaging—ie, spine radiography, computed tomography, or magnetic resonance imaging—is unlikely to be helpful in a patient with nonspecific low back pain and may expose him unnecessarily to radiation and the anxiety of findings that are clinically insignificant.

Imaging studies are often ordered inappropriately as part of the evaluation of back pain in patients such as this. In 2008, the total national cost of treating spine (neck and back) problems was estimated to be $86 billion, representing 9% of total health care costs, which is close to the estimated $89 billion per year spent on cancer care.¹

Spine imaging should be considered only in patients who have a “red flag” such as advanced age, history of trauma, history of cancer, and prolonged corticosteroid use, all of which have been associated with an increased probability (from 9% to 33%) of either spinal fracture or malignancy.² Other red flags include duration longer than 6 weeks, fever, weight loss, and progressive neurologic findings on examination. This patient has none of these.

GUIDELINES AND CHOOSING WISELY

High-quality guidelines from different groups recommend against spine imaging in patients with low back pain.^3–6 These guidelines vary slightly in their patient populations and definitions of uncomplicated low back pain.

The American College of Radiology⁴ and the American College of Occupational and Environmental Medicine⁶ recommend against imaging for patients with both nonspecific and radicular low back pain in the first 6 weeks as long as no red flags are present.

The National Institute for Health and Clinical Excellence³ and, jointly, the American College of Physicians and American Pain Society (ACP/APS)⁵ recommend against imaging for patients with nonspecific low back pain in both the acute and chronic settings. Nonspecific low back pain is defined as pain without signs of a serious underlying condition (eg, cancer, infection, cauda equina syndrome), spinal stenosis or radiculopathy, or another specific spinal cause (eg, vertebral compression fracture, ankylosing spondylitis).

In addition, imaging in patients with nonspecific low back pain is one of the top five practices that should be questioned by physicians and patients, according to the American Board of Internal Medicine Foundation in its Choosing Wisely campaign (www.choosingwisely.org).

HARMS ASSOCIATED WITH SPINE IMAGING

Several guidelines cite radiation exposure as a potential harmful consequence of spinal imaging by plain radiography and computed tomography. The American College of Radiology guideline⁴ estimates that the radiation exposure of plain lumbar radiography or lumbar computed tomography ranges between 1 and 10 mSv (3 mSv is the annual amount of ambient radiation in the United States), placing both studies in the medium-range category for relative radiation exposure. The ACP/APS guideline⁵ states that radiation exposure from imaging is a reason to dissuade clinicians from routine use.

Although lumbar magnetic resonance imaging does not carry the risk of radiation exposure, it may result in harm by detecting clinically insignificant abnormalities in more than 30% of patients.⁷ These incidental findings increase with age and may lead to additional and possibly unnecessary testing and invasive treatments. The American College of Occupational and Environmental Medicine guideline⁶ also cites the high prevalence of abnormal findings on plain radiography, magnetic resonance imaging, and other diagnostic tests that are unrelated to symptoms.

CLINICAL BOTTOM LINE

On the basis of current data, the patient described at the beginning of this article should not undergo spine imaging; the results are unlikely to affect his medical management and improve his clinical outcome, and imaging carries a small risk of harm.

A practical approach would be to treat his pain with simple analgesia (a different nonsteroidal anti-inflammatory drug or acetaminophen), address his functional challenges, and reassure him that his chance of having a serious underlying cause of back pain is low (< 1%). He should be told to expect significant improvement in his symptoms within 30 days, be encouraged to stay active, and should be offered patient-focused self-help resources.

The recommendation to conservatively manage patients at low risk without imaging is consistent among all four guidelines. Imaging can be considered for a small subset of patients at high risk with red-flag indications. Potential harms associated with routine imaging of all patients with low back pain include radiation exposure and the high rate of clinically insignificant abnormalities that may lead to unnecessary and invasive interventions that increase expense, patient risk, and anxiety without improving outcomes.

A 38-year-old man is evaluated in an urgent care center for back pain. He is a high school mathematics teacher who reports the insidious onset of low back pain 3 weeks ago. Over the last week the pain has become constant, is worsened by movement, and does not respond to naproxen. He has no history of trauma, malignancy, fever, weight loss, or bladder or bowel symptoms. He does not use intravenous drugs. On examination, he appears uncomfortable and stiff, protecting his back against motion. He has intact sensation, strength, and reflexes. The straight-leg-raising maneuver reproduces his lower back pain but does not cause radicular pain. Should I now order an imaging study such as spinal radiography, computed tomography, or magnetic resonance imaging to direct therapy?

IMAGING STUDIES ARE UNLIKELY TO HELP

This man with acute, nonspecific low back pain does not need spinal imaging. Imaging—ie, spine radiography, computed tomography, or magnetic resonance imaging—is unlikely to be helpful in a patient with nonspecific low back pain and may expose him unnecessarily to radiation and the anxiety of findings that are clinically insignificant.

Imaging studies are often ordered inappropriately as part of the evaluation of back pain in patients such as this. In 2008, the total national cost of treating spine (neck and back) problems was estimated to be $86 billion, representing 9% of total health care costs, which is close to the estimated $89 billion per year spent on cancer care.¹

Spine imaging should be considered only in patients who have a “red flag” such as advanced age, history of trauma, history of cancer, and prolonged corticosteroid use, all of which have been associated with an increased probability (from 9% to 33%) of either spinal fracture or malignancy.² Other red flags include duration longer than 6 weeks, fever, weight loss, and progressive neurologic findings on examination. This patient has none of these.

GUIDELINES AND CHOOSING WISELY

High-quality guidelines from different groups recommend against spine imaging in patients with low back pain.^3–6 These guidelines vary slightly in their patient populations and definitions of uncomplicated low back pain.

The American College of Radiology⁴ and the American College of Occupational and Environmental Medicine⁶ recommend against imaging for patients with both nonspecific and radicular low back pain in the first 6 weeks as long as no red flags are present.

The National Institute for Health and Clinical Excellence³ and, jointly, the American College of Physicians and American Pain Society (ACP/APS)⁵ recommend against imaging for patients with nonspecific low back pain in both the acute and chronic settings. Nonspecific low back pain is defined as pain without signs of a serious underlying condition (eg, cancer, infection, cauda equina syndrome), spinal stenosis or radiculopathy, or another specific spinal cause (eg, vertebral compression fracture, ankylosing spondylitis).

In addition, imaging in patients with nonspecific low back pain is one of the top five practices that should be questioned by physicians and patients, according to the American Board of Internal Medicine Foundation in its Choosing Wisely campaign (www.choosingwisely.org).

HARMS ASSOCIATED WITH SPINE IMAGING

Several guidelines cite radiation exposure as a potential harmful consequence of spinal imaging by plain radiography and computed tomography. The American College of Radiology guideline⁴ estimates that the radiation exposure of plain lumbar radiography or lumbar computed tomography ranges between 1 and 10 mSv (3 mSv is the annual amount of ambient radiation in the United States), placing both studies in the medium-range category for relative radiation exposure. The ACP/APS guideline⁵ states that radiation exposure from imaging is a reason to dissuade clinicians from routine use.

Although lumbar magnetic resonance imaging does not carry the risk of radiation exposure, it may result in harm by detecting clinically insignificant abnormalities in more than 30% of patients.⁷ These incidental findings increase with age and may lead to additional and possibly unnecessary testing and invasive treatments. The American College of Occupational and Environmental Medicine guideline⁶ also cites the high prevalence of abnormal findings on plain radiography, magnetic resonance imaging, and other diagnostic tests that are unrelated to symptoms.

CLINICAL BOTTOM LINE

On the basis of current data, the patient described at the beginning of this article should not undergo spine imaging; the results are unlikely to affect his medical management and improve his clinical outcome, and imaging carries a small risk of harm.

A practical approach would be to treat his pain with simple analgesia (a different nonsteroidal anti-inflammatory drug or acetaminophen), address his functional challenges, and reassure him that his chance of having a serious underlying cause of back pain is low (< 1%). He should be told to expect significant improvement in his symptoms within 30 days, be encouraged to stay active, and should be offered patient-focused self-help resources.

The recommendation to conservatively manage patients at low risk without imaging is consistent among all four guidelines. Imaging can be considered for a small subset of patients at high risk with red-flag indications. Potential harms associated with routine imaging of all patients with low back pain include radiation exposure and the high rate of clinically insignificant abnormalities that may lead to unnecessary and invasive interventions that increase expense, patient risk, and anxiety without improving outcomes.

"I view every patient as a potential lawsuit." This statement is jolting. Yet more than 69% of neurosurgeons in a recent study said they agreed or strongly agreed with this survey question.¹ What are its implications for patients, for clinical practice, and for the US health care system?

See related article

There are many frustrations in the delivery of health care today, for patients as well as for physicians. For physicians, concern about medical liability is a large one, with secondary implications for both health care costs and quality. The Institute of Medicine has estimated that $765 billion—or 30 cents out of every dollar spent on health care—is wasted annually in the United States, adding to the financial burden of health care without benefiting patients.² A significant portion of this waste, estimated at $210 billion, is related to unnecessary services that are under the control of physicians, including overuse and misuse of diagnostic testing and treatment. This type of care is not only wasteful, but also has the potential to harm.

Factors thought to be responsible for this inappropriate care include the expectations of patients, physician or patient discomfort with uncertainty, and unnecessary and costly consultations. But the factor that physicians cite most often is concern about malpractice suits, raised by 76% of physicians responding to a survey.³

THE DILEMMAS ILLUSTRATED

Here are two cases—to which we will return later—that illustrate the dilemmas faced by physicians deciding how aggressively to pursue a diagnosis:

Patient 1. A 32-year-old woman comes to your office for evaluation of intermittent headaches over the past year. After a detailed history and a normal physical examination, you believe that these are tension headaches. Should you order an imaging study of the brain, just to avoid the risk of a malpractice suit in the unlikely event that this could be the presenting symptom of a brain tumor?

Patient 2. A 60-year-old man presents to the emergency room with pleuritic chest pain. Calculation of pretest probability by modified Wells criteria indicates that pulmonary embolus is unlikely. Because missing the diagnosis can lead to a malpractice suit, should you still order computed tomographic (CT) pulmonary angiography to rule out an embolus?

JUST ONE MORE TEST CAN’T HURT…

Defensive medicine is the ordering or avoiding of tests or procedures primarily out of concern about malpractice liability.⁴ It increases health care costs, but by how much is unclear.⁵ It can harm the patient-physician relationship and trust and can also harm patients, especially if overtesting and treatment lead to false-positive results and more tests, which actually can result in liability. And it is not the highest-value care for patients.

Physicians have an ethical duty to do what is best for the individual patient; they also have a responsibility to society to practice effective health care that uses resources responsibly.⁶ And despite telling ourselves and our patients that one more test will give us confirmation of results and therefore comfort, a recent review found that tests performed based on symptoms with low risk of being caused by serious illness “do little to reassure patients, decrease their anxiety, or resolve their symptoms.”⁷

MALPRACTICE LIABILITY RISK: PERCEPTION AND REALITY

Physicians often overestimate their risk of liability. Only a small percentage (5%) of claims go to trial, and of those, 90% are won by the physician, according to a 2008 analysis by the Physician Insurers Association of America.⁸ A study of claims between 2002 and 2005 found that 4.5% of claims resulted in trial verdicts, of which 80% were in favor of the physician, with cases against internists and internal medicine-based subspecialists least likely to result in a trial verdict (2.7%).⁹

Even so, being sued is extremely stressful and is associated with distinct physical and emotional distress for most physicians.^10,11 Charles has found that, “As a group, physicians are acutely sensitive to any suggestions that they have failed to meet the standard of care or are not ‘good’ doctors… This accusation of failure represents a personal assault.”¹¹

Physician concerns about liability are not very different in states with tort reforms such as damage caps compared with those without.⁵ Some posit that physicians may overestimate the risk of liability as part of the human tendency to overestimate the risk of rare events that are difficult to experience and difficult to control.¹²

In the study of neurosurgeons cited previously, 72% of respondents said they ordered imaging, 67% did laboratory tests, and 66% referred patients for consults “solely” to “minimize the risk of a lawsuit.”¹ The authors of the study maintain that, over time, this affects the standard of care. “While physicians in the past may have used a thorough history and physical to guide imaging, in this study, 72% of neurosurgeons surveyed stated that they order additional imaging studies solely to mitigate liability risk. This suggests that in reality, imaging is becoming a standard part of the initial workup.”¹ Unfortunately, this new standard of care is based on false assumptions and is artificially and inappropriately changed. That perception of liability risk deeply influences practice.

DO THE RIGHT THING: AVOIDING UNNECESSARY TESTING

But physicians also acknowledge the need to follow practice guidelines and to avoid unnecessary testing. In one survey,¹³ 79% strongly or moderately agreed with the statement that physicians “should adhere to clinical guidelines that discourage the use of interventions that have a small proven advantage over standard intervention but cost much more”; 89% strongly or moderately agreed that “doctors need to take a more prominent role in limiting use of unnecessary tests”; and 78% said they “should be solely devoted to individual patients’ best interests, even if that is expensive.”¹³

This may be summarized as, “Provide the clinically appropriate care to the patient based on the best evidence.” But of course, this is easier said than done.

THE ROLE OF EVIDENCE-BASED GUIDELINES

Evidence-based practice guidelines can help support the provision of clinically (and ethically) appropriate care. Medical custom—the care expected of reasonable clinicians under similar circumstances—is generally the legal standard in determining whether a clinician has met a duty of care to a patient in a lawsuit.¹⁴ But practice guidelines can provide strong evidence of what constitutes reasonable care and can, over time, help set the standard for quality of care.

Clinical practice guidelines have grown in recent years, especially after the Institute of Medicine embraced them as a means to address variation in practice patterns and quality of care. But guidelines can conflict. Their effective implementation relies on clinical judgment. If a guideline is not appropriate in a particular case, documentation of why the guideline was not followed may prove prudent. Guidelines are not a safe harbor and have and will be used both defensively and offensively. They are not the last word, but rather another type of expert evidence.¹⁵ However, they are an important one. At the end of the day, the best care is the best defense.

Guidelines not only educate physicians, they also should be used by physicians to educate patients. In addition to developing guidelines for physicians, professional societies should develop and disseminate public education materials that inform patients and their families and caregivers about clinically appropriate care and the problems resulting from overuse and misuse of care.

GETTING BACK TO BASICS

Kroenke noted that preliminary data suggest that the history typically accounts for 75% or more of the diagnostic yield when evaluating common symptoms, the physical examination 10% to 15%, and testing generally less than 10%.¹⁶ Yet health care reimbursement in the United States contains incentives in precisely the reverse order. So, not surprisingly, we keep on testing away. Kroenke says that countering the rush to test will be as challenging and slow as trying to reverse a generation of antibiotic overprescribing.¹⁶

Over time, our reliance on technology as a diagnostic tool has increased, with less emphasis on the history and particularly on the physical examination to solve diagnostic puzzles. Yet most diagnostic errors in a study of outpatient primary care visits were related to breakdowns in the clinical interaction, including the taking of the medical history, the performance of the physical examination, and the ordering of tests. Technologies such as the electronic health record, which can assist in the care of patients, are also a potential source of error and shortcuts in care, as when copying and pasting is used inappropriately.¹⁷ Recognizing the increasing use of technology in practice and team-based approaches to improving care, Singh et al have called for caution and for more “focus on basic clinical skills and related cognitive processes.”¹⁸

The erosion of physical examination skills, discomfort with diagnostic uncertainty, and fear of malpractice litigation have combined to create a perfect storm of technologic overuse and misuse. Unfortunately, this means that our modus operandi is all too frequently built around testing rather than touching.¹⁹

At the same time, it is well established that patients often sue because of dissatisfaction, especially with physician communication and interpersonal skills.¹⁴ Emphasizing the basic skills that include taking a carefully crafted history, performing a skillful physical examination, and communicating effectively and compassionately with patients at every encounter is probably the most successful strategy for simultaneously avoiding malpractice litigation, reducing overused and misused diagnostic testing, and conserving precious health care resources.

Another part of the strategy should include routinely considering a number of straightforward questions before ordering diagnostic tests, such as “Will the test result change my care of the patient?” and “How does ordering this test compare in value with other management strategies for the patient?”^20,21

RETURNING TO THE CASES

Regarding patient 1, the 32-year-old woman with intermittent headaches, the American College of Radiology identified imaging for headache in its list of five areas submitted to the Choosing Wisely campaign in which care may be overused or misused. Specifically, the American College of Radiology says, “Don’t do imaging for uncomplicated headache” in the absence of specific risk factors for structural disease, noting that “incidental findings lead to additional medical procedures and expense that do not improve patient well-being.”²²

For patient 2, the 60-year-old man with pleuritic chest pain, both the American College of Physicians and the American College of Radiology strongly recommend against CT pulmonary angiography for patients in whom calculation of pretest probability indicates a low pretest probability of pulmonary embolism.^22,23 Patients such as these should undergo D-dimer testing rather than CT pulmonary angiography. In this setting, a negative D-dimer test effectively rules out pulmonary embolism and avoids both the radiation and cost associated with the unnecessary imaging study.

According to the Ethics Manual of the American College of Physicians,⁶ “physicians have an obligation to promote their patients’ welfare in an increasingly complex health care system. This entails forthrightly helping patients to understand clinical recommendations and make informed choices among all appropriate care options… It also includes stewardship of finite health care resources so that as many health care needs as possible can be met, whether in the physician’s office, in the hospital or long-term care facility, or at home.”⁶ The basic principles of beneficence and nonmaleficence are aligned with doing the right thing for our patients—ie, providing the appropriate care at the right time and avoiding too much care or too little care. Guided by scientific evidence as well as by guidelines and official recommendations based on such evidence, we are in the best position to provide optimal care for our patients while simultaneously minimizing the risk of malpractice litigation.

As is the case with overprescribing, we must look critically at the inappropriate use of tests and other care applied under the rationale of not wanting to “miss anything”—and the unspoken drivers of financial incentives, new or advanced tests and procedures, and defensive medicine. We know what needs to be done. And nothing short of evidence-based high-value care will do.

Acknowledgment: The authors would like to thank Kathy Wynkoop for editorial assistance.

"I view every patient as a potential lawsuit." This statement is jolting. Yet more than 69% of neurosurgeons in a recent study said they agreed or strongly agreed with this survey question.¹ What are its implications for patients, for clinical practice, and for the US health care system?

See related article

There are many frustrations in the delivery of health care today, for patients as well as for physicians. For physicians, concern about medical liability is a large one, with secondary implications for both health care costs and quality. The Institute of Medicine has estimated that $765 billion—or 30 cents out of every dollar spent on health care—is wasted annually in the United States, adding to the financial burden of health care without benefiting patients.² A significant portion of this waste, estimated at $210 billion, is related to unnecessary services that are under the control of physicians, including overuse and misuse of diagnostic testing and treatment. This type of care is not only wasteful, but also has the potential to harm.

Factors thought to be responsible for this inappropriate care include the expectations of patients, physician or patient discomfort with uncertainty, and unnecessary and costly consultations. But the factor that physicians cite most often is concern about malpractice suits, raised by 76% of physicians responding to a survey.³

THE DILEMMAS ILLUSTRATED

Here are two cases—to which we will return later—that illustrate the dilemmas faced by physicians deciding how aggressively to pursue a diagnosis:

Patient 1. A 32-year-old woman comes to your office for evaluation of intermittent headaches over the past year. After a detailed history and a normal physical examination, you believe that these are tension headaches. Should you order an imaging study of the brain, just to avoid the risk of a malpractice suit in the unlikely event that this could be the presenting symptom of a brain tumor?

Patient 2. A 60-year-old man presents to the emergency room with pleuritic chest pain. Calculation of pretest probability by modified Wells criteria indicates that pulmonary embolus is unlikely. Because missing the diagnosis can lead to a malpractice suit, should you still order computed tomographic (CT) pulmonary angiography to rule out an embolus?

JUST ONE MORE TEST CAN’T HURT…

Defensive medicine is the ordering or avoiding of tests or procedures primarily out of concern about malpractice liability.⁴ It increases health care costs, but by how much is unclear.⁵ It can harm the patient-physician relationship and trust and can also harm patients, especially if overtesting and treatment lead to false-positive results and more tests, which actually can result in liability. And it is not the highest-value care for patients.

Physicians have an ethical duty to do what is best for the individual patient; they also have a responsibility to society to practice effective health care that uses resources responsibly.⁶ And despite telling ourselves and our patients that one more test will give us confirmation of results and therefore comfort, a recent review found that tests performed based on symptoms with low risk of being caused by serious illness “do little to reassure patients, decrease their anxiety, or resolve their symptoms.”⁷

MALPRACTICE LIABILITY RISK: PERCEPTION AND REALITY

Physicians often overestimate their risk of liability. Only a small percentage (5%) of claims go to trial, and of those, 90% are won by the physician, according to a 2008 analysis by the Physician Insurers Association of America.⁸ A study of claims between 2002 and 2005 found that 4.5% of claims resulted in trial verdicts, of which 80% were in favor of the physician, with cases against internists and internal medicine-based subspecialists least likely to result in a trial verdict (2.7%).⁹

Even so, being sued is extremely stressful and is associated with distinct physical and emotional distress for most physicians.^10,11 Charles has found that, “As a group, physicians are acutely sensitive to any suggestions that they have failed to meet the standard of care or are not ‘good’ doctors… This accusation of failure represents a personal assault.”¹¹

Physician concerns about liability are not very different in states with tort reforms such as damage caps compared with those without.⁵ Some posit that physicians may overestimate the risk of liability as part of the human tendency to overestimate the risk of rare events that are difficult to experience and difficult to control.¹²

In the study of neurosurgeons cited previously, 72% of respondents said they ordered imaging, 67% did laboratory tests, and 66% referred patients for consults “solely” to “minimize the risk of a lawsuit.”¹ The authors of the study maintain that, over time, this affects the standard of care. “While physicians in the past may have used a thorough history and physical to guide imaging, in this study, 72% of neurosurgeons surveyed stated that they order additional imaging studies solely to mitigate liability risk. This suggests that in reality, imaging is becoming a standard part of the initial workup.”¹ Unfortunately, this new standard of care is based on false assumptions and is artificially and inappropriately changed. That perception of liability risk deeply influences practice.

DO THE RIGHT THING: AVOIDING UNNECESSARY TESTING

But physicians also acknowledge the need to follow practice guidelines and to avoid unnecessary testing. In one survey,¹³ 79% strongly or moderately agreed with the statement that physicians “should adhere to clinical guidelines that discourage the use of interventions that have a small proven advantage over standard intervention but cost much more”; 89% strongly or moderately agreed that “doctors need to take a more prominent role in limiting use of unnecessary tests”; and 78% said they “should be solely devoted to individual patients’ best interests, even if that is expensive.”¹³

This may be summarized as, “Provide the clinically appropriate care to the patient based on the best evidence.” But of course, this is easier said than done.

THE ROLE OF EVIDENCE-BASED GUIDELINES

Evidence-based practice guidelines can help support the provision of clinically (and ethically) appropriate care. Medical custom—the care expected of reasonable clinicians under similar circumstances—is generally the legal standard in determining whether a clinician has met a duty of care to a patient in a lawsuit.¹⁴ But practice guidelines can provide strong evidence of what constitutes reasonable care and can, over time, help set the standard for quality of care.

Clinical practice guidelines have grown in recent years, especially after the Institute of Medicine embraced them as a means to address variation in practice patterns and quality of care. But guidelines can conflict. Their effective implementation relies on clinical judgment. If a guideline is not appropriate in a particular case, documentation of why the guideline was not followed may prove prudent. Guidelines are not a safe harbor and have and will be used both defensively and offensively. They are not the last word, but rather another type of expert evidence.¹⁵ However, they are an important one. At the end of the day, the best care is the best defense.

Guidelines not only educate physicians, they also should be used by physicians to educate patients. In addition to developing guidelines for physicians, professional societies should develop and disseminate public education materials that inform patients and their families and caregivers about clinically appropriate care and the problems resulting from overuse and misuse of care.

GETTING BACK TO BASICS

Kroenke noted that preliminary data suggest that the history typically accounts for 75% or more of the diagnostic yield when evaluating common symptoms, the physical examination 10% to 15%, and testing generally less than 10%.¹⁶ Yet health care reimbursement in the United States contains incentives in precisely the reverse order. So, not surprisingly, we keep on testing away. Kroenke says that countering the rush to test will be as challenging and slow as trying to reverse a generation of antibiotic overprescribing.¹⁶

Over time, our reliance on technology as a diagnostic tool has increased, with less emphasis on the history and particularly on the physical examination to solve diagnostic puzzles. Yet most diagnostic errors in a study of outpatient primary care visits were related to breakdowns in the clinical interaction, including the taking of the medical history, the performance of the physical examination, and the ordering of tests. Technologies such as the electronic health record, which can assist in the care of patients, are also a potential source of error and shortcuts in care, as when copying and pasting is used inappropriately.¹⁷ Recognizing the increasing use of technology in practice and team-based approaches to improving care, Singh et al have called for caution and for more “focus on basic clinical skills and related cognitive processes.”¹⁸

The erosion of physical examination skills, discomfort with diagnostic uncertainty, and fear of malpractice litigation have combined to create a perfect storm of technologic overuse and misuse. Unfortunately, this means that our modus operandi is all too frequently built around testing rather than touching.¹⁹

At the same time, it is well established that patients often sue because of dissatisfaction, especially with physician communication and interpersonal skills.¹⁴ Emphasizing the basic skills that include taking a carefully crafted history, performing a skillful physical examination, and communicating effectively and compassionately with patients at every encounter is probably the most successful strategy for simultaneously avoiding malpractice litigation, reducing overused and misused diagnostic testing, and conserving precious health care resources.

Another part of the strategy should include routinely considering a number of straightforward questions before ordering diagnostic tests, such as “Will the test result change my care of the patient?” and “How does ordering this test compare in value with other management strategies for the patient?”^20,21

RETURNING TO THE CASES

Regarding patient 1, the 32-year-old woman with intermittent headaches, the American College of Radiology identified imaging for headache in its list of five areas submitted to the Choosing Wisely campaign in which care may be overused or misused. Specifically, the American College of Radiology says, “Don’t do imaging for uncomplicated headache” in the absence of specific risk factors for structural disease, noting that “incidental findings lead to additional medical procedures and expense that do not improve patient well-being.”²²

For patient 2, the 60-year-old man with pleuritic chest pain, both the American College of Physicians and the American College of Radiology strongly recommend against CT pulmonary angiography for patients in whom calculation of pretest probability indicates a low pretest probability of pulmonary embolism.^22,23 Patients such as these should undergo D-dimer testing rather than CT pulmonary angiography. In this setting, a negative D-dimer test effectively rules out pulmonary embolism and avoids both the radiation and cost associated with the unnecessary imaging study.

According to the Ethics Manual of the American College of Physicians,⁶ “physicians have an obligation to promote their patients’ welfare in an increasingly complex health care system. This entails forthrightly helping patients to understand clinical recommendations and make informed choices among all appropriate care options… It also includes stewardship of finite health care resources so that as many health care needs as possible can be met, whether in the physician’s office, in the hospital or long-term care facility, or at home.”⁶ The basic principles of beneficence and nonmaleficence are aligned with doing the right thing for our patients—ie, providing the appropriate care at the right time and avoiding too much care or too little care. Guided by scientific evidence as well as by guidelines and official recommendations based on such evidence, we are in the best position to provide optimal care for our patients while simultaneously minimizing the risk of malpractice litigation.

As is the case with overprescribing, we must look critically at the inappropriate use of tests and other care applied under the rationale of not wanting to “miss anything”—and the unspoken drivers of financial incentives, new or advanced tests and procedures, and defensive medicine. We know what needs to be done. And nothing short of evidence-based high-value care will do.

Acknowledgment: The authors would like to thank Kathy Wynkoop for editorial assistance.

"I view every patient as a potential lawsuit." This statement is jolting. Yet more than 69% of neurosurgeons in a recent study said they agreed or strongly agreed with this survey question.¹ What are its implications for patients, for clinical practice, and for the US health care system?

See related article

There are many frustrations in the delivery of health care today, for patients as well as for physicians. For physicians, concern about medical liability is a large one, with secondary implications for both health care costs and quality. The Institute of Medicine has estimated that $765 billion—or 30 cents out of every dollar spent on health care—is wasted annually in the United States, adding to the financial burden of health care without benefiting patients.² A significant portion of this waste, estimated at $210 billion, is related to unnecessary services that are under the control of physicians, including overuse and misuse of diagnostic testing and treatment. This type of care is not only wasteful, but also has the potential to harm.

Factors thought to be responsible for this inappropriate care include the expectations of patients, physician or patient discomfort with uncertainty, and unnecessary and costly consultations. But the factor that physicians cite most often is concern about malpractice suits, raised by 76% of physicians responding to a survey.³

THE DILEMMAS ILLUSTRATED

Here are two cases—to which we will return later—that illustrate the dilemmas faced by physicians deciding how aggressively to pursue a diagnosis:

Patient 1. A 32-year-old woman comes to your office for evaluation of intermittent headaches over the past year. After a detailed history and a normal physical examination, you believe that these are tension headaches. Should you order an imaging study of the brain, just to avoid the risk of a malpractice suit in the unlikely event that this could be the presenting symptom of a brain tumor?

Patient 2. A 60-year-old man presents to the emergency room with pleuritic chest pain. Calculation of pretest probability by modified Wells criteria indicates that pulmonary embolus is unlikely. Because missing the diagnosis can lead to a malpractice suit, should you still order computed tomographic (CT) pulmonary angiography to rule out an embolus?

JUST ONE MORE TEST CAN’T HURT…

Defensive medicine is the ordering or avoiding of tests or procedures primarily out of concern about malpractice liability.⁴ It increases health care costs, but by how much is unclear.⁵ It can harm the patient-physician relationship and trust and can also harm patients, especially if overtesting and treatment lead to false-positive results and more tests, which actually can result in liability. And it is not the highest-value care for patients.

Physicians have an ethical duty to do what is best for the individual patient; they also have a responsibility to society to practice effective health care that uses resources responsibly.⁶ And despite telling ourselves and our patients that one more test will give us confirmation of results and therefore comfort, a recent review found that tests performed based on symptoms with low risk of being caused by serious illness “do little to reassure patients, decrease their anxiety, or resolve their symptoms.”⁷

MALPRACTICE LIABILITY RISK: PERCEPTION AND REALITY

Physicians often overestimate their risk of liability. Only a small percentage (5%) of claims go to trial, and of those, 90% are won by the physician, according to a 2008 analysis by the Physician Insurers Association of America.⁸ A study of claims between 2002 and 2005 found that 4.5% of claims resulted in trial verdicts, of which 80% were in favor of the physician, with cases against internists and internal medicine-based subspecialists least likely to result in a trial verdict (2.7%).⁹

Even so, being sued is extremely stressful and is associated with distinct physical and emotional distress for most physicians.^10,11 Charles has found that, “As a group, physicians are acutely sensitive to any suggestions that they have failed to meet the standard of care or are not ‘good’ doctors… This accusation of failure represents a personal assault.”¹¹

Physician concerns about liability are not very different in states with tort reforms such as damage caps compared with those without.⁵ Some posit that physicians may overestimate the risk of liability as part of the human tendency to overestimate the risk of rare events that are difficult to experience and difficult to control.¹²

In the study of neurosurgeons cited previously, 72% of respondents said they ordered imaging, 67% did laboratory tests, and 66% referred patients for consults “solely” to “minimize the risk of a lawsuit.”¹ The authors of the study maintain that, over time, this affects the standard of care. “While physicians in the past may have used a thorough history and physical to guide imaging, in this study, 72% of neurosurgeons surveyed stated that they order additional imaging studies solely to mitigate liability risk. This suggests that in reality, imaging is becoming a standard part of the initial workup.”¹ Unfortunately, this new standard of care is based on false assumptions and is artificially and inappropriately changed. That perception of liability risk deeply influences practice.

DO THE RIGHT THING: AVOIDING UNNECESSARY TESTING

But physicians also acknowledge the need to follow practice guidelines and to avoid unnecessary testing. In one survey,¹³ 79% strongly or moderately agreed with the statement that physicians “should adhere to clinical guidelines that discourage the use of interventions that have a small proven advantage over standard intervention but cost much more”; 89% strongly or moderately agreed that “doctors need to take a more prominent role in limiting use of unnecessary tests”; and 78% said they “should be solely devoted to individual patients’ best interests, even if that is expensive.”¹³

This may be summarized as, “Provide the clinically appropriate care to the patient based on the best evidence.” But of course, this is easier said than done.

THE ROLE OF EVIDENCE-BASED GUIDELINES

Evidence-based practice guidelines can help support the provision of clinically (and ethically) appropriate care. Medical custom—the care expected of reasonable clinicians under similar circumstances—is generally the legal standard in determining whether a clinician has met a duty of care to a patient in a lawsuit.¹⁴ But practice guidelines can provide strong evidence of what constitutes reasonable care and can, over time, help set the standard for quality of care.

Clinical practice guidelines have grown in recent years, especially after the Institute of Medicine embraced them as a means to address variation in practice patterns and quality of care. But guidelines can conflict. Their effective implementation relies on clinical judgment. If a guideline is not appropriate in a particular case, documentation of why the guideline was not followed may prove prudent. Guidelines are not a safe harbor and have and will be used both defensively and offensively. They are not the last word, but rather another type of expert evidence.¹⁵ However, they are an important one. At the end of the day, the best care is the best defense.

Guidelines not only educate physicians, they also should be used by physicians to educate patients. In addition to developing guidelines for physicians, professional societies should develop and disseminate public education materials that inform patients and their families and caregivers about clinically appropriate care and the problems resulting from overuse and misuse of care.

GETTING BACK TO BASICS

Kroenke noted that preliminary data suggest that the history typically accounts for 75% or more of the diagnostic yield when evaluating common symptoms, the physical examination 10% to 15%, and testing generally less than 10%.¹⁶ Yet health care reimbursement in the United States contains incentives in precisely the reverse order. So, not surprisingly, we keep on testing away. Kroenke says that countering the rush to test will be as challenging and slow as trying to reverse a generation of antibiotic overprescribing.¹⁶

Over time, our reliance on technology as a diagnostic tool has increased, with less emphasis on the history and particularly on the physical examination to solve diagnostic puzzles. Yet most diagnostic errors in a study of outpatient primary care visits were related to breakdowns in the clinical interaction, including the taking of the medical history, the performance of the physical examination, and the ordering of tests. Technologies such as the electronic health record, which can assist in the care of patients, are also a potential source of error and shortcuts in care, as when copying and pasting is used inappropriately.¹⁷ Recognizing the increasing use of technology in practice and team-based approaches to improving care, Singh et al have called for caution and for more “focus on basic clinical skills and related cognitive processes.”¹⁸

The erosion of physical examination skills, discomfort with diagnostic uncertainty, and fear of malpractice litigation have combined to create a perfect storm of technologic overuse and misuse. Unfortunately, this means that our modus operandi is all too frequently built around testing rather than touching.¹⁹

At the same time, it is well established that patients often sue because of dissatisfaction, especially with physician communication and interpersonal skills.¹⁴ Emphasizing the basic skills that include taking a carefully crafted history, performing a skillful physical examination, and communicating effectively and compassionately with patients at every encounter is probably the most successful strategy for simultaneously avoiding malpractice litigation, reducing overused and misused diagnostic testing, and conserving precious health care resources.

Another part of the strategy should include routinely considering a number of straightforward questions before ordering diagnostic tests, such as “Will the test result change my care of the patient?” and “How does ordering this test compare in value with other management strategies for the patient?”^20,21

RETURNING TO THE CASES

Regarding patient 1, the 32-year-old woman with intermittent headaches, the American College of Radiology identified imaging for headache in its list of five areas submitted to the Choosing Wisely campaign in which care may be overused or misused. Specifically, the American College of Radiology says, “Don’t do imaging for uncomplicated headache” in the absence of specific risk factors for structural disease, noting that “incidental findings lead to additional medical procedures and expense that do not improve patient well-being.”²²

For patient 2, the 60-year-old man with pleuritic chest pain, both the American College of Physicians and the American College of Radiology strongly recommend against CT pulmonary angiography for patients in whom calculation of pretest probability indicates a low pretest probability of pulmonary embolism.^22,23 Patients such as these should undergo D-dimer testing rather than CT pulmonary angiography. In this setting, a negative D-dimer test effectively rules out pulmonary embolism and avoids both the radiation and cost associated with the unnecessary imaging study.

According to the Ethics Manual of the American College of Physicians,⁶ “physicians have an obligation to promote their patients’ welfare in an increasingly complex health care system. This entails forthrightly helping patients to understand clinical recommendations and make informed choices among all appropriate care options… It also includes stewardship of finite health care resources so that as many health care needs as possible can be met, whether in the physician’s office, in the hospital or long-term care facility, or at home.”⁶ The basic principles of beneficence and nonmaleficence are aligned with doing the right thing for our patients—ie, providing the appropriate care at the right time and avoiding too much care or too little care. Guided by scientific evidence as well as by guidelines and official recommendations based on such evidence, we are in the best position to provide optimal care for our patients while simultaneously minimizing the risk of malpractice litigation.

As is the case with overprescribing, we must look critically at the inappropriate use of tests and other care applied under the rationale of not wanting to “miss anything”—and the unspoken drivers of financial incentives, new or advanced tests and procedures, and defensive medicine. We know what needs to be done. And nothing short of evidence-based high-value care will do.

Acknowledgment: The authors would like to thank Kathy Wynkoop for editorial assistance.

We have all seen cartoons of an unhappy wife awake in bed next to her loudly snoring husband. Casual conversations with friends, particularly female ones, indicate that this is an accurate representation of a common scenario. As I have started to probe more diligently for evidence of obstructive sleep apnea (OSA) in my patients, not just in those who complain of “fatigue” (more patients use this term with me than “sleepiness”), I see a lot of shaking of heads from the wives of men who deny that they snore or have disrupted sleep. I am not implying that this is solely a male disease. Far from it. But as in other medical scenarios, the Y chromosome seems somehow linked to denial or lack of awareness of symptoms. In any event, I was not a bit surprised to read in the review by Dr. Mehra in this issue of the Journal that 17% of adults may have OSA.

As awareness of OSA has grown and testing for it has become easier, multiple reports have documented associated comorbidities: hypertension, restless leg syndrome, gout, and neurocognitive deficits. Home devices to treat OSA have significantly improved. Technological advances have led to the development of small, quiet, smart pumps that provide continuous positive airway pressure (CPAP) via nasal or relatively comfortable full-face masks. Compliance and patient acceptance of CPAP have improved, although patient education and a bit of cajoling in the office are still necessary—less so if the bedroom partner is also present for this discussion.

Perhaps surprising is a growing pool of data showing that CPAP’s benefits extend to more than just reducing sleepiness. It can reduce nocturia, restless leg syndrome, arrhythmias including atrial fibrillation, gastric reflux, and fatal and nonfatal cardiovascular events. Snoring and thus probably sleep-partner satisfaction are also improved.

Several physiologic mechanisms may explain the benefits of CPAP, including reducing hypoxic episodes (explaining its effect on atrial fibrillation), altered atrial natriuretic factor levels (thus reducing nocturia), and changing intrathoracic pressure (thus reducing gastric reflux). It will be interesting to see if there are long-term effects of successfully applied CPAP on neurocognition and progression of neurodegenerative diseases.

While high-decibel snoring and snorting are not present in all patients with OSA, it is quite clear now that they represent far more than an annoyance. We should be vigilant about looking for OSA and strongly encourage a trial of CPAP in appropriately diagnosed patients.

We have all seen cartoons of an unhappy wife awake in bed next to her loudly snoring husband. Casual conversations with friends, particularly female ones, indicate that this is an accurate representation of a common scenario. As I have started to probe more diligently for evidence of obstructive sleep apnea (OSA) in my patients, not just in those who complain of “fatigue” (more patients use this term with me than “sleepiness”), I see a lot of shaking of heads from the wives of men who deny that they snore or have disrupted sleep. I am not implying that this is solely a male disease. Far from it. But as in other medical scenarios, the Y chromosome seems somehow linked to denial or lack of awareness of symptoms. In any event, I was not a bit surprised to read in the review by Dr. Mehra in this issue of the Journal that 17% of adults may have OSA.

As awareness of OSA has grown and testing for it has become easier, multiple reports have documented associated comorbidities: hypertension, restless leg syndrome, gout, and neurocognitive deficits. Home devices to treat OSA have significantly improved. Technological advances have led to the development of small, quiet, smart pumps that provide continuous positive airway pressure (CPAP) via nasal or relatively comfortable full-face masks. Compliance and patient acceptance of CPAP have improved, although patient education and a bit of cajoling in the office are still necessary—less so if the bedroom partner is also present for this discussion.

Perhaps surprising is a growing pool of data showing that CPAP’s benefits extend to more than just reducing sleepiness. It can reduce nocturia, restless leg syndrome, arrhythmias including atrial fibrillation, gastric reflux, and fatal and nonfatal cardiovascular events. Snoring and thus probably sleep-partner satisfaction are also improved.

Several physiologic mechanisms may explain the benefits of CPAP, including reducing hypoxic episodes (explaining its effect on atrial fibrillation), altered atrial natriuretic factor levels (thus reducing nocturia), and changing intrathoracic pressure (thus reducing gastric reflux). It will be interesting to see if there are long-term effects of successfully applied CPAP on neurocognition and progression of neurodegenerative diseases.

While high-decibel snoring and snorting are not present in all patients with OSA, it is quite clear now that they represent far more than an annoyance. We should be vigilant about looking for OSA and strongly encourage a trial of CPAP in appropriately diagnosed patients.

We have all seen cartoons of an unhappy wife awake in bed next to her loudly snoring husband. Casual conversations with friends, particularly female ones, indicate that this is an accurate representation of a common scenario. As I have started to probe more diligently for evidence of obstructive sleep apnea (OSA) in my patients, not just in those who complain of “fatigue” (more patients use this term with me than “sleepiness”), I see a lot of shaking of heads from the wives of men who deny that they snore or have disrupted sleep. I am not implying that this is solely a male disease. Far from it. But as in other medical scenarios, the Y chromosome seems somehow linked to denial or lack of awareness of symptoms. In any event, I was not a bit surprised to read in the review by Dr. Mehra in this issue of the Journal that 17% of adults may have OSA.

As awareness of OSA has grown and testing for it has become easier, multiple reports have documented associated comorbidities: hypertension, restless leg syndrome, gout, and neurocognitive deficits. Home devices to treat OSA have significantly improved. Technological advances have led to the development of small, quiet, smart pumps that provide continuous positive airway pressure (CPAP) via nasal or relatively comfortable full-face masks. Compliance and patient acceptance of CPAP have improved, although patient education and a bit of cajoling in the office are still necessary—less so if the bedroom partner is also present for this discussion.

Perhaps surprising is a growing pool of data showing that CPAP’s benefits extend to more than just reducing sleepiness. It can reduce nocturia, restless leg syndrome, arrhythmias including atrial fibrillation, gastric reflux, and fatal and nonfatal cardiovascular events. Snoring and thus probably sleep-partner satisfaction are also improved.

Several physiologic mechanisms may explain the benefits of CPAP, including reducing hypoxic episodes (explaining its effect on atrial fibrillation), altered atrial natriuretic factor levels (thus reducing nocturia), and changing intrathoracic pressure (thus reducing gastric reflux). It will be interesting to see if there are long-term effects of successfully applied CPAP on neurocognition and progression of neurodegenerative diseases.

While high-decibel snoring and snorting are not present in all patients with OSA, it is quite clear now that they represent far more than an annoyance. We should be vigilant about looking for OSA and strongly encourage a trial of CPAP in appropriately diagnosed patients.

Obstructive sleep apnea (OSA) is common and poorly recognized and, if untreated, leads to serious health consequences. This article discusses the epidemiology of OSA, describes common presenting signs and symptoms, and reviews diagnostic testing and treatment options. Adverse health effects related to untreated sleep apnea are also discussed.

COMMON, POORLY RECOGNIZED, AND COSTLY IF UNTREATED

OSA is very common in the general population and is associated with substantial morbidity and mortality. An estimated 17% of the general adult population has OSA, and the numbers are increasing with the obesity epidemic. Nearly 1 in 15 adults has at least moderate sleep apnea,^1,2 and approximately 85% of cases are estimated to be undiagnosed.³ A 1999 study estimated that untreated OSA resulted in approximately $3.4 billion in additional medical costs per year in the United States,⁴ a figure that is likely to be higher now, given the rising prevalence of OSA. The prevalence of OSA in primary care and subspecialty clinics is even higher than in the community, as more than half of patients who have diabetes or hypertension and 30% to 40% of patients with coronary artery disease are estimated to have OSA.^5–7

REPETITIVE UPPER-AIRWAY COLLAPSE

During sleep, parasympathetic activity is enhanced and the muscle tone of the upper airway is decreased, particularly in the pharyngeal dilator muscles. Still, even in the supine position, a healthy person maintains patency of the airway and adequate airflow during sleep.

OSA is characterized by repetitive complete or partial collapse of the upper airway during sleep, resulting in an apneic or hypopneic event, respectively, and often causing snoring from upper-airway tissue vibration.

People who are susceptible to OSA typically have a smaller, more collapsible airway that is often less distensible and has a higher critical closing pressure. Radiographic and physiologic data have shown that the airway dimensions of patients with OSA are smaller than in those without OSA. The shape of the airway of a patient with OSA is often elliptical, given the extrinsic compression of the lateral aspects of the airway by increased size of the parapharyngeal fat pads. OSA episodes are characterized by closure of the upper airway and by progressively increasing respiratory efforts driven by chemoreceptor and mechanoreceptor stimuli, culminating in an arousal from sleep and a reopening of the airway.

The disease-defining metric used for assessing OSA severity is the apnea-hypopnea index, ie, the number of apneas and hypopneas that occur per hour of sleep.⁸ An apneic or hypopneic event is identified during polysomnography by the complete cessation of airflow or by a reduction in airflow for 10 seconds or longer (Figure 1).

HEALTH CONSEQUENCES IF UNTREATED

Untreated sleep apnea causes numerous pathophysiologic perturbations, including chronic intermittent hypoxia, ventilatory overshoot hyperoxia, increased sympathetic nervous system activity, intrathoracic pressure swings, hypercapnea, sleep fragmentation, increased arousals, reduced sleep duration, and fragmentation of rapid-eye-movement sleep.

Intermittent hypoxia activates the sympathetic nervous system and causes pulmonary vasoconstriction, with increases in pulmonary arterial pressures and myocardial workload. Sympathetic activation, ascertained by peroneal microneurography, has been shown to be increased not only during sleep but also persisting during wakefulness in patients with untreated OSA vs those without OSA.⁹ Autonomic nervous system fluctuations accompany apneic episodes, resulting in enhanced parasympathetic tone and sympathetic activation associated with a rise in blood pressure and heart rate that occur after the respiratory event.

Intermediate pathways that link the negative pathophysiologic effects of OSA with adverse health outcomes include increased systemic inflammation, increased oxidative stress, metabolic dysfunction, insulin resistance, hypercoagulability, endothelial dysfunction, and autonomic dysfunction.

As a result, a variety of adverse clinical outcomes are associated with untreated OSA, including systemic hypertension, ischemic heart disease and atherosclerosis, diastolic dysfunction, congestive heart failure, cardiac arrhythmias, stroke, increased risk of death, and sudden death, as well as noncardiovascular outcomes such as gout, neurocognitive deficits, and mood disorders.¹⁰

Inflammatory and atherogenic effects

Increased levels of markers of systemic inflammation, prothrombosis, and oxidative stress have been observed in OSA and may be key pathophysiologic links between OSA and cardiovascular sequelae. OSA has been associated with up-regulation of a number of inflammatory mediators: interleukin (IL) 6, soluble IL-6 receptor, IL-8, tumor necrosis factor alpha, and C-reactive protein. Soluble IL-6 levels in particular are higher in people who have sleep-disordered breathing, as reflected by the apnea-hypopnea index independent of obesity, with relationships stronger in the morning than in the evening. This likely reflects the overnight OSA-related physiologic stress.¹¹

Thrombotic potential is also enhanced, with higher levels of plasminogen activator inhibitor 1, fibrinogen, P-selectin, and vascular endothelial growth factor. Some of these factors normally have a diurnal cycle, with higher levels in the morning, but in OSA, increasing OSA severity is associated with increased prothrombotic potential in the morning hours. Of interest, levels of these substances showed a plateau effect, rising in people who had only mildly elevated apnea-hypopnea indices and then leveling off.¹² Intermittent hypoxia followed by ventilatory overshoot hyperoxia, characteristic of sleep apnea, provides the ideal environment for augmentation of oxidative stress, with evidence of increased oxidation of serum proteins and lipids. Hypoxia and oxygen-derived free radicals may result in cardiac myocyte injury. Experimental data demonstrate that intermittent hypoxia combined with a high-fat diet results in synergistic acceleration of evidence of atherogenic lesions.

Patients with OSA also have evidence of endothelial dysfunction, insulin resistance, and dyslipidemia, all pathways that can facilitate the progression of atherosclerosis in OSA.^13–15

Cardiac arrhythmias

In the Sleep Heart Health Study, a multicenter epidemiologic study designed to examine the relationships of OSA and cardiovascular outcomes, those who had moderate to severe OSA had a risk of ventricular and atrial arrhythmias two to four times higher than those without OSA, even after correction for the confounding influences of obesity and underlying cardiovascular risk.¹⁴ These findings were corroborated in subsequent work highlighting monotonic dose-response relationships with increasing OSA severity and increased odds of atrial and ventricular arrhythmia in a cohort of about 3,000 older men.¹¹ Additional compelling evidence of a causal relationship is that the risk of discrete arrhythmic events is markedly increased after a respiratory disturbance in sleep.¹⁶

In patients who successfully underwent cardioversion for atrial fibrillation, those who had sleep apnea but were not treated with continuous positive airway pressure (CPAP) had a much higher rate of recurrence of atrial fibrillation during the subsequent year than those with CPAP-treated sleep apnea and than controls never diagnosed with sleep apnea. In the untreated patients with sleep apnea, the mean nocturnal fall in oxygen saturation was significantly greater in those who had recurrence of atrial fibrillation than in those who did not, suggesting hypoxia as an important mechanism contributing to atrial fibrillation.¹⁷

Since then, several other retrospective studies have shown similar findings after pulmonary vein antrum isolation and ablation in terms of reduction of atrial fibrillation recurrence with CPAP treatment in OSA.¹⁸

Walia et al¹⁹ described a patient with moderate sleep apnea who underwent a split-night study. During the baseline part of the study, the patient had about 18 ectopic beats per minute. During the second portion of the study while CPAP was applied, progressively fewer ectopic beats occurred as airway pressure was increased until a normal rhythm without ectopic beats was achieved at the goal treatment CPAP pressure setting.

Cardiovascular disease, stroke, and death

Marin et al²⁰ followed about 1,500 men for 10 years, including some who had severe OSA, some with sleep apnea who were treated with CPAP, and controls. The risk of nonfatal and fatal cardiovascular disease events was nearly three times higher in those with severe disease than in healthy participants. Those treated with CPAP had a risk approximately the same as in the control group.

The Sleep Heart Study followed approximately 6,000 people with untreated sleep apnea for a median of nearly 9 years. It found a significant association between the apnea-hypopnea index and ischemic stroke, especially in men.²¹ Survival in patients with heart failure is also associated with the degree of OSA; patients with more severe disease (an apnea-hypopnea index ≥ 15) have a nearly three times greater risk of death than those with no disease or only mild disease (apnea-hypopnea index < 15).²²

From the standpoint of health care utilization, findings that central sleep apnea predicts an increased risk of hospital readmission in heart failure are of particular interest.²³

People with OSA are at increased risk of nocturnal sudden cardiac death.²⁴ Sleep apnea is also associated with an increased overall death rate, and the higher the apnea-hypopnea index, the higher the death rate,²⁵ even after adjusting for age, sex, body mass index, and underlying cardiovascular risk, with findings most pronounced in men under age 70.

Motor vehicle accidents

The need for caution during driving should be discussed with every patient, as motor vehicle accidents are an immediate danger to the patient and others. The association with motor vehicle accidents is independent of sleepiness, and drivers with sleep apnea often do not perceive performance impairment. Young et al²⁶ found that men who snored were 3.4 times as likely to have an accident over a 5-year period, and that men and women with an apnea-hypopnea index greater than 15 were more than 7 times as likely to have multiple accidents over a 5-year period, highlighting the importance of discussing, documenting, and expeditiously diagnosing and treating OSA, particularly in those who report drowsiness while driving.

CLINICAL RISK FACTORS

Risk factors can be divided into nonmodifiable and modifiable ones.

Nonmodifiable factors

Age. Bimodal distributions in OSA prevalence have been observed; ie, that the pediatric population and people who are middle-aged have the highest prevalence of OSA. A linear relationship between sleep apnea prevalence and age until about age 65 was identified in data from the Sleep Heart Health Study.²⁷ After that, the prevalence rates plateau; it is unclear if this is secondary to natural remission of the disease after a certain age or because patients with more severe disease have died by that age (ie, survivorship bias), blunting an increase in prevalence.

Sex. Men develop sleep apnea at a rate three to five times that of women. Several explanations have been proposed to account for this.^28,29 Sex hormones are one factor; women with sleep apnea on hormone replacement therapy have a significantly less-severe sleep apnea burden than other postmenopausal women,³⁰ suggesting a positive effect from estrogen. Sex-based differences in fat distribution, length and collapsibility of the upper airway, genioglossal activity, neurochemical control mechanisms, and arousal response may also contribute to prevalence differences between men and women.

As with coronary artery disease, the presentation of sleep apnea may be atypical in women, particularly around menopause. Sleep apnea should be considered in women who have snoring and daytime sleepiness.

Race. Whites, African Americans, and Asians have a similar prevalence of sleep apnea, but groups differ in obesity rates and craniofacial anatomy.^31–34 Asians tend to have craniofacial skeletal restriction. African Americans are more likely to have upper-airway soft-tissue risk and to develop more severe OSA. Whites tend to have both craniofacial and soft-tissue risk. For those with craniofacial anatomy predisposing to OSA, even mild obesity can make it manifest.

Syndromes that predispose to OSA can include craniofacial structural abnormalities, connective tissue problems, or alterations in ventilatory control (eg, Marfan, Down, and Pierre Robin syndromes).

Modifiable risk factors

Obesity (body mass index ≥ 30 kg/m²) is a firmly established risk factor, but not all obese patients develop obstructive sleep apnea, and not all people with sleep apnea are obese.

Obesity increases risk by altering the geometry and function of the upper airway, increasing collapsibility. The changes are particularly pronounced in the lateral aspects of the pharynx.³⁵

Obesity also affects respiratory drive, likely in part from leptin resistance. Load compensation is another contributing factor: the increased mass in the thorax and abdomen increases the work of breathing and reduces functional residual capacity, increasing oxygen demands and leading to atelectasis and ventilation-perfusion mismatch.

Although obesity is an important risk factor, it is important to recognize that obesity is not the only one to consider: most people with an apnea-hypopnea index of 5 or greater are not obese. The relationship between body mass index and sleep apnea is weaker in children and in the elderly, probably because other risk factors are more pronounced.³⁶

Craniofacial structural abnormalities such as retrognathia (abnormal posterior position of the mandible) and micrognathia (undersized mandible) can increase the risk of OSA because of a resulting posteriorly displaced genioglossus muscle. Other conditions can alter chemosensitivity, affecting the pH and carbon dioxide level of the blood and therefore affecting ventilatory control mechanisms, making the person more prone to developing sleep apnea. Children and young adults may have tonsillar tissue that obstructs the airway.

The site of obstruction can be behind the palate (retropalatal), behind the tongue (retroglossal), or below the pharynx (hypopharyngeal). This helps explain why positive air way pressure—unlike surgery, which addresses a specific area—is often successful, as it serves to splint or treat all aspects of the airway.

FATIGUE, SLEEPINESS, SNORING, RESTLESS SLEEP

Sleep apnea can result in presentation of multiple signs and symptoms (Table 1).

Daytime sleepiness and fatigue are the most common symptoms. Although nonspecific, they are often quite pronounced. Two short questionnaires—the Epworth Sleepiness Scale³⁷ and the Fatigue Severity Scale—can help distinguish between these two symptoms and assess their impact on a patient’s daily life. In the Epworth Sleepiness Scale, the patient rates his or her chance of dozing on a 4-point scale (0 = would never doze, to 3 = high chance of dozing) in eight situations:

• Sitting and reading
• Watching television
• Sitting inactive in a public place
• As a passenger in a car for an hour without a break
• Lying down to rest in the afternoon
• Sitting and talking to someone
• Sitting quietly after a lunch without alcohol
• In a car while stopped for a few minutes in traffic.

A score of 10 or more is consistent with significant subjective sleepiness.

The Fatigue Severity Scale assesses the impact of fatigue on daily living.

Snoring is a common and specific symptom of sleep apnea; however, not all patients who snore have OSA.

Restlessness during sleep is very common—patients may disturb their bed partner by moving around a lot during sleep or report that the sheets are “all over the place” by morning.

Nocturia can also be a sign of sleep apnea and can contribute to sleep fragmentation. A proposed mechanism of this symptom includes alterations of intrathoracic pressure resulting in atrial stretch, which release atrial natriuretic peptide, leading to nocturia. Treating with CPAP has been found to reduce levels of atrial natriuretic peptide, contributing to better sleep.³⁸

Morning headache may occur and is likely related to increased CO₂ levels, which appear to culminate in the morning hours. End-tidal or transcutaneous CO₂ monitoring during polysomnography can help elucidate the presence of sleep-related hypoventilation.

Libido is often diminished and can actually be improved with CPAP. This is therefore an important point to discuss with patients, as improved libido can often serve as an incentive for adherence to OSA treatment.

Insomnia exists in about 15% of patients, primarily as a result of sleep apnea-related with treatment.

Sweating, particularly forehead sweating associated with sleep apnea, more commonly occurs in children.

The STOP-BANG questionnaire (Table 2)³⁹ was primarily validated in preoperative anesthesia testing. However, because of its ease of use and favorable performance characteristics, it is increasingly used to predict the likelihood of finding OSA before polysomnography. A score of 3 or more has a sensitivity of 93%.

PHYSICAL EXAMINATION PROVIDES CLUES

Although the physical examination may be normal, certain findings indicate risk (Table 3). Obesity alone is not an accepted indication for polysomnography unless there are concomitant worrisome signs or symptoms. Of note, those who are morbidly obese (BMI > 40 kg/m²) have a prevalence of sleep apnea greater than 70%.

The classification by Friedman et al⁴⁰ provides an indicator of risk. The patient is examined with the mouth opened wide and the tongue in a neutral natural position. Grades:

• I—Entire uvula and tonsils are visible
• II—Entire uvula is visible, but tonsils are not
• III—Soft palate is visible, but uvula is not
• IV—Only the hard palate is visible.

Especially in children and young adults, enlarged tonsils (or “kissing tonsils”) and a boggy edematous uvula set the stage for obstructive sleep apnea.

DIAGNOSIS REQUIRES SLEEP TESTING

A sleep study is the primary means of diagnosing OSA. Polysomnography includes electrooculography to determine when rapid-eye-movement sleep occurs; electromyography to measure muscle activity in the chin to help determine onset of sleep, with peripheral leads in the leg to measure leg movements; electroencephalography (EEG) to measure neural activity; electrocardiography; pulse oximetry to measure oxygen saturation; measurement of oronasal flow; and measurements of chest wall effort and body position using thoracic and abdominal belts that expand and contract with breathing; and audio recording to detect snoring.

Attended polysomnography requires the constant presence of a trained sleep technologist to monitor for technical issues and patient adherence.

End-tidal CO₂ monitoring is a reasonable method to detect sleep-related hypoventilation but is not routinely performed in the United States. Transcutaneous CO₂ monitoring is a different way to monitor CO₂ used in the setting of positive airway pressure.

Polysomnography in a normal patient shows a regular pattern of increasing and decreasing airflow with inspiration and expiration while stable oxygen saturation is maintained.

In contrast, polysomnography of a patient with sleep apnea shows repetitive periods of no airflow, oxygen desaturation, and often evidence of thoracoabdominal paradox, punctuated by arousals on EEG associated with sympathetic activation (Figure 1). When the patient falls asleep, upper-airway muscle tone is reduced, causing an apneic event with hypoxia and pleural pressure swings. These prompt arousals with sympathetic activation that reestablish upper-airway muscle tone, allowing ventilation and reoxygenation to resume with a return to sleep.

Apnea-hypopnea index indicates severity

Sleep apnea severity is graded using the apnea-hypopnea index, ie, the number of apneic and hypopneic events per hour of sleep (Table 4).⁴¹ Events must last at least 10 seconds to be considered, ie, two consecutive missed breaths based on an average normal respiratory rate of about 12 breaths per minute for the typical adult.

The apnea-hypopnea index usually correlates with the severity of oxygen desaturation and with electrocardiographic abnormalities, including tachybradycardia and arrhythmias.

Although history, physical examination, and prediction tools are helpful in determining the likelihood that a patient has OSA, only polysomnography testing can establish the diagnosis. To diagnose OSA, 15 or more obstructive events per hour must be observed by polysomnography, or at least 5 events per hour with one of the following:

• Daytime sleepiness, sleep attacks, unrefreshing sleep, fatigue, or insomnia
• Waking with breath-holding, gasping, or choking
• Observer-reported loud snoring or breathing interruptions.⁴¹

Split-night study determines diagnosis and optimum treatment

The split-night study has two parts: the first is diagnostic polysomnography, followed by identification of the positive airway pressure that optimally treats the sleep apnea. The apnea-hypopnea index guides the need for the split-night study, with 40 being the established threshold according to the American Academy of Sleep Medicine.

A home sleep study is appropriate for some patients

Home sleep testing is typically more limited than standard polysomnography; it monitors airflow, effort, and oxygenation. The test is intended for adults with a high pretest probability of moderate to severe obstructive sleep apnea (STOP-BANG score ≥ 3). It is not intended for screening of asymptomatic patients or for those with coexisting sleep disorders (eg, central sleep apnea, sleep hypoventilation, periodic limb movements, insomnia, circadian rhythm disorders, parasomnias, narcolepsy) or medical disorders (eg, moderate to severe heart failure or other cardiac disease, symptomatic neurologic disease, moderate to severe pulmonary disease).⁴² Since March 2008, the Centers for Medicare and Medicaid Services has covered CPAP for obstructive sleep apnea based on diagnosis by home sleep study testing.⁴³

TREATMENT OF SLEEP APNEA

Basic steps for reducing OSA are:

Weight loss. Even small weight changes can significantly affect the severity of sleep apnea, perhaps even leading to a reassessment of the degree of OSA and CPAP requirements. Longitudinal epidemiologic data demonstrate that a 10% weight loss correlates with a 26% reduction in the apnea-hypopnea index, and conversely, a 10% weight gain is associated with a 32% increase.⁴⁴

Some studies have found that bariatric surgery cures OSA in 75% to 88% of cases, independent of approach.^45,46 However, a trial in 60 obese patients with OSA who were randomized to either a low-calorie diet or bariatric surgery found no statistical difference in the apnea-hypopnea index between the two groups despite greater weight loss in the surgery group.⁴⁷

Avoiding certain medications. Benzodiazepines, narcotics, and alcohol reduce upper airway muscle tone and should be avoided. No medications are associated with improvement of OSA, although acetazolamide may be used to treat central sleep apnea.

Positional therapy. Sleeping on the back exacerbates the problem. Supine-related OSA occurs as a result of several factors, including gravity, airway anatomy, airway critical closing pressures, and effects on upper-airway dilator muscle function.

Sleep hygiene. General recommendations to engage in behaviors to promote sleep are recommended, including keeping consistent sleep-wake times, not watching television in bed, and avoidance of caffeine intake, particularly within 4 to 6 hours of bedtime.

POSITIVE AIRWAY PRESSURE THERAPY

Nasal CPAP is the treatment of choice and is successful in 95% of patients when used consistently. It is not as costly as surgery, and results in improved long-term survival compared with uvulopalatopharyngoplasty. Another advantage is that the pressure can be retitrated as the patient’s condition changes, for example after a weight change or during pregnancy.

More than 15 randomized controlled trials have examined the effect of sleep apnea treatment with CPAP compared with either sham CPAP or another control. In a meta-analysis, CPAP was found to lead to an average systolic blood pressure reduction of about 2.5 mm Hg and a diastolic blood pressure reduction of 1.8 mm Hg. Although these reductions may seem negligible, benefits may be significant for cardiovascular outcomes.^48,49

Challenges to treatment adherence

Adherence is the most commonly discussed problem with CPAP, but long-term adherence rates are comparable to medication compliance—about 60% to 70%. To optimize adherence, communication is important to ensure that problems are identified and addressed as they arise. Showing patients examples of apneic events and oxygen desaturation from their sleep study can enhance their understanding of OSA and its importance. Patients need to understand the serious nature of the disease and that CPAP therapy can significantly improve their quality of life and overall health, particularly from a cardiovascular perspective.

CPAP masks can be uncomfortable, posing a major barrier to compliance. But a number of mask designs are available, such as the nasal mask, the nasal pillow mask, and the oronasal mask. For patients with claustrophobia, the nasal pillow mask is an option, as it does not cover the face.

Some patients note symptoms of nasal congestion, although in many patients CPAP improves it. If congestion is a problem, the use of heated humidification with the machine, intranasal saline or gel, or nasal corticosteroids can help relieve it.

Pressure intolerance is a common problem. For those who feel that the pressure is too high, settings can be adjusted so that the pressure is gradually reduced between inspiration and expiration, ie, the use of expiratory pressure relief or consideration of the use of bilevel positive airway pressure.

Aerophagia (swallowing air) is a less common problem. It can also potentially be relieved with use of bilevel positive airway pressure.

Many patients develop skin irritation, which can be helped with moleskin, available at any pharmacy.

Social stigma can be a problem. Education regarding the importance of the treatment to health is essential.

Machine noise is less of a problem with the new machine models, but if it is a problem, a white-noise device or earplugs may help.

Other measures to improve compliance are keeping the regimen simple and ensuring that family support is adequate.

Medicare requires evidence of use and benefit

Medicare requires that clinical benefit be documented between the 31st and 91st day after initiating CPAP therapy. This requires face-to-face clinical reevaluation by the treating physician to document improved symptoms and objective evidence of adherence to use of the device. The devices can store usage patterns, and Medicare requires at least 4 hours per night on 70% of nights during a consecutive 30-day period in the first 3 months of use.

ALTERNATIVE THERAPIES

Alternative therapies may be options for some patients, in particular those who cannot use CPAP or who get no benefit from it. These include oral appliances for those with mild to moderate OSA^50–53 and various surgical procedures, eg, uvulopalatopharyngoplasty,^54,55 maxillomanibular advancement,⁵⁶ tracheostomy (standard treatment before CPAP was identified as an effective treatment),^57,58 and adenotonsillectomy (in children).⁵⁹

Supplemental oxygen is not a first-line treatment for OSA and in general has not been found to be very effective, particularly in terms of intermediate cardiovascular outcomes,^60–62 although a subset of patients with high loop gain may benefit from it.⁶³ Loop gain is a measure of the tendency of the ventilatory control system to amplify respiration in response to a change, conferring less stable control of breathing.

Several novel alternative therapies are starting to be used. Although all of them have been shown to improve measures of OSA, none is as effective as CPAP in improving OSA severity. New therapies include the nasal expiratory positive airway pressure device,⁶⁴ oral pressure therapy,⁶⁵ and hypoglossal nerve stimulation.⁶⁶

Obstructive sleep apnea (OSA) is common and poorly recognized and, if untreated, leads to serious health consequences. This article discusses the epidemiology of OSA, describes common presenting signs and symptoms, and reviews diagnostic testing and treatment options. Adverse health effects related to untreated sleep apnea are also discussed.

COMMON, POORLY RECOGNIZED, AND COSTLY IF UNTREATED

OSA is very common in the general population and is associated with substantial morbidity and mortality. An estimated 17% of the general adult population has OSA, and the numbers are increasing with the obesity epidemic. Nearly 1 in 15 adults has at least moderate sleep apnea,^1,2 and approximately 85% of cases are estimated to be undiagnosed.³ A 1999 study estimated that untreated OSA resulted in approximately $3.4 billion in additional medical costs per year in the United States,⁴ a figure that is likely to be higher now, given the rising prevalence of OSA. The prevalence of OSA in primary care and subspecialty clinics is even higher than in the community, as more than half of patients who have diabetes or hypertension and 30% to 40% of patients with coronary artery disease are estimated to have OSA.^5–7

REPETITIVE UPPER-AIRWAY COLLAPSE

During sleep, parasympathetic activity is enhanced and the muscle tone of the upper airway is decreased, particularly in the pharyngeal dilator muscles. Still, even in the supine position, a healthy person maintains patency of the airway and adequate airflow during sleep.

OSA is characterized by repetitive complete or partial collapse of the upper airway during sleep, resulting in an apneic or hypopneic event, respectively, and often causing snoring from upper-airway tissue vibration.

People who are susceptible to OSA typically have a smaller, more collapsible airway that is often less distensible and has a higher critical closing pressure. Radiographic and physiologic data have shown that the airway dimensions of patients with OSA are smaller than in those without OSA. The shape of the airway of a patient with OSA is often elliptical, given the extrinsic compression of the lateral aspects of the airway by increased size of the parapharyngeal fat pads. OSA episodes are characterized by closure of the upper airway and by progressively increasing respiratory efforts driven by chemoreceptor and mechanoreceptor stimuli, culminating in an arousal from sleep and a reopening of the airway.

The disease-defining metric used for assessing OSA severity is the apnea-hypopnea index, ie, the number of apneas and hypopneas that occur per hour of sleep.⁸ An apneic or hypopneic event is identified during polysomnography by the complete cessation of airflow or by a reduction in airflow for 10 seconds or longer (Figure 1).

HEALTH CONSEQUENCES IF UNTREATED

Untreated sleep apnea causes numerous pathophysiologic perturbations, including chronic intermittent hypoxia, ventilatory overshoot hyperoxia, increased sympathetic nervous system activity, intrathoracic pressure swings, hypercapnea, sleep fragmentation, increased arousals, reduced sleep duration, and fragmentation of rapid-eye-movement sleep.

Intermittent hypoxia activates the sympathetic nervous system and causes pulmonary vasoconstriction, with increases in pulmonary arterial pressures and myocardial workload. Sympathetic activation, ascertained by peroneal microneurography, has been shown to be increased not only during sleep but also persisting during wakefulness in patients with untreated OSA vs those without OSA.⁹ Autonomic nervous system fluctuations accompany apneic episodes, resulting in enhanced parasympathetic tone and sympathetic activation associated with a rise in blood pressure and heart rate that occur after the respiratory event.

Intermediate pathways that link the negative pathophysiologic effects of OSA with adverse health outcomes include increased systemic inflammation, increased oxidative stress, metabolic dysfunction, insulin resistance, hypercoagulability, endothelial dysfunction, and autonomic dysfunction.

As a result, a variety of adverse clinical outcomes are associated with untreated OSA, including systemic hypertension, ischemic heart disease and atherosclerosis, diastolic dysfunction, congestive heart failure, cardiac arrhythmias, stroke, increased risk of death, and sudden death, as well as noncardiovascular outcomes such as gout, neurocognitive deficits, and mood disorders.¹⁰

Inflammatory and atherogenic effects

Increased levels of markers of systemic inflammation, prothrombosis, and oxidative stress have been observed in OSA and may be key pathophysiologic links between OSA and cardiovascular sequelae. OSA has been associated with up-regulation of a number of inflammatory mediators: interleukin (IL) 6, soluble IL-6 receptor, IL-8, tumor necrosis factor alpha, and C-reactive protein. Soluble IL-6 levels in particular are higher in people who have sleep-disordered breathing, as reflected by the apnea-hypopnea index independent of obesity, with relationships stronger in the morning than in the evening. This likely reflects the overnight OSA-related physiologic stress.¹¹

Thrombotic potential is also enhanced, with higher levels of plasminogen activator inhibitor 1, fibrinogen, P-selectin, and vascular endothelial growth factor. Some of these factors normally have a diurnal cycle, with higher levels in the morning, but in OSA, increasing OSA severity is associated with increased prothrombotic potential in the morning hours. Of interest, levels of these substances showed a plateau effect, rising in people who had only mildly elevated apnea-hypopnea indices and then leveling off.¹² Intermittent hypoxia followed by ventilatory overshoot hyperoxia, characteristic of sleep apnea, provides the ideal environment for augmentation of oxidative stress, with evidence of increased oxidation of serum proteins and lipids. Hypoxia and oxygen-derived free radicals may result in cardiac myocyte injury. Experimental data demonstrate that intermittent hypoxia combined with a high-fat diet results in synergistic acceleration of evidence of atherogenic lesions.

Patients with OSA also have evidence of endothelial dysfunction, insulin resistance, and dyslipidemia, all pathways that can facilitate the progression of atherosclerosis in OSA.^13–15

Cardiac arrhythmias

In the Sleep Heart Health Study, a multicenter epidemiologic study designed to examine the relationships of OSA and cardiovascular outcomes, those who had moderate to severe OSA had a risk of ventricular and atrial arrhythmias two to four times higher than those without OSA, even after correction for the confounding influences of obesity and underlying cardiovascular risk.¹⁴ These findings were corroborated in subsequent work highlighting monotonic dose-response relationships with increasing OSA severity and increased odds of atrial and ventricular arrhythmia in a cohort of about 3,000 older men.¹¹ Additional compelling evidence of a causal relationship is that the risk of discrete arrhythmic events is markedly increased after a respiratory disturbance in sleep.¹⁶

In patients who successfully underwent cardioversion for atrial fibrillation, those who had sleep apnea but were not treated with continuous positive airway pressure (CPAP) had a much higher rate of recurrence of atrial fibrillation during the subsequent year than those with CPAP-treated sleep apnea and than controls never diagnosed with sleep apnea. In the untreated patients with sleep apnea, the mean nocturnal fall in oxygen saturation was significantly greater in those who had recurrence of atrial fibrillation than in those who did not, suggesting hypoxia as an important mechanism contributing to atrial fibrillation.¹⁷

Since then, several other retrospective studies have shown similar findings after pulmonary vein antrum isolation and ablation in terms of reduction of atrial fibrillation recurrence with CPAP treatment in OSA.¹⁸

Walia et al¹⁹ described a patient with moderate sleep apnea who underwent a split-night study. During the baseline part of the study, the patient had about 18 ectopic beats per minute. During the second portion of the study while CPAP was applied, progressively fewer ectopic beats occurred as airway pressure was increased until a normal rhythm without ectopic beats was achieved at the goal treatment CPAP pressure setting.

Cardiovascular disease, stroke, and death

Marin et al²⁰ followed about 1,500 men for 10 years, including some who had severe OSA, some with sleep apnea who were treated with CPAP, and controls. The risk of nonfatal and fatal cardiovascular disease events was nearly three times higher in those with severe disease than in healthy participants. Those treated with CPAP had a risk approximately the same as in the control group.

The Sleep Heart Study followed approximately 6,000 people with untreated sleep apnea for a median of nearly 9 years. It found a significant association between the apnea-hypopnea index and ischemic stroke, especially in men.²¹ Survival in patients with heart failure is also associated with the degree of OSA; patients with more severe disease (an apnea-hypopnea index ≥ 15) have a nearly three times greater risk of death than those with no disease or only mild disease (apnea-hypopnea index < 15).²²

From the standpoint of health care utilization, findings that central sleep apnea predicts an increased risk of hospital readmission in heart failure are of particular interest.²³

People with OSA are at increased risk of nocturnal sudden cardiac death.²⁴ Sleep apnea is also associated with an increased overall death rate, and the higher the apnea-hypopnea index, the higher the death rate,²⁵ even after adjusting for age, sex, body mass index, and underlying cardiovascular risk, with findings most pronounced in men under age 70.

Motor vehicle accidents

The need for caution during driving should be discussed with every patient, as motor vehicle accidents are an immediate danger to the patient and others. The association with motor vehicle accidents is independent of sleepiness, and drivers with sleep apnea often do not perceive performance impairment. Young et al²⁶ found that men who snored were 3.4 times as likely to have an accident over a 5-year period, and that men and women with an apnea-hypopnea index greater than 15 were more than 7 times as likely to have multiple accidents over a 5-year period, highlighting the importance of discussing, documenting, and expeditiously diagnosing and treating OSA, particularly in those who report drowsiness while driving.

CLINICAL RISK FACTORS

Risk factors can be divided into nonmodifiable and modifiable ones.

Nonmodifiable factors

Age. Bimodal distributions in OSA prevalence have been observed; ie, that the pediatric population and people who are middle-aged have the highest prevalence of OSA. A linear relationship between sleep apnea prevalence and age until about age 65 was identified in data from the Sleep Heart Health Study.²⁷ After that, the prevalence rates plateau; it is unclear if this is secondary to natural remission of the disease after a certain age or because patients with more severe disease have died by that age (ie, survivorship bias), blunting an increase in prevalence.

Sex. Men develop sleep apnea at a rate three to five times that of women. Several explanations have been proposed to account for this.^28,29 Sex hormones are one factor; women with sleep apnea on hormone replacement therapy have a significantly less-severe sleep apnea burden than other postmenopausal women,³⁰ suggesting a positive effect from estrogen. Sex-based differences in fat distribution, length and collapsibility of the upper airway, genioglossal activity, neurochemical control mechanisms, and arousal response may also contribute to prevalence differences between men and women.

As with coronary artery disease, the presentation of sleep apnea may be atypical in women, particularly around menopause. Sleep apnea should be considered in women who have snoring and daytime sleepiness.

Race. Whites, African Americans, and Asians have a similar prevalence of sleep apnea, but groups differ in obesity rates and craniofacial anatomy.^31–34 Asians tend to have craniofacial skeletal restriction. African Americans are more likely to have upper-airway soft-tissue risk and to develop more severe OSA. Whites tend to have both craniofacial and soft-tissue risk. For those with craniofacial anatomy predisposing to OSA, even mild obesity can make it manifest.

Syndromes that predispose to OSA can include craniofacial structural abnormalities, connective tissue problems, or alterations in ventilatory control (eg, Marfan, Down, and Pierre Robin syndromes).

Modifiable risk factors

Obesity (body mass index ≥ 30 kg/m²) is a firmly established risk factor, but not all obese patients develop obstructive sleep apnea, and not all people with sleep apnea are obese.

Obesity increases risk by altering the geometry and function of the upper airway, increasing collapsibility. The changes are particularly pronounced in the lateral aspects of the pharynx.³⁵

Obesity also affects respiratory drive, likely in part from leptin resistance. Load compensation is another contributing factor: the increased mass in the thorax and abdomen increases the work of breathing and reduces functional residual capacity, increasing oxygen demands and leading to atelectasis and ventilation-perfusion mismatch.

Although obesity is an important risk factor, it is important to recognize that obesity is not the only one to consider: most people with an apnea-hypopnea index of 5 or greater are not obese. The relationship between body mass index and sleep apnea is weaker in children and in the elderly, probably because other risk factors are more pronounced.³⁶

Craniofacial structural abnormalities such as retrognathia (abnormal posterior position of the mandible) and micrognathia (undersized mandible) can increase the risk of OSA because of a resulting posteriorly displaced genioglossus muscle. Other conditions can alter chemosensitivity, affecting the pH and carbon dioxide level of the blood and therefore affecting ventilatory control mechanisms, making the person more prone to developing sleep apnea. Children and young adults may have tonsillar tissue that obstructs the airway.

The site of obstruction can be behind the palate (retropalatal), behind the tongue (retroglossal), or below the pharynx (hypopharyngeal). This helps explain why positive air way pressure—unlike surgery, which addresses a specific area—is often successful, as it serves to splint or treat all aspects of the airway.

FATIGUE, SLEEPINESS, SNORING, RESTLESS SLEEP

Sleep apnea can result in presentation of multiple signs and symptoms (Table 1).

Daytime sleepiness and fatigue are the most common symptoms. Although nonspecific, they are often quite pronounced. Two short questionnaires—the Epworth Sleepiness Scale³⁷ and the Fatigue Severity Scale—can help distinguish between these two symptoms and assess their impact on a patient’s daily life. In the Epworth Sleepiness Scale, the patient rates his or her chance of dozing on a 4-point scale (0 = would never doze, to 3 = high chance of dozing) in eight situations:

• Sitting and reading
• Watching television
• Sitting inactive in a public place
• As a passenger in a car for an hour without a break
• Lying down to rest in the afternoon
• Sitting and talking to someone
• Sitting quietly after a lunch without alcohol
• In a car while stopped for a few minutes in traffic.

A score of 10 or more is consistent with significant subjective sleepiness.

The Fatigue Severity Scale assesses the impact of fatigue on daily living.

Snoring is a common and specific symptom of sleep apnea; however, not all patients who snore have OSA.

Restlessness during sleep is very common—patients may disturb their bed partner by moving around a lot during sleep or report that the sheets are “all over the place” by morning.

Nocturia can also be a sign of sleep apnea and can contribute to sleep fragmentation. A proposed mechanism of this symptom includes alterations of intrathoracic pressure resulting in atrial stretch, which release atrial natriuretic peptide, leading to nocturia. Treating with CPAP has been found to reduce levels of atrial natriuretic peptide, contributing to better sleep.³⁸

Morning headache may occur and is likely related to increased CO₂ levels, which appear to culminate in the morning hours. End-tidal or transcutaneous CO₂ monitoring during polysomnography can help elucidate the presence of sleep-related hypoventilation.

Libido is often diminished and can actually be improved with CPAP. This is therefore an important point to discuss with patients, as improved libido can often serve as an incentive for adherence to OSA treatment.

Insomnia exists in about 15% of patients, primarily as a result of sleep apnea-related with treatment.

Sweating, particularly forehead sweating associated with sleep apnea, more commonly occurs in children.

The STOP-BANG questionnaire (Table 2)³⁹ was primarily validated in preoperative anesthesia testing. However, because of its ease of use and favorable performance characteristics, it is increasingly used to predict the likelihood of finding OSA before polysomnography. A score of 3 or more has a sensitivity of 93%.

PHYSICAL EXAMINATION PROVIDES CLUES

Although the physical examination may be normal, certain findings indicate risk (Table 3). Obesity alone is not an accepted indication for polysomnography unless there are concomitant worrisome signs or symptoms. Of note, those who are morbidly obese (BMI > 40 kg/m²) have a prevalence of sleep apnea greater than 70%.

The classification by Friedman et al⁴⁰ provides an indicator of risk. The patient is examined with the mouth opened wide and the tongue in a neutral natural position. Grades:

• I—Entire uvula and tonsils are visible
• II—Entire uvula is visible, but tonsils are not
• III—Soft palate is visible, but uvula is not
• IV—Only the hard palate is visible.

Especially in children and young adults, enlarged tonsils (or “kissing tonsils”) and a boggy edematous uvula set the stage for obstructive sleep apnea.

DIAGNOSIS REQUIRES SLEEP TESTING

A sleep study is the primary means of diagnosing OSA. Polysomnography includes electrooculography to determine when rapid-eye-movement sleep occurs; electromyography to measure muscle activity in the chin to help determine onset of sleep, with peripheral leads in the leg to measure leg movements; electroencephalography (EEG) to measure neural activity; electrocardiography; pulse oximetry to measure oxygen saturation; measurement of oronasal flow; and measurements of chest wall effort and body position using thoracic and abdominal belts that expand and contract with breathing; and audio recording to detect snoring.

Attended polysomnography requires the constant presence of a trained sleep technologist to monitor for technical issues and patient adherence.

End-tidal CO₂ monitoring is a reasonable method to detect sleep-related hypoventilation but is not routinely performed in the United States. Transcutaneous CO₂ monitoring is a different way to monitor CO₂ used in the setting of positive airway pressure.

Polysomnography in a normal patient shows a regular pattern of increasing and decreasing airflow with inspiration and expiration while stable oxygen saturation is maintained.

In contrast, polysomnography of a patient with sleep apnea shows repetitive periods of no airflow, oxygen desaturation, and often evidence of thoracoabdominal paradox, punctuated by arousals on EEG associated with sympathetic activation (Figure 1). When the patient falls asleep, upper-airway muscle tone is reduced, causing an apneic event with hypoxia and pleural pressure swings. These prompt arousals with sympathetic activation that reestablish upper-airway muscle tone, allowing ventilation and reoxygenation to resume with a return to sleep.

Apnea-hypopnea index indicates severity

Sleep apnea severity is graded using the apnea-hypopnea index, ie, the number of apneic and hypopneic events per hour of sleep (Table 4).⁴¹ Events must last at least 10 seconds to be considered, ie, two consecutive missed breaths based on an average normal respiratory rate of about 12 breaths per minute for the typical adult.

The apnea-hypopnea index usually correlates with the severity of oxygen desaturation and with electrocardiographic abnormalities, including tachybradycardia and arrhythmias.

Although history, physical examination, and prediction tools are helpful in determining the likelihood that a patient has OSA, only polysomnography testing can establish the diagnosis. To diagnose OSA, 15 or more obstructive events per hour must be observed by polysomnography, or at least 5 events per hour with one of the following:

• Daytime sleepiness, sleep attacks, unrefreshing sleep, fatigue, or insomnia
• Waking with breath-holding, gasping, or choking
• Observer-reported loud snoring or breathing interruptions.⁴¹

Split-night study determines diagnosis and optimum treatment

The split-night study has two parts: the first is diagnostic polysomnography, followed by identification of the positive airway pressure that optimally treats the sleep apnea. The apnea-hypopnea index guides the need for the split-night study, with 40 being the established threshold according to the American Academy of Sleep Medicine.

A home sleep study is appropriate for some patients

Home sleep testing is typically more limited than standard polysomnography; it monitors airflow, effort, and oxygenation. The test is intended for adults with a high pretest probability of moderate to severe obstructive sleep apnea (STOP-BANG score ≥ 3). It is not intended for screening of asymptomatic patients or for those with coexisting sleep disorders (eg, central sleep apnea, sleep hypoventilation, periodic limb movements, insomnia, circadian rhythm disorders, parasomnias, narcolepsy) or medical disorders (eg, moderate to severe heart failure or other cardiac disease, symptomatic neurologic disease, moderate to severe pulmonary disease).⁴² Since March 2008, the Centers for Medicare and Medicaid Services has covered CPAP for obstructive sleep apnea based on diagnosis by home sleep study testing.⁴³

TREATMENT OF SLEEP APNEA

Basic steps for reducing OSA are:

Weight loss. Even small weight changes can significantly affect the severity of sleep apnea, perhaps even leading to a reassessment of the degree of OSA and CPAP requirements. Longitudinal epidemiologic data demonstrate that a 10% weight loss correlates with a 26% reduction in the apnea-hypopnea index, and conversely, a 10% weight gain is associated with a 32% increase.⁴⁴

Some studies have found that bariatric surgery cures OSA in 75% to 88% of cases, independent of approach.^45,46 However, a trial in 60 obese patients with OSA who were randomized to either a low-calorie diet or bariatric surgery found no statistical difference in the apnea-hypopnea index between the two groups despite greater weight loss in the surgery group.⁴⁷

Avoiding certain medications. Benzodiazepines, narcotics, and alcohol reduce upper airway muscle tone and should be avoided. No medications are associated with improvement of OSA, although acetazolamide may be used to treat central sleep apnea.

Positional therapy. Sleeping on the back exacerbates the problem. Supine-related OSA occurs as a result of several factors, including gravity, airway anatomy, airway critical closing pressures, and effects on upper-airway dilator muscle function.

Sleep hygiene. General recommendations to engage in behaviors to promote sleep are recommended, including keeping consistent sleep-wake times, not watching television in bed, and avoidance of caffeine intake, particularly within 4 to 6 hours of bedtime.

POSITIVE AIRWAY PRESSURE THERAPY

Nasal CPAP is the treatment of choice and is successful in 95% of patients when used consistently. It is not as costly as surgery, and results in improved long-term survival compared with uvulopalatopharyngoplasty. Another advantage is that the pressure can be retitrated as the patient’s condition changes, for example after a weight change or during pregnancy.

More than 15 randomized controlled trials have examined the effect of sleep apnea treatment with CPAP compared with either sham CPAP or another control. In a meta-analysis, CPAP was found to lead to an average systolic blood pressure reduction of about 2.5 mm Hg and a diastolic blood pressure reduction of 1.8 mm Hg. Although these reductions may seem negligible, benefits may be significant for cardiovascular outcomes.^48,49

Challenges to treatment adherence

Adherence is the most commonly discussed problem with CPAP, but long-term adherence rates are comparable to medication compliance—about 60% to 70%. To optimize adherence, communication is important to ensure that problems are identified and addressed as they arise. Showing patients examples of apneic events and oxygen desaturation from their sleep study can enhance their understanding of OSA and its importance. Patients need to understand the serious nature of the disease and that CPAP therapy can significantly improve their quality of life and overall health, particularly from a cardiovascular perspective.

CPAP masks can be uncomfortable, posing a major barrier to compliance. But a number of mask designs are available, such as the nasal mask, the nasal pillow mask, and the oronasal mask. For patients with claustrophobia, the nasal pillow mask is an option, as it does not cover the face.

Some patients note symptoms of nasal congestion, although in many patients CPAP improves it. If congestion is a problem, the use of heated humidification with the machine, intranasal saline or gel, or nasal corticosteroids can help relieve it.

Pressure intolerance is a common problem. For those who feel that the pressure is too high, settings can be adjusted so that the pressure is gradually reduced between inspiration and expiration, ie, the use of expiratory pressure relief or consideration of the use of bilevel positive airway pressure.

Aerophagia (swallowing air) is a less common problem. It can also potentially be relieved with use of bilevel positive airway pressure.

Many patients develop skin irritation, which can be helped with moleskin, available at any pharmacy.

Social stigma can be a problem. Education regarding the importance of the treatment to health is essential.

Machine noise is less of a problem with the new machine models, but if it is a problem, a white-noise device or earplugs may help.

Other measures to improve compliance are keeping the regimen simple and ensuring that family support is adequate.

Medicare requires evidence of use and benefit

Medicare requires that clinical benefit be documented between the 31st and 91st day after initiating CPAP therapy. This requires face-to-face clinical reevaluation by the treating physician to document improved symptoms and objective evidence of adherence to use of the device. The devices can store usage patterns, and Medicare requires at least 4 hours per night on 70% of nights during a consecutive 30-day period in the first 3 months of use.

ALTERNATIVE THERAPIES

Alternative therapies may be options for some patients, in particular those who cannot use CPAP or who get no benefit from it. These include oral appliances for those with mild to moderate OSA^50–53 and various surgical procedures, eg, uvulopalatopharyngoplasty,^54,55 maxillomanibular advancement,⁵⁶ tracheostomy (standard treatment before CPAP was identified as an effective treatment),^57,58 and adenotonsillectomy (in children).⁵⁹

Supplemental oxygen is not a first-line treatment for OSA and in general has not been found to be very effective, particularly in terms of intermediate cardiovascular outcomes,^60–62 although a subset of patients with high loop gain may benefit from it.⁶³ Loop gain is a measure of the tendency of the ventilatory control system to amplify respiration in response to a change, conferring less stable control of breathing.

Several novel alternative therapies are starting to be used. Although all of them have been shown to improve measures of OSA, none is as effective as CPAP in improving OSA severity. New therapies include the nasal expiratory positive airway pressure device,⁶⁴ oral pressure therapy,⁶⁵ and hypoglossal nerve stimulation.⁶⁶

Obstructive sleep apnea (OSA) is common and poorly recognized and, if untreated, leads to serious health consequences. This article discusses the epidemiology of OSA, describes common presenting signs and symptoms, and reviews diagnostic testing and treatment options. Adverse health effects related to untreated sleep apnea are also discussed.

COMMON, POORLY RECOGNIZED, AND COSTLY IF UNTREATED

OSA is very common in the general population and is associated with substantial morbidity and mortality. An estimated 17% of the general adult population has OSA, and the numbers are increasing with the obesity epidemic. Nearly 1 in 15 adults has at least moderate sleep apnea,^1,2 and approximately 85% of cases are estimated to be undiagnosed.³ A 1999 study estimated that untreated OSA resulted in approximately $3.4 billion in additional medical costs per year in the United States,⁴ a figure that is likely to be higher now, given the rising prevalence of OSA. The prevalence of OSA in primary care and subspecialty clinics is even higher than in the community, as more than half of patients who have diabetes or hypertension and 30% to 40% of patients with coronary artery disease are estimated to have OSA.^5–7

REPETITIVE UPPER-AIRWAY COLLAPSE

During sleep, parasympathetic activity is enhanced and the muscle tone of the upper airway is decreased, particularly in the pharyngeal dilator muscles. Still, even in the supine position, a healthy person maintains patency of the airway and adequate airflow during sleep.

OSA is characterized by repetitive complete or partial collapse of the upper airway during sleep, resulting in an apneic or hypopneic event, respectively, and often causing snoring from upper-airway tissue vibration.

People who are susceptible to OSA typically have a smaller, more collapsible airway that is often less distensible and has a higher critical closing pressure. Radiographic and physiologic data have shown that the airway dimensions of patients with OSA are smaller than in those without OSA. The shape of the airway of a patient with OSA is often elliptical, given the extrinsic compression of the lateral aspects of the airway by increased size of the parapharyngeal fat pads. OSA episodes are characterized by closure of the upper airway and by progressively increasing respiratory efforts driven by chemoreceptor and mechanoreceptor stimuli, culminating in an arousal from sleep and a reopening of the airway.

The disease-defining metric used for assessing OSA severity is the apnea-hypopnea index, ie, the number of apneas and hypopneas that occur per hour of sleep.⁸ An apneic or hypopneic event is identified during polysomnography by the complete cessation of airflow or by a reduction in airflow for 10 seconds or longer (Figure 1).

HEALTH CONSEQUENCES IF UNTREATED

Untreated sleep apnea causes numerous pathophysiologic perturbations, including chronic intermittent hypoxia, ventilatory overshoot hyperoxia, increased sympathetic nervous system activity, intrathoracic pressure swings, hypercapnea, sleep fragmentation, increased arousals, reduced sleep duration, and fragmentation of rapid-eye-movement sleep.

Intermittent hypoxia activates the sympathetic nervous system and causes pulmonary vasoconstriction, with increases in pulmonary arterial pressures and myocardial workload. Sympathetic activation, ascertained by peroneal microneurography, has been shown to be increased not only during sleep but also persisting during wakefulness in patients with untreated OSA vs those without OSA.⁹ Autonomic nervous system fluctuations accompany apneic episodes, resulting in enhanced parasympathetic tone and sympathetic activation associated with a rise in blood pressure and heart rate that occur after the respiratory event.

Intermediate pathways that link the negative pathophysiologic effects of OSA with adverse health outcomes include increased systemic inflammation, increased oxidative stress, metabolic dysfunction, insulin resistance, hypercoagulability, endothelial dysfunction, and autonomic dysfunction.

As a result, a variety of adverse clinical outcomes are associated with untreated OSA, including systemic hypertension, ischemic heart disease and atherosclerosis, diastolic dysfunction, congestive heart failure, cardiac arrhythmias, stroke, increased risk of death, and sudden death, as well as noncardiovascular outcomes such as gout, neurocognitive deficits, and mood disorders.¹⁰

Inflammatory and atherogenic effects

Increased levels of markers of systemic inflammation, prothrombosis, and oxidative stress have been observed in OSA and may be key pathophysiologic links between OSA and cardiovascular sequelae. OSA has been associated with up-regulation of a number of inflammatory mediators: interleukin (IL) 6, soluble IL-6 receptor, IL-8, tumor necrosis factor alpha, and C-reactive protein. Soluble IL-6 levels in particular are higher in people who have sleep-disordered breathing, as reflected by the apnea-hypopnea index independent of obesity, with relationships stronger in the morning than in the evening. This likely reflects the overnight OSA-related physiologic stress.¹¹

Thrombotic potential is also enhanced, with higher levels of plasminogen activator inhibitor 1, fibrinogen, P-selectin, and vascular endothelial growth factor. Some of these factors normally have a diurnal cycle, with higher levels in the morning, but in OSA, increasing OSA severity is associated with increased prothrombotic potential in the morning hours. Of interest, levels of these substances showed a plateau effect, rising in people who had only mildly elevated apnea-hypopnea indices and then leveling off.¹² Intermittent hypoxia followed by ventilatory overshoot hyperoxia, characteristic of sleep apnea, provides the ideal environment for augmentation of oxidative stress, with evidence of increased oxidation of serum proteins and lipids. Hypoxia and oxygen-derived free radicals may result in cardiac myocyte injury. Experimental data demonstrate that intermittent hypoxia combined with a high-fat diet results in synergistic acceleration of evidence of atherogenic lesions.

Patients with OSA also have evidence of endothelial dysfunction, insulin resistance, and dyslipidemia, all pathways that can facilitate the progression of atherosclerosis in OSA.^13–15

Cardiac arrhythmias

In the Sleep Heart Health Study, a multicenter epidemiologic study designed to examine the relationships of OSA and cardiovascular outcomes, those who had moderate to severe OSA had a risk of ventricular and atrial arrhythmias two to four times higher than those without OSA, even after correction for the confounding influences of obesity and underlying cardiovascular risk.¹⁴ These findings were corroborated in subsequent work highlighting monotonic dose-response relationships with increasing OSA severity and increased odds of atrial and ventricular arrhythmia in a cohort of about 3,000 older men.¹¹ Additional compelling evidence of a causal relationship is that the risk of discrete arrhythmic events is markedly increased after a respiratory disturbance in sleep.¹⁶

In patients who successfully underwent cardioversion for atrial fibrillation, those who had sleep apnea but were not treated with continuous positive airway pressure (CPAP) had a much higher rate of recurrence of atrial fibrillation during the subsequent year than those with CPAP-treated sleep apnea and than controls never diagnosed with sleep apnea. In the untreated patients with sleep apnea, the mean nocturnal fall in oxygen saturation was significantly greater in those who had recurrence of atrial fibrillation than in those who did not, suggesting hypoxia as an important mechanism contributing to atrial fibrillation.¹⁷

Since then, several other retrospective studies have shown similar findings after pulmonary vein antrum isolation and ablation in terms of reduction of atrial fibrillation recurrence with CPAP treatment in OSA.¹⁸

Walia et al¹⁹ described a patient with moderate sleep apnea who underwent a split-night study. During the baseline part of the study, the patient had about 18 ectopic beats per minute. During the second portion of the study while CPAP was applied, progressively fewer ectopic beats occurred as airway pressure was increased until a normal rhythm without ectopic beats was achieved at the goal treatment CPAP pressure setting.

Cardiovascular disease, stroke, and death

Marin et al²⁰ followed about 1,500 men for 10 years, including some who had severe OSA, some with sleep apnea who were treated with CPAP, and controls. The risk of nonfatal and fatal cardiovascular disease events was nearly three times higher in those with severe disease than in healthy participants. Those treated with CPAP had a risk approximately the same as in the control group.

The Sleep Heart Study followed approximately 6,000 people with untreated sleep apnea for a median of nearly 9 years. It found a significant association between the apnea-hypopnea index and ischemic stroke, especially in men.²¹ Survival in patients with heart failure is also associated with the degree of OSA; patients with more severe disease (an apnea-hypopnea index ≥ 15) have a nearly three times greater risk of death than those with no disease or only mild disease (apnea-hypopnea index < 15).²²

From the standpoint of health care utilization, findings that central sleep apnea predicts an increased risk of hospital readmission in heart failure are of particular interest.²³

People with OSA are at increased risk of nocturnal sudden cardiac death.²⁴ Sleep apnea is also associated with an increased overall death rate, and the higher the apnea-hypopnea index, the higher the death rate,²⁵ even after adjusting for age, sex, body mass index, and underlying cardiovascular risk, with findings most pronounced in men under age 70.

Motor vehicle accidents

The need for caution during driving should be discussed with every patient, as motor vehicle accidents are an immediate danger to the patient and others. The association with motor vehicle accidents is independent of sleepiness, and drivers with sleep apnea often do not perceive performance impairment. Young et al²⁶ found that men who snored were 3.4 times as likely to have an accident over a 5-year period, and that men and women with an apnea-hypopnea index greater than 15 were more than 7 times as likely to have multiple accidents over a 5-year period, highlighting the importance of discussing, documenting, and expeditiously diagnosing and treating OSA, particularly in those who report drowsiness while driving.

CLINICAL RISK FACTORS

Risk factors can be divided into nonmodifiable and modifiable ones.

Nonmodifiable factors

Age. Bimodal distributions in OSA prevalence have been observed; ie, that the pediatric population and people who are middle-aged have the highest prevalence of OSA. A linear relationship between sleep apnea prevalence and age until about age 65 was identified in data from the Sleep Heart Health Study.²⁷ After that, the prevalence rates plateau; it is unclear if this is secondary to natural remission of the disease after a certain age or because patients with more severe disease have died by that age (ie, survivorship bias), blunting an increase in prevalence.

Sex. Men develop sleep apnea at a rate three to five times that of women. Several explanations have been proposed to account for this.^28,29 Sex hormones are one factor; women with sleep apnea on hormone replacement therapy have a significantly less-severe sleep apnea burden than other postmenopausal women,³⁰ suggesting a positive effect from estrogen. Sex-based differences in fat distribution, length and collapsibility of the upper airway, genioglossal activity, neurochemical control mechanisms, and arousal response may also contribute to prevalence differences between men and women.

As with coronary artery disease, the presentation of sleep apnea may be atypical in women, particularly around menopause. Sleep apnea should be considered in women who have snoring and daytime sleepiness.

Race. Whites, African Americans, and Asians have a similar prevalence of sleep apnea, but groups differ in obesity rates and craniofacial anatomy.^31–34 Asians tend to have craniofacial skeletal restriction. African Americans are more likely to have upper-airway soft-tissue risk and to develop more severe OSA. Whites tend to have both craniofacial and soft-tissue risk. For those with craniofacial anatomy predisposing to OSA, even mild obesity can make it manifest.

Syndromes that predispose to OSA can include craniofacial structural abnormalities, connective tissue problems, or alterations in ventilatory control (eg, Marfan, Down, and Pierre Robin syndromes).

Modifiable risk factors

Obesity (body mass index ≥ 30 kg/m²) is a firmly established risk factor, but not all obese patients develop obstructive sleep apnea, and not all people with sleep apnea are obese.

Obesity increases risk by altering the geometry and function of the upper airway, increasing collapsibility. The changes are particularly pronounced in the lateral aspects of the pharynx.³⁵