Reviews

Measuring serum creatine kinase (CK) is an important part of the evaluation of patients with muscle weakness or myalgia, and of assessing patients with myopathies or rhabdomyolysis. But elevated CK sometimes is an incidental finding in a patient without muscle-related symptoms or with only minimal  nonspecific muscle symptoms (eg, cramps, spasms, fatigue) that do not significantly interfere with activities of daily living. This condition is sometimes referred to as “asymptomatic hyper-CK-emia.” Four other muscle enzymes that may also be elevated are aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and aldolase.

This review focuses on the evaluation of patients with elevated CK without significant muscle-related symptoms and proposes an algorithm for this purpose (Figure 1).

CURRENT THRESHOLDS MAY BE LOW

What appears to be an elevated CK level may in fact be normal, and it is important to determine in the initial assessment whether a CK value is truly abnormal.

Most laboratories use the central 95% of observations in white people as a reference range for serum CK, assuming that levels have a gaussian (bell-shaped) distribution, which is usually about 0 to 200 IU/L. Using these parameters, an abnormal CK level was observed in 19% of men and 5% of women in a study of nearly 1,000 healthy young people,¹ leading to overdiagnosis.

The actual distribution of serum CK levels in a healthy population is markedly skewed toward higher values and is nongaussian.^1–3 A 97.5% normal threshold is associated with a much lower false-positive rate and is recommended by the European Federation of Neurological Societies (now the European Academy of Neurology).⁴ This group also recommends pursuing further investigation only for patients whose level is at least 1.5 times the upper limit of normal; this threshold results in only a small reduction in sensitivity.

CK levels vary significantly by sex and race.⁵ Possible reasons include differences in muscle mass or total body mass and inherited differences in the permeability of the sarcolemma to CK.⁶ There is also a small reduction in CK levels as people age.²

The European Federation of Neurological Societies suggests redefining elevated CK as values 1.5 times beyond the upper limit of normal. Based on a 97.5% threshold and normal values determined by Brewster et al³ for black and white men and women, the following thresholds can be used to help decide whether to pursue further evaluation⁴:

• White women—325 IU/L
• White men—504 IU/L
• Black women—621 IU/L
• Black men—1,200 IU/L

PHYSICAL ACTIVITY RAISES CK

CK levels transiently rise after exercise or heavy manual labor. Serum CK levels may increase to as much as 30 times the upper limit of normal within 24 hours of strenuous physical activity, then slowly decline over the next 7 days. The degree of CK elevation depends on the type and duration of exercise, with greater elevation in those who are untrained.^2,4

In assessing asymptomatic or minimally symptomatic CK elevation, the test should be repeated after 7 days without exercise. A large community study in Norway found that repeat CK levels in people with incidentally discovered elevated CK were normal after 3 days of rest in 70% of cases.²

NONNEUROMUSCULAR CAUSES
NEED TO BE INVESTIGATED

Asymptomatic or minimally symptomatic elevated CK can be due to a primary neuromuscular disease or a variety of nonneuromuscular causes.

Patients who still have elevated CK after taking into account the 97.5% threshold, repeat testing after a week of rest, and a level more than 1.5 times the upper limit of normal for sex and race should first be evaluated for the many nonneuromuscular conditions that can cause elevated CK (Table 1).^7–9

Cardiac causes should be evaluated by history and physical examination, electrocardiography, and possibly testing for cardiac troponins.

Drugs commonly elevate CK

Prescription drugs and supplements are an important and common cause of CK elevation, so it is important to carefully review medications the patient is taking.

Statins can cause myalgia, muscle weakness, and rhabdomyolysis. Up to 5% of users develop CK elevation, typically 2 to 10 times the upper limit of normal.¹⁰ CK usually drops after stopping statins but may require weeks to months to normalize. Rarely, statin users develop a serious immune-mediated necrotizing myopathy.^11–13

The diversity of response to statin therapy appears to have a genetic basis. The SEARCH Collaborative Group¹⁴ conducted a genome-wide association study of 300,000 markers in 85 patients with definite or incipient myopathy and in 90 controls, all of whom were taking simvastatin 80 mg daily. They identified a single-nucleotide polymorphism in the SLCO1B1 gene on chromosome 12 that was strongly associated with a higher risk of statin-induced myopathy.

Patients with statin-related myopathy seem to have a higher frequency of occult metabolic muscle disease than the general population, also suggesting genetic susceptibility, although ascertainment bias could be a factor.¹⁴

Mechanisms of CK elevation in response to statins include increased muscle membrane fragility due to decreased cholesterol content, inhibition of isoprenoid production (a necessary step in the synthesis of membrane proteins), and depletion of ubiquinone, leading to mitochondrial dysfunction.

Macro CK: An abnormal enzyme complex

About 4% of patients with asymptomatic or minimally symptomatic elevated CK have “macro CK,” an enzyme complex with an atypically high molecular mass and reduced clearance, resulting in abnormally high blood levels of CK. Macro CK type 1 is more common and is found in up to 1.2% of the general population: complexes are composed of CK and immunoglobulin and are associated with autoimmune diseases.^9,15 Macro CK type 2 complexes consist of CK and an undetermined protein and are associated with malignancies.

CK electrophoresis is required to detect macro CK. Types 1 and 2 can be distinguished by protein G affinity chromatography.^9,15 

Endocrine disorders

Muscle involvement in endocrine disorders often presents with muscle weakness in addition to muscle enzyme abnormalities.

Hypothyroidism often causes weakness, cramps, myalgia, and a mild to moderate serum CK elevation.¹⁶ Severe CK elevation has been reported to occur after vigorous exercise.¹⁷ Thyroid replacement usually results in normalization of serum CK levels in 1 to 2 months.¹⁸

Hyperthyroidism is typically associated with normal serum CK concentrations, but in rare cases it can cause rhabdomyolysis.¹⁹

NEUROMUSCULAR CAUSES ARE NOT ALWAYS WORTH PURSUING

Only after the nonneuromuscular causes of elevated CK have been ruled out should neuromuscular disorders be considered (Table 2). Evaluation with electromyography, nerve conduction studies, and muscle biopsy may lead to the diagnosis of a specific neuromuscular disorder: patients may be in the presymptomatic stage of disease and may or may not eventually develop muscle weakness or other symptoms.^20,21

Is testing needed?

Most adult dystrophies and metabolic myopathies have no available treatment and their course is often benign, particularly if they present only with asymptomatic elevated CK. The value of a potentially extensive, expensive, and invasive evaluation for a specific neuromuscular cause should be weighed against the limited yield and treatment options. Moreover, specialized testing such as biochemical muscle enzyme analysis, sarcolemmal protein staining, and genetic testing are not available at all centers.

The European Federation of Neurological Societies guidelines recommend biopsy for  patients with asymptomatic elevated CK who also have any of the following:

• Abnormal (myopathic) findings on electromyography
• CK more than three times the upper limit of normal
• Age less than 25
• Exercise intolerance.⁴

Idiopathic inflammatory myopathies rarely present with asymptomatic elevated CK.^22–26 In one study,²⁷ they were found in just 5% of patients with asymptomatic elevated CK.

Hypomyopathic dermatomyositis and inclusion body myositis can present with mild CK elevations with normal muscle strength, especially early in the disease course. A myositis subset of antisynthetase syndrome can present with mildly elevated CK and interstitial lung disease.²⁷ Many of the inflammatory myopathies respond to treatment so are worth investigating.

In view of complexities in diagnosis of these conditions, one should proceed with testing only after discussing it with patients. Referral to a rheumatology specialist is preferred.

MUSCLE BIOPSY, ELECTROMYOGRAPHY, AND NERVE CONDUCTION STUDIES

Electromyography, nerve conduction studies, or muscle biopsy, or a combination of these tests, is usually needed to investigate neuromuscular causes of elevated CK.

Muscle biopsy abnormalities are found in about two-thirds of cases of asymptomatic elevated CK, but most abnormalities include nonspecific myopathic changes that are not diagnostic. A muscle biopsy that may include special stains for sarcolemmal proteins for muscular dystrophy and biochemical muscle enzyme analysis for metabolic myopathies is diagnostic in only 20% to 25% cases of asymptomatic elevated CK on average, with a variation between different series of 0% to 79%.^7,21,27–33

Electromyography and nerve conduction studies alone add little to the workup of asymp­tomatic elevated CK apart from a modest negative predictive value and as a guide for muscle biopsy. For a very few neuromuscular disorders causing an elevated CK (eg, motor neuron disease, Charcot-Marie-Tooth disease, myotonic dystrophy), electromyography and nerve conduction studies could suffice to make the diagnosis. 

Electromyography and nerve conduction studies detect abnormalities in nearly half of cases of asymptomatic CK elevation,^{7,21,27,28,30,31,33} but, as with biopsy, most changes are nonspecific. Although electromyography and nerve conduction studies can help distinguish primary neuropathic from myopathic disorders, the sensitivity and specificity are low for diagnosis. Normal studies do not rule out a condition, and abnormal studies are not diagnostic of a particular condition, although completely normal studies provide strong evidence against a severe neuromuscular disorder.

Combined testing

Using combined muscle biopsy, electromyography, and nerve conduction studies, the likelihood of making a diagnosis in patients with asymptomatic elevated CK is 28% on average (range of studies 4%–79%),^{2,7,21,26–28,30–32} and findings are nonspecific in 30% to 40% of cases. Findings are normal in about 30% to 40% of cases, which are thus diagnosed as idiopathic asymptomatic elevated CK.^28–31,34

Prelle et al³¹ retrospectively reviewed the cases of 114 patients, ages 3 to 70, with incidentally discovered elevated CK and few or no symptoms, who underwent muscle biopsy, electromyography, and nerve conduction studies after nonneuromuscular causes were ruled out. Although muscle biopsy findings were abnormal in 39% of cases, a diagnosis was established in only 18% of cases after an extensive workup: the diagnosis was definitive in only 10% and included dystrophinopathies, metabolic myopathies, and rare noninflammatory myopathies. For the remaining 8%, the diagnosis was probable and included four cases of partial carnitine palmitoyl transferase deficiency, three cases of malignant hyperthermia, and two rare inherited disorders.

DNA testing

In women with a serum CK less than three times the upper limit of normal who have a family history of Duchenne or Becker muscular dystrophy, DNA analysis of blood lymphocytes identifies 70% of carriers.⁴

IDIOPATHIC ELEVATED SERUM CK

Rowland et al³⁵ first coined the term “idiopathic hyper-CK-emia” and defined it as persistent elevation of serum CK despite a normal neurologic examination and testing, including electromyography, nerve conduction studies, and muscle biopsy.^35,36 To receive this diagnosis, patients must also have no family history or clinical evidence of neuromuscular disease.

Idiopathic elevated serum CK is sometimes familial. In one study,³⁷ elevated CK was found in family members of 13 of 28 unrelated probands. In the 13 families, 41 individuals had elevated CK. Genetic studies revealed that the condition is genetically heterogeneous and autosomal dominant in at least 60% of cases, with higher penetrance  in men.

D’Adda et al26 followed 55 people with idiopathic elevated CK for 7 years. Ten percent were eventually diagnosed with a neuromuscular disorder, 10% developed malignancy, and the remaining 80% developed no new condition. The CK level normalized or decreased in many patients, but most continued to have persistent CK elevations with minimal or no symptoms.

Measuring serum creatine kinase (CK) is an important part of the evaluation of patients with muscle weakness or myalgia, and of assessing patients with myopathies or rhabdomyolysis. But elevated CK sometimes is an incidental finding in a patient without muscle-related symptoms or with only minimal  nonspecific muscle symptoms (eg, cramps, spasms, fatigue) that do not significantly interfere with activities of daily living. This condition is sometimes referred to as “asymptomatic hyper-CK-emia.” Four other muscle enzymes that may also be elevated are aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and aldolase.

This review focuses on the evaluation of patients with elevated CK without significant muscle-related symptoms and proposes an algorithm for this purpose (Figure 1).

CURRENT THRESHOLDS MAY BE LOW

What appears to be an elevated CK level may in fact be normal, and it is important to determine in the initial assessment whether a CK value is truly abnormal.

Most laboratories use the central 95% of observations in white people as a reference range for serum CK, assuming that levels have a gaussian (bell-shaped) distribution, which is usually about 0 to 200 IU/L. Using these parameters, an abnormal CK level was observed in 19% of men and 5% of women in a study of nearly 1,000 healthy young people,¹ leading to overdiagnosis.

The actual distribution of serum CK levels in a healthy population is markedly skewed toward higher values and is nongaussian.^1–3 A 97.5% normal threshold is associated with a much lower false-positive rate and is recommended by the European Federation of Neurological Societies (now the European Academy of Neurology).⁴ This group also recommends pursuing further investigation only for patients whose level is at least 1.5 times the upper limit of normal; this threshold results in only a small reduction in sensitivity.

CK levels vary significantly by sex and race.⁵ Possible reasons include differences in muscle mass or total body mass and inherited differences in the permeability of the sarcolemma to CK.⁶ There is also a small reduction in CK levels as people age.²

The European Federation of Neurological Societies suggests redefining elevated CK as values 1.5 times beyond the upper limit of normal. Based on a 97.5% threshold and normal values determined by Brewster et al³ for black and white men and women, the following thresholds can be used to help decide whether to pursue further evaluation⁴:

• White women—325 IU/L
• White men—504 IU/L
• Black women—621 IU/L
• Black men—1,200 IU/L

PHYSICAL ACTIVITY RAISES CK

CK levels transiently rise after exercise or heavy manual labor. Serum CK levels may increase to as much as 30 times the upper limit of normal within 24 hours of strenuous physical activity, then slowly decline over the next 7 days. The degree of CK elevation depends on the type and duration of exercise, with greater elevation in those who are untrained.^2,4

In assessing asymptomatic or minimally symptomatic CK elevation, the test should be repeated after 7 days without exercise. A large community study in Norway found that repeat CK levels in people with incidentally discovered elevated CK were normal after 3 days of rest in 70% of cases.²

NONNEUROMUSCULAR CAUSES
NEED TO BE INVESTIGATED

Asymptomatic or minimally symptomatic elevated CK can be due to a primary neuromuscular disease or a variety of nonneuromuscular causes.

Patients who still have elevated CK after taking into account the 97.5% threshold, repeat testing after a week of rest, and a level more than 1.5 times the upper limit of normal for sex and race should first be evaluated for the many nonneuromuscular conditions that can cause elevated CK (Table 1).^7–9

Cardiac causes should be evaluated by history and physical examination, electrocardiography, and possibly testing for cardiac troponins.

Drugs commonly elevate CK

Prescription drugs and supplements are an important and common cause of CK elevation, so it is important to carefully review medications the patient is taking.

Statins can cause myalgia, muscle weakness, and rhabdomyolysis. Up to 5% of users develop CK elevation, typically 2 to 10 times the upper limit of normal.¹⁰ CK usually drops after stopping statins but may require weeks to months to normalize. Rarely, statin users develop a serious immune-mediated necrotizing myopathy.^11–13

The diversity of response to statin therapy appears to have a genetic basis. The SEARCH Collaborative Group¹⁴ conducted a genome-wide association study of 300,000 markers in 85 patients with definite or incipient myopathy and in 90 controls, all of whom were taking simvastatin 80 mg daily. They identified a single-nucleotide polymorphism in the SLCO1B1 gene on chromosome 12 that was strongly associated with a higher risk of statin-induced myopathy.

Patients with statin-related myopathy seem to have a higher frequency of occult metabolic muscle disease than the general population, also suggesting genetic susceptibility, although ascertainment bias could be a factor.¹⁴

Mechanisms of CK elevation in response to statins include increased muscle membrane fragility due to decreased cholesterol content, inhibition of isoprenoid production (a necessary step in the synthesis of membrane proteins), and depletion of ubiquinone, leading to mitochondrial dysfunction.

Macro CK: An abnormal enzyme complex

About 4% of patients with asymptomatic or minimally symptomatic elevated CK have “macro CK,” an enzyme complex with an atypically high molecular mass and reduced clearance, resulting in abnormally high blood levels of CK. Macro CK type 1 is more common and is found in up to 1.2% of the general population: complexes are composed of CK and immunoglobulin and are associated with autoimmune diseases.^9,15 Macro CK type 2 complexes consist of CK and an undetermined protein and are associated with malignancies.

CK electrophoresis is required to detect macro CK. Types 1 and 2 can be distinguished by protein G affinity chromatography.^9,15 

Endocrine disorders

Muscle involvement in endocrine disorders often presents with muscle weakness in addition to muscle enzyme abnormalities.

Hypothyroidism often causes weakness, cramps, myalgia, and a mild to moderate serum CK elevation.¹⁶ Severe CK elevation has been reported to occur after vigorous exercise.¹⁷ Thyroid replacement usually results in normalization of serum CK levels in 1 to 2 months.¹⁸

Hyperthyroidism is typically associated with normal serum CK concentrations, but in rare cases it can cause rhabdomyolysis.¹⁹

NEUROMUSCULAR CAUSES ARE NOT ALWAYS WORTH PURSUING

Only after the nonneuromuscular causes of elevated CK have been ruled out should neuromuscular disorders be considered (Table 2). Evaluation with electromyography, nerve conduction studies, and muscle biopsy may lead to the diagnosis of a specific neuromuscular disorder: patients may be in the presymptomatic stage of disease and may or may not eventually develop muscle weakness or other symptoms.^20,21

Is testing needed?

Most adult dystrophies and metabolic myopathies have no available treatment and their course is often benign, particularly if they present only with asymptomatic elevated CK. The value of a potentially extensive, expensive, and invasive evaluation for a specific neuromuscular cause should be weighed against the limited yield and treatment options. Moreover, specialized testing such as biochemical muscle enzyme analysis, sarcolemmal protein staining, and genetic testing are not available at all centers.

The European Federation of Neurological Societies guidelines recommend biopsy for  patients with asymptomatic elevated CK who also have any of the following:

• Abnormal (myopathic) findings on electromyography
• CK more than three times the upper limit of normal
• Age less than 25
• Exercise intolerance.⁴

Idiopathic inflammatory myopathies rarely present with asymptomatic elevated CK.^22–26 In one study,²⁷ they were found in just 5% of patients with asymptomatic elevated CK.

Hypomyopathic dermatomyositis and inclusion body myositis can present with mild CK elevations with normal muscle strength, especially early in the disease course. A myositis subset of antisynthetase syndrome can present with mildly elevated CK and interstitial lung disease.²⁷ Many of the inflammatory myopathies respond to treatment so are worth investigating.

In view of complexities in diagnosis of these conditions, one should proceed with testing only after discussing it with patients. Referral to a rheumatology specialist is preferred.

MUSCLE BIOPSY, ELECTROMYOGRAPHY, AND NERVE CONDUCTION STUDIES

Electromyography, nerve conduction studies, or muscle biopsy, or a combination of these tests, is usually needed to investigate neuromuscular causes of elevated CK.

Muscle biopsy abnormalities are found in about two-thirds of cases of asymptomatic elevated CK, but most abnormalities include nonspecific myopathic changes that are not diagnostic. A muscle biopsy that may include special stains for sarcolemmal proteins for muscular dystrophy and biochemical muscle enzyme analysis for metabolic myopathies is diagnostic in only 20% to 25% cases of asymptomatic elevated CK on average, with a variation between different series of 0% to 79%.^7,21,27–33

Electromyography and nerve conduction studies alone add little to the workup of asymp­tomatic elevated CK apart from a modest negative predictive value and as a guide for muscle biopsy. For a very few neuromuscular disorders causing an elevated CK (eg, motor neuron disease, Charcot-Marie-Tooth disease, myotonic dystrophy), electromyography and nerve conduction studies could suffice to make the diagnosis. 

Electromyography and nerve conduction studies detect abnormalities in nearly half of cases of asymptomatic CK elevation,^{7,21,27,28,30,31,33} but, as with biopsy, most changes are nonspecific. Although electromyography and nerve conduction studies can help distinguish primary neuropathic from myopathic disorders, the sensitivity and specificity are low for diagnosis. Normal studies do not rule out a condition, and abnormal studies are not diagnostic of a particular condition, although completely normal studies provide strong evidence against a severe neuromuscular disorder.

Combined testing

Using combined muscle biopsy, electromyography, and nerve conduction studies, the likelihood of making a diagnosis in patients with asymptomatic elevated CK is 28% on average (range of studies 4%–79%),^{2,7,21,26–28,30–32} and findings are nonspecific in 30% to 40% of cases. Findings are normal in about 30% to 40% of cases, which are thus diagnosed as idiopathic asymptomatic elevated CK.^28–31,34

Prelle et al³¹ retrospectively reviewed the cases of 114 patients, ages 3 to 70, with incidentally discovered elevated CK and few or no symptoms, who underwent muscle biopsy, electromyography, and nerve conduction studies after nonneuromuscular causes were ruled out. Although muscle biopsy findings were abnormal in 39% of cases, a diagnosis was established in only 18% of cases after an extensive workup: the diagnosis was definitive in only 10% and included dystrophinopathies, metabolic myopathies, and rare noninflammatory myopathies. For the remaining 8%, the diagnosis was probable and included four cases of partial carnitine palmitoyl transferase deficiency, three cases of malignant hyperthermia, and two rare inherited disorders.

DNA testing

In women with a serum CK less than three times the upper limit of normal who have a family history of Duchenne or Becker muscular dystrophy, DNA analysis of blood lymphocytes identifies 70% of carriers.⁴

IDIOPATHIC ELEVATED SERUM CK

Rowland et al³⁵ first coined the term “idiopathic hyper-CK-emia” and defined it as persistent elevation of serum CK despite a normal neurologic examination and testing, including electromyography, nerve conduction studies, and muscle biopsy.^35,36 To receive this diagnosis, patients must also have no family history or clinical evidence of neuromuscular disease.

Idiopathic elevated serum CK is sometimes familial. In one study,³⁷ elevated CK was found in family members of 13 of 28 unrelated probands. In the 13 families, 41 individuals had elevated CK. Genetic studies revealed that the condition is genetically heterogeneous and autosomal dominant in at least 60% of cases, with higher penetrance  in men.

D’Adda et al26 followed 55 people with idiopathic elevated CK for 7 years. Ten percent were eventually diagnosed with a neuromuscular disorder, 10% developed malignancy, and the remaining 80% developed no new condition. The CK level normalized or decreased in many patients, but most continued to have persistent CK elevations with minimal or no symptoms.

Measuring serum creatine kinase (CK) is an important part of the evaluation of patients with muscle weakness or myalgia, and of assessing patients with myopathies or rhabdomyolysis. But elevated CK sometimes is an incidental finding in a patient without muscle-related symptoms or with only minimal  nonspecific muscle symptoms (eg, cramps, spasms, fatigue) that do not significantly interfere with activities of daily living. This condition is sometimes referred to as “asymptomatic hyper-CK-emia.” Four other muscle enzymes that may also be elevated are aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and aldolase.

This review focuses on the evaluation of patients with elevated CK without significant muscle-related symptoms and proposes an algorithm for this purpose (Figure 1).

CURRENT THRESHOLDS MAY BE LOW

What appears to be an elevated CK level may in fact be normal, and it is important to determine in the initial assessment whether a CK value is truly abnormal.

Most laboratories use the central 95% of observations in white people as a reference range for serum CK, assuming that levels have a gaussian (bell-shaped) distribution, which is usually about 0 to 200 IU/L. Using these parameters, an abnormal CK level was observed in 19% of men and 5% of women in a study of nearly 1,000 healthy young people,¹ leading to overdiagnosis.

The actual distribution of serum CK levels in a healthy population is markedly skewed toward higher values and is nongaussian.^1–3 A 97.5% normal threshold is associated with a much lower false-positive rate and is recommended by the European Federation of Neurological Societies (now the European Academy of Neurology).⁴ This group also recommends pursuing further investigation only for patients whose level is at least 1.5 times the upper limit of normal; this threshold results in only a small reduction in sensitivity.

CK levels vary significantly by sex and race.⁵ Possible reasons include differences in muscle mass or total body mass and inherited differences in the permeability of the sarcolemma to CK.⁶ There is also a small reduction in CK levels as people age.²

The European Federation of Neurological Societies suggests redefining elevated CK as values 1.5 times beyond the upper limit of normal. Based on a 97.5% threshold and normal values determined by Brewster et al³ for black and white men and women, the following thresholds can be used to help decide whether to pursue further evaluation⁴:

• White women—325 IU/L
• White men—504 IU/L
• Black women—621 IU/L
• Black men—1,200 IU/L

PHYSICAL ACTIVITY RAISES CK

CK levels transiently rise after exercise or heavy manual labor. Serum CK levels may increase to as much as 30 times the upper limit of normal within 24 hours of strenuous physical activity, then slowly decline over the next 7 days. The degree of CK elevation depends on the type and duration of exercise, with greater elevation in those who are untrained.^2,4

In assessing asymptomatic or minimally symptomatic CK elevation, the test should be repeated after 7 days without exercise. A large community study in Norway found that repeat CK levels in people with incidentally discovered elevated CK were normal after 3 days of rest in 70% of cases.²

NONNEUROMUSCULAR CAUSES
NEED TO BE INVESTIGATED

Asymptomatic or minimally symptomatic elevated CK can be due to a primary neuromuscular disease or a variety of nonneuromuscular causes.

Patients who still have elevated CK after taking into account the 97.5% threshold, repeat testing after a week of rest, and a level more than 1.5 times the upper limit of normal for sex and race should first be evaluated for the many nonneuromuscular conditions that can cause elevated CK (Table 1).^7–9

Cardiac causes should be evaluated by history and physical examination, electrocardiography, and possibly testing for cardiac troponins.

Drugs commonly elevate CK

Prescription drugs and supplements are an important and common cause of CK elevation, so it is important to carefully review medications the patient is taking.

Statins can cause myalgia, muscle weakness, and rhabdomyolysis. Up to 5% of users develop CK elevation, typically 2 to 10 times the upper limit of normal.¹⁰ CK usually drops after stopping statins but may require weeks to months to normalize. Rarely, statin users develop a serious immune-mediated necrotizing myopathy.^11–13

The diversity of response to statin therapy appears to have a genetic basis. The SEARCH Collaborative Group¹⁴ conducted a genome-wide association study of 300,000 markers in 85 patients with definite or incipient myopathy and in 90 controls, all of whom were taking simvastatin 80 mg daily. They identified a single-nucleotide polymorphism in the SLCO1B1 gene on chromosome 12 that was strongly associated with a higher risk of statin-induced myopathy.

Patients with statin-related myopathy seem to have a higher frequency of occult metabolic muscle disease than the general population, also suggesting genetic susceptibility, although ascertainment bias could be a factor.¹⁴

Mechanisms of CK elevation in response to statins include increased muscle membrane fragility due to decreased cholesterol content, inhibition of isoprenoid production (a necessary step in the synthesis of membrane proteins), and depletion of ubiquinone, leading to mitochondrial dysfunction.

Macro CK: An abnormal enzyme complex

About 4% of patients with asymptomatic or minimally symptomatic elevated CK have “macro CK,” an enzyme complex with an atypically high molecular mass and reduced clearance, resulting in abnormally high blood levels of CK. Macro CK type 1 is more common and is found in up to 1.2% of the general population: complexes are composed of CK and immunoglobulin and are associated with autoimmune diseases.^9,15 Macro CK type 2 complexes consist of CK and an undetermined protein and are associated with malignancies.

CK electrophoresis is required to detect macro CK. Types 1 and 2 can be distinguished by protein G affinity chromatography.^9,15 

Endocrine disorders

Muscle involvement in endocrine disorders often presents with muscle weakness in addition to muscle enzyme abnormalities.

Hypothyroidism often causes weakness, cramps, myalgia, and a mild to moderate serum CK elevation.¹⁶ Severe CK elevation has been reported to occur after vigorous exercise.¹⁷ Thyroid replacement usually results in normalization of serum CK levels in 1 to 2 months.¹⁸

Hyperthyroidism is typically associated with normal serum CK concentrations, but in rare cases it can cause rhabdomyolysis.¹⁹

NEUROMUSCULAR CAUSES ARE NOT ALWAYS WORTH PURSUING

Only after the nonneuromuscular causes of elevated CK have been ruled out should neuromuscular disorders be considered (Table 2). Evaluation with electromyography, nerve conduction studies, and muscle biopsy may lead to the diagnosis of a specific neuromuscular disorder: patients may be in the presymptomatic stage of disease and may or may not eventually develop muscle weakness or other symptoms.^20,21

Is testing needed?

Most adult dystrophies and metabolic myopathies have no available treatment and their course is often benign, particularly if they present only with asymptomatic elevated CK. The value of a potentially extensive, expensive, and invasive evaluation for a specific neuromuscular cause should be weighed against the limited yield and treatment options. Moreover, specialized testing such as biochemical muscle enzyme analysis, sarcolemmal protein staining, and genetic testing are not available at all centers.

The European Federation of Neurological Societies guidelines recommend biopsy for  patients with asymptomatic elevated CK who also have any of the following:

• Abnormal (myopathic) findings on electromyography
• CK more than three times the upper limit of normal
• Age less than 25
• Exercise intolerance.⁴

Idiopathic inflammatory myopathies rarely present with asymptomatic elevated CK.^22–26 In one study,²⁷ they were found in just 5% of patients with asymptomatic elevated CK.

Hypomyopathic dermatomyositis and inclusion body myositis can present with mild CK elevations with normal muscle strength, especially early in the disease course. A myositis subset of antisynthetase syndrome can present with mildly elevated CK and interstitial lung disease.²⁷ Many of the inflammatory myopathies respond to treatment so are worth investigating.

In view of complexities in diagnosis of these conditions, one should proceed with testing only after discussing it with patients. Referral to a rheumatology specialist is preferred.

MUSCLE BIOPSY, ELECTROMYOGRAPHY, AND NERVE CONDUCTION STUDIES

Electromyography, nerve conduction studies, or muscle biopsy, or a combination of these tests, is usually needed to investigate neuromuscular causes of elevated CK.

Muscle biopsy abnormalities are found in about two-thirds of cases of asymptomatic elevated CK, but most abnormalities include nonspecific myopathic changes that are not diagnostic. A muscle biopsy that may include special stains for sarcolemmal proteins for muscular dystrophy and biochemical muscle enzyme analysis for metabolic myopathies is diagnostic in only 20% to 25% cases of asymptomatic elevated CK on average, with a variation between different series of 0% to 79%.^7,21,27–33

Electromyography and nerve conduction studies alone add little to the workup of asymp­tomatic elevated CK apart from a modest negative predictive value and as a guide for muscle biopsy. For a very few neuromuscular disorders causing an elevated CK (eg, motor neuron disease, Charcot-Marie-Tooth disease, myotonic dystrophy), electromyography and nerve conduction studies could suffice to make the diagnosis. 

Electromyography and nerve conduction studies detect abnormalities in nearly half of cases of asymptomatic CK elevation,^{7,21,27,28,30,31,33} but, as with biopsy, most changes are nonspecific. Although electromyography and nerve conduction studies can help distinguish primary neuropathic from myopathic disorders, the sensitivity and specificity are low for diagnosis. Normal studies do not rule out a condition, and abnormal studies are not diagnostic of a particular condition, although completely normal studies provide strong evidence against a severe neuromuscular disorder.

Combined testing

Using combined muscle biopsy, electromyography, and nerve conduction studies, the likelihood of making a diagnosis in patients with asymptomatic elevated CK is 28% on average (range of studies 4%–79%),^{2,7,21,26–28,30–32} and findings are nonspecific in 30% to 40% of cases. Findings are normal in about 30% to 40% of cases, which are thus diagnosed as idiopathic asymptomatic elevated CK.^28–31,34

Prelle et al³¹ retrospectively reviewed the cases of 114 patients, ages 3 to 70, with incidentally discovered elevated CK and few or no symptoms, who underwent muscle biopsy, electromyography, and nerve conduction studies after nonneuromuscular causes were ruled out. Although muscle biopsy findings were abnormal in 39% of cases, a diagnosis was established in only 18% of cases after an extensive workup: the diagnosis was definitive in only 10% and included dystrophinopathies, metabolic myopathies, and rare noninflammatory myopathies. For the remaining 8%, the diagnosis was probable and included four cases of partial carnitine palmitoyl transferase deficiency, three cases of malignant hyperthermia, and two rare inherited disorders.

DNA testing

In women with a serum CK less than three times the upper limit of normal who have a family history of Duchenne or Becker muscular dystrophy, DNA analysis of blood lymphocytes identifies 70% of carriers.⁴

IDIOPATHIC ELEVATED SERUM CK

Rowland et al³⁵ first coined the term “idiopathic hyper-CK-emia” and defined it as persistent elevation of serum CK despite a normal neurologic examination and testing, including electromyography, nerve conduction studies, and muscle biopsy.^35,36 To receive this diagnosis, patients must also have no family history or clinical evidence of neuromuscular disease.

Idiopathic elevated serum CK is sometimes familial. In one study,³⁷ elevated CK was found in family members of 13 of 28 unrelated probands. In the 13 families, 41 individuals had elevated CK. Genetic studies revealed that the condition is genetically heterogeneous and autosomal dominant in at least 60% of cases, with higher penetrance  in men.

D’Adda et al26 followed 55 people with idiopathic elevated CK for 7 years. Ten percent were eventually diagnosed with a neuromuscular disorder, 10% developed malignancy, and the remaining 80% developed no new condition. The CK level normalized or decreased in many patients, but most continued to have persistent CK elevations with minimal or no symptoms.

A 79-year-old woman with a history of breast cancer in remission and hypertension presented to a local emergency department because of subacute memory loss and compulsive shopping. Her serum sodium concentration was 127 mmol/L (reference range 132–148). Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were normal, and she was sent home.

Three days later, she experienced a generalized tonic-clonic seizure that evolved into status epilepticus. She was intubated and admitted to the intensive care unit. Cerebrospinal fluid analysis was normal, and infectious causes of encephalitis were ruled out. MRI showed increased signal in both hippocampi (Figure 1). Her seizures were refractory to treatment, and she was given pentobarbital to induce a coma.

Serum evaluation of neuronal antibodies revealed elevated titers of the voltage-gated potassium channel (VGKC) complex antibody, with subsequent subtyping confirming the leucine-rich glioma-inactivated protein 1 (LGI1) protein as the antigenic target.

She received a 5-day course of intravenous immunoglobulin and methylprednisolone, pentobarbital was withdrawn, and the seizures did not recur, but weeks later she remained comatose. Positron emission tomography (PET) of the brain revealed hypermetabolism in the medial and anterior aspects of both temporal lobes. She underwent five sessions of plasma exchange, after which she began to improve and follow commands. She was ultimately discharged to an acute rehabilitation facility after a 4-week hospital stay.

She received infusions of intravenous immunoglobulin twice a month for 6 months.  At her last follow-up visit, she was seizure-free and neurologically intact except for mild inattention.

NEWLY RECOGNIZED DISEASES

Although autoantibody-mediated encephalitic syndromes were first described more than 50 years ago,^1,2 their autoimmune basis was not recognized until the early 1980s.³ In the past 10 years, a flood of novel clinical syndromes associated with neuronal autoantibodies has been described that may be markedly improved or even completely resolved with immunotherapy. In cases of unexplained seizure, encephalitis, or acute-onset psychiatric syndromes, suspecting these syndromes can lead to diagnosis, treatment, and a good outcome.

This review describes the key clinical autoantibody-mediated encephalitic syndromes, explains the better-characterized antibody associations, and discusses their diagnosis and treatment. 

CLASSIFIED ANATOMICALLY, IMMUNOLOGICALLY, OR EPONYMOUSLY

Autoantibody-mediated encephalitis is also known as autoimmune-mediated encephalitis, autoimmune-mediated limbic encephalitis, and autoimmune synaptic encephalitis.

How to categorize these syndromes is still in flux: they can be listed by the area of the brain affected, the antibody involved, or the name of the discoverer (eg, Morvan syndrome).

Autoantibodies identified in autoimmune encephalitis fall under two broad categories:

• Those targeting intracellular (intranuclear or intracytoplasmic) antigens; the syndromes they cause are more likely to be paraneoplastic and less responsive to immunotherapy
• Those targeting antigens on the neuronal surface: the syndromes they cause are less likely to be paraneoplastic and are more responsive to immunotherapy.⁴

SYNDROMES DEFINED BY BRAIN AREA AFFECTED

Below, we provide examples of neurologic syndromes of autoantibody-mediated encephalitis according to the region of the brain most affected, ie, the limbic system, the brainstem, or the cerebellum (Figure 2).

LIMBIC ENCEPHALITIS

Memory loss, behavioral changes, seizures

Patients with limbic encephalitis (such as the patient described in the vignette above) present with symptoms attributed to dysfunction of mesial temporal lobe structures, most notably the hippocampus. Prominent symptoms include short-term memory loss, behavioral disturbances such as agitation and confusion, and psychiatric problems such as depression and psychosis. Recurrent seizures are a salient feature and, not uncommonly, progress to status epilepticus.

Antibodies are not all cancer-associated

Cerebrospinal fluid analysis can be normal or show abnormalities suggesting immune activation, eg, slight pleocytosis, elevated protein, increased immunoglobulin G synthesis, and oligoclonal banding.⁵

In many cases, an autoantibody is found in the blood or in the cerebrospinal fluid. Some patients may express more than one autoantibody, so the traditional view of “one antibody, one syndrome” is incorrect.

Although initially identified as a rare paraneoplastic disorder, limbic encephalitis sometimes occurs in the absence of malignancy.

Multiple antibodies have been linked to the syndrome (Table 1).^6–9 The “classic” antibodies initially found in paraneoplastic forms are now generally viewed as nonpathogenic, in part because they are directed against intracellular antigens. Neuronal injury in paraneo­plastic limbic encephalitis is believed to be mediated by cytotoxic T lymphocytes, with neuronal autoantibodies being produced after the injury.⁴ Recently defined antibodies, such as those targeting the N-methyl-d-aspartate (NMDA) receptor⁶ and the LGI1 protein,⁷ are now understood to be common causes of limbic encephalitis. 

Imaging usually shows limbic focal changes

Structural MRI or functional fluorodeoxyglucose (FDG)-PET imaging may show focal changes in limbic system structures, such as the mesial temporal lobes.  It is now recognized that other cortical areas may be involved, and the term “limbic encephalitis” may give way to “cortical” or “focal encephalitis.”

In about 60% of patients, MRI shows hyperintense fluid-attenuated inversion recovery (FLAIR) or T2 signal changes in the mesial temporal lobes, likely reflecting inflammatory changes.^4,10,11 On FDG-PET, hypermetabolism may be observed in the mesial temporal lobes early in the disease despite normal findings on MRI.¹² Hypometabolism, either diffuse or localized to the mesial temporal lobes, eventually sets in, likely reflecting cytotoxic injury in the aftermath of prolonged inflammation or seizures.

Consider other causes

Before diagnosing limbic encephalitis, it is essential to evaluate for infectious meningoencephalitis, especially herpes simplex viral encephalitis. Thiamine deficiency (Wernicke encephalopathy), drug intoxication, prion disease, Hashimoto encephalopathy, tumor, and subclinical status epilepticus should also be considered. Some of these conditions are associated with the same neuronal autoantibodies detected in limbic encephalitis. Further complicating the picture, case reports have shown the presence of serum neuronal autoantibodies—VGKC complex^13–15 and NMDA-receptor antibodies^16,17—in confirmed cases of prion disease. In addition, adequately treated herpes simplex viral encephalitis can precipitate the production of NMDA-receptor antibodies and their characteristic syndrome.^18–20

BRAINSTEM ENCEPHALITIS

The brainstem—the midbrain, pons, and medulla—can be affected, either in isolation or more commonly as part of a more widespread autoantibody-mediated encephalitis. Symptoms and signs include eye movement abnormalities, ptosis, dysphagia, dysarthria, ataxia, facial palsy, vertigo, hearing impairment, reduced consciousness, and hypoventilation.²¹

Anti-Hu, anti-Ri, and anti-Ma2 antibodies are most commonly associated with brainstem encephalitis (Table 2). Anti-Ma2-associated encephalitis may improve after a combination of immunotherapy and tumor removal²¹; the others have a poor prognosis.

Neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders most commonly involve demyelination affecting the optic nerves and spinal cord, leading to  unilateral or bilateral optic neuritis and transverse myelitis spanning three or more vertebral segments.²² The initial clinical manifestation may be an encephalitic pattern, affecting predominantly the brainstem in a restricted fashion,²² or the central nervous system in a more diffuse pattern, mimicking either acute disseminated encephalomyelitis or, in less severe cases, posterior reversible encephalopathy syndrome.²³

Testing for antiaquaporin-4 antibody, also known as neuromyelitis optica immunoglobulin G, is the single most decisive laboratory test for diagnosing neuromyelitis optica spectrum disorders, so serum and cerebrospinal fluid evaluation for this autoantibody should be considered when caring for a patient whose clinical picture suggests brainstem encephalitis.²²

Bickerstaff brainstem encephalitis

Bickerstaff brainstem encephalitis was first described more than half a century ago in patients with postinfectious ataxia, ophthalmoparesis, and altered consciousness. This rare disease was later found to be associated with antiganglioside GQ1b (anti-GQ1b) autoantibody. MRI is normal in about 90% of cases, so recognizing the clinical presentation and analyzing anti-GQ1b serum titers are critical to diagnosis.

Recovery is usually spontaneous and complete and can be hastened by immunotherapy, especially intravenous immunoglobulin.²⁴

Other causes of brainstem encephalitis

The differential diagnosis of a presentation of brainstem encephalitis includes:

• Infectious causes, the most common being Listeria species followed by enterovirus 71 and herpes simplex virus.²⁵ Tuberculosis, brucellosis, and Whipple disease should also be considered.
• Primary central nervous system inflammatory and demyelinating conditions, eg, multiple sclerosis and acute disseminated encephalomyelitis.
• Systemic inflammatory conditions, eg, Beh­çet disease, systemic lupus erythematosus, and sarcoidosis.
• Direct brainstem neoplastic involvement, as might occur in primary central nervous system lymphoma or leptomeningeal carcinomatosis.

CEREBELLAR SYNDROME

Patients with autoantibody-mediated encephalitis localized predominantly to the cerebellum typically present with dizziness, vertigo, and unsteady gait, progressing eventually to limb and gait ataxia.⁴ Symptoms are often subacute, progressing over weeks.

Multiple neuronal autoantibodies have been found to occur with cerebellar encephalitis (Table 2). In most cases, they are paraneo­plastic and considered not to be pathogenic, given the intracellular location of their target antigen.⁴ In such cases, the syndrome is more accurately described as autoantibody-associated rather than autoantibody-mediated. Only in a minority of cases have neuronal autoantibodies been demonstrated to be directly pathogenic, ie, antimetabotropic glutamate receptor type 1 (anti-mGluR1) antibody-associated cerebellitis²⁶ and antiglutamic acid decarboxylase (anti-GAD)-associated cerebellar ataxia.²⁷

Differential diagnosis of cerebellar syndromes

The differential diagnosis of autoantibody-associated cerebellar syndromes is broad and includes:

• Alcohol-induced atrophy
• Drug-induced cerebellar atrophy (eg, from lithium, phenytoin, gabapentin, metronidazole, amiodarone, carbamazepine)
• Vitamin B₁ and E deficiency
• Hypothyroidism, hypoparathyroidism
• Neurodegenerative disease (eg, prion disease, multiple system atrophy)
• Parainfectious causes (eg, after infection with Epstein-Barr virus)
• Immune-mediated diseases (Miller-Fisher syndrome, associated with anti-GQ1b antibodies, and antigliadin-associated ataxia, which can occur in isolation or as part of celiac disease).⁴

SYNDROMES ASSOCIATED WITH SPECIFIC ANTIBODIES

A few of the autoantibody-mediated encephalitic syndromes have specific antibody associations and characteristic clinical presentations. The most prominent of these syndromes are VGKC complex antibody encephalitis (as in the patient described at the beginning of this article) and anti-NMDA receptor encephalitis.

VGKC COMPLEX ANTIBODY-MEDIATED LIMBIC ENCEPHALITIS

VGKC complex antibodies, initially reported to be associated with the peripheral nerve hyperexcitability disorder neuromyotonia, were subsequently found in Morvan syndrome.^28,29 Patients with this syndrome often present with autonomic dysfunction and peripheral nerve hyperexcitability but also develop insomnia, confusion, hallucinations, and memory loss. Drawing on the clinical overlap between Morvan syndrome and limbic encephalitis, Buckley et al³⁰ were the first to report VGKC complex antibodies in two cases of limbic encephalitis.

VGKC complex antibodies are now understood to be associated with a wide variety of neurologic conditions, including chronic idiopathic pain, epilepsy,³¹ movement disorders, cranial nerve abnormalities, autonomic dysfunction,³² and gut dysmotility.³³ In contrast, these antibodies are rare in healthy people.³⁴ Limbic encephalitis associated with VGKC complex antibody usually lacks cerebellar and brainstem dysfunction, which may help distinguish it from other types of autoantibody-mediated limbic encephalitis.¹²

VGKC complex antibody does not bind to the potassium channel itself. Instead it recognizes other constituents of the channel complex, most notably LGI1 and contactin-associated protein 2 (CASPR2). LGI1 antibody is more commonly associated with limbic encephalitis—as illustrated in our case study—in addition to a distinctive type of seizure affecting the arm and face (faciobrachial dystonic seizure).³⁴ The CASPR2 antibody, on the other hand, more often correlates with peripheral nerve manifestations and Morvan syndrome.²⁹ Hyponatremia is commonly seen on serum chemical analysis and provides a clue that these syndromes are present.¹²

Good response to immunotherapy

A critical change in therapy came as clinicians realized that seizures were often refractory to standard antiepileptic drugs but responded well to immunotherapies. On the basis of these observations, sera of patients with long-standing epilepsy have been reanalyzed to look for neuronal autoantibodies.³¹ These antibodies should be checked in cases of new-onset refractory status epilepticus of unknown origin that does not respond to antiepileptic medications.

About half of patients with VGKC complex antibody-mediated limbic encephalitis have normal findings on brain MRI.⁵ Seven of 10 patients who were prospectively followed for VGKC complex antibody-mediated faciobrachial dystonic seizures had normal brain MRIs.³⁵

VGKC complex antibody-mediated limbic encephalitis does not usually recur.³⁶ Most cases are nonparaneoplastic, as evidenced by failure to detect a single active tumor in 64 patients after a median follow-up of 3 years. The prognosis is generally favorable except in cases with coexisting tumors.¹²

ANTI-NMDA RECEPTOR ENCEPHALITIS

Often associated with ovarian teratoma

Anti-NMDA receptor encephalitis typically affects women in their 20s and 30s, and about half of patients have an ovarian teratoma. It can also occur in younger patients and in men, in whom it is less likely to be associated with a neoplasm.³⁷

Typical initial symptoms include striking and often stereotyped neuropsychiatric disturbances manifesting as psychosis, confusion, seizures, and amnesia. After 1 to 2 weeks, new symptoms set in, including reduced consciousness, movement disorders (ranging from orolingualfacial dyskinesia to rigidity and choreoathetosis), autonomic dysfunction, and hypoventilation, often prompting admission to the intensive care unit.³⁸

Although the outcome is favorable in most cases, recovery, in contrast to VGKC complex antibody-mediated limbic encephalitis, is slow and may take longer than 1 year. Up to a quarter of patients have a relapse, underscoring the importance of maintenance immunotherapy.

It is important to undertake an intensive search for possible ovarian and extraovarian teratomas in young women with this syndrome—including CT of the pelvis, vaginal ultrasonography, and PET imaging—as removal of the teratoma may be curative.³⁷

DIAGNOSIS OF AUTOANTIBODY-MEDIATED ENCEPHALITIS

Critical to diagnosing autoantibody-mediated encephalitis is awareness of these disorders. Since antibody testing may be very specific and is not usually part of the standard batteries of tests, a high level of suspicion is needed. Patients may present to different specialists in different settings; therefore, clinicians in pediatrics, rheumatology, psychiatry, and intensive care medicine need to be aware of these syndromes to avoid delay and misdiagnosis.

Clinical features suggesting autoantibody-mediated encephalitis include:

• Acute or subacute onset of a neurologic syndrome
• New-onset refractory status epilepticus of unknown etiology
• Acute or subacute psychiatric illness with unexpected progression to neurologic symptoms or delirium
• Unusual movement disorders not conforming to standard syndromes
• Cognitive impairment, psychosis, or behavioral or language disorders with atypical findings on imaging or cerebrospinal fluid analysis.

Imaging. Diagnosis of autoantibody-mediated encephalitis focuses on evidence suggesting an inflammatory central nervous system syndrome. MRI may show hyperintense signals on T2, FLAIR, or diffusion-weighted imaging changes in various brain regions. In many cases, however, MRI is negative despite severe clinical symptoms. In a study of 72 patients suspected of having autoimmune dementia of various etiologies, including but not restricted to antineuronal surface antibody-mediated causes, Flanagan et al³⁹ identified atypical neuroimaging findings in only 29%. PET imaging may show hypermetabolism in certain brain areas correlating to clinical syndromes but is often difficult to obtain in a timely fashion.

Cerebrospinal fluid is often abnormal, showing elevated protein, increased immunoglobulin G synthesis, or oligoclonal banding. As with imaging studies, the cerebrospinal fluid may be normal despite severe clinical manifestations.

Electroencephalography may show focal slowing or seizure activity. Neuropsychologic testing may show different patterns of abnormalities.

Antibody testing. None of these tests can be used in isolation, and the diagnosis of autoantibody-mediated encephalitis hinges on recognizing a clinical syndrome and ordering supportive testing. Specific antibodies are more likely in different clinical syndromes and should be sought (Table 3).

Patients who have autoantibody-mediated encephalitis may test negative for autoantibodies for many possible reasons:

• Blood testing for antibodies may be less sensitive than cerebrospinal fluid testing
• Antibody titers may vary in the course of the disease
• The patient may be expressing an antibody that is less often tested for (eg, anti-AMPA receptor or antigamma-aminobutyric acid B) or one that has not yet been isolated.

Evaluating for malignancy is recommended in all cases of autoantibody-mediated encephalitis. The initial workup may involve CT of the chest, abdomen, and pelvis, as well as mammography in women and serum prostate-specific antigen testing and testicular ultrasonography in men. Ordering FDG-PET in cases in which CT is negative or inconclusive increases cancer detection.⁴⁰ If no cancer is found, close tumor surveillance—every 3 to 6 months—is recommended for at least 2 years.⁴¹

TREATMENT

Owing in large part to the rarity of autoantibody-mediated encephalitides, no randomized trials of therapy have been performed. Treatment at present is guided mostly by case series and expert consensus, which suggest first-line therapy with intravenous immunoglobulin, high-dose corticosteroids, plasmapheresis, or a combination.

Different syndromes and antibody-related disorders respond differently to therapy. Syndromes associated with antibodies against intracellular antigens tend to be more resistant to immune therapy than cell surface antigen-related syndromes.⁴

Tiered approach

Combined treatment with intravenous immunoglobulin and high-dose corticosteroids may be superior to treatment with steroids alone for LGI1-antibody mediated limbic encephalitis.⁴²

In cases refractory to first-line (“tier 1”) therapy, second-line immunotherapy with drugs affecting B-cell populations (eg, rituximab, cyclophosphamide, and mycophenolate mofetil) has been used.

A tiered approach has been most extensively studied for anti-NMDA-receptor encephalitis, with better outcomes found using second-line therapy.⁴³

Treatment strategies for these disorders will likely evolve over time with additional experience.

Outpatient management

Once the patient is discharged from the hospital, a multidisciplinary approach to care is recommended, including physical rehabilitation, speech therapy, neuropsychiatric and neuroimmunologic follow-up, and annual surveillance for malignancies.

A 79-year-old woman with a history of breast cancer in remission and hypertension presented to a local emergency department because of subacute memory loss and compulsive shopping. Her serum sodium concentration was 127 mmol/L (reference range 132–148). Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were normal, and she was sent home.

Three days later, she experienced a generalized tonic-clonic seizure that evolved into status epilepticus. She was intubated and admitted to the intensive care unit. Cerebrospinal fluid analysis was normal, and infectious causes of encephalitis were ruled out. MRI showed increased signal in both hippocampi (Figure 1). Her seizures were refractory to treatment, and she was given pentobarbital to induce a coma.

Serum evaluation of neuronal antibodies revealed elevated titers of the voltage-gated potassium channel (VGKC) complex antibody, with subsequent subtyping confirming the leucine-rich glioma-inactivated protein 1 (LGI1) protein as the antigenic target.

She received a 5-day course of intravenous immunoglobulin and methylprednisolone, pentobarbital was withdrawn, and the seizures did not recur, but weeks later she remained comatose. Positron emission tomography (PET) of the brain revealed hypermetabolism in the medial and anterior aspects of both temporal lobes. She underwent five sessions of plasma exchange, after which she began to improve and follow commands. She was ultimately discharged to an acute rehabilitation facility after a 4-week hospital stay.

She received infusions of intravenous immunoglobulin twice a month for 6 months.  At her last follow-up visit, she was seizure-free and neurologically intact except for mild inattention.

NEWLY RECOGNIZED DISEASES

Although autoantibody-mediated encephalitic syndromes were first described more than 50 years ago,^1,2 their autoimmune basis was not recognized until the early 1980s.³ In the past 10 years, a flood of novel clinical syndromes associated with neuronal autoantibodies has been described that may be markedly improved or even completely resolved with immunotherapy. In cases of unexplained seizure, encephalitis, or acute-onset psychiatric syndromes, suspecting these syndromes can lead to diagnosis, treatment, and a good outcome.

This review describes the key clinical autoantibody-mediated encephalitic syndromes, explains the better-characterized antibody associations, and discusses their diagnosis and treatment. 

CLASSIFIED ANATOMICALLY, IMMUNOLOGICALLY, OR EPONYMOUSLY

Autoantibody-mediated encephalitis is also known as autoimmune-mediated encephalitis, autoimmune-mediated limbic encephalitis, and autoimmune synaptic encephalitis.

How to categorize these syndromes is still in flux: they can be listed by the area of the brain affected, the antibody involved, or the name of the discoverer (eg, Morvan syndrome).

Autoantibodies identified in autoimmune encephalitis fall under two broad categories:

• Those targeting intracellular (intranuclear or intracytoplasmic) antigens; the syndromes they cause are more likely to be paraneoplastic and less responsive to immunotherapy
• Those targeting antigens on the neuronal surface: the syndromes they cause are less likely to be paraneoplastic and are more responsive to immunotherapy.⁴

SYNDROMES DEFINED BY BRAIN AREA AFFECTED

Below, we provide examples of neurologic syndromes of autoantibody-mediated encephalitis according to the region of the brain most affected, ie, the limbic system, the brainstem, or the cerebellum (Figure 2).

LIMBIC ENCEPHALITIS

Memory loss, behavioral changes, seizures

Patients with limbic encephalitis (such as the patient described in the vignette above) present with symptoms attributed to dysfunction of mesial temporal lobe structures, most notably the hippocampus. Prominent symptoms include short-term memory loss, behavioral disturbances such as agitation and confusion, and psychiatric problems such as depression and psychosis. Recurrent seizures are a salient feature and, not uncommonly, progress to status epilepticus.

Antibodies are not all cancer-associated

Cerebrospinal fluid analysis can be normal or show abnormalities suggesting immune activation, eg, slight pleocytosis, elevated protein, increased immunoglobulin G synthesis, and oligoclonal banding.⁵

In many cases, an autoantibody is found in the blood or in the cerebrospinal fluid. Some patients may express more than one autoantibody, so the traditional view of “one antibody, one syndrome” is incorrect.

Although initially identified as a rare paraneoplastic disorder, limbic encephalitis sometimes occurs in the absence of malignancy.

Multiple antibodies have been linked to the syndrome (Table 1).^6–9 The “classic” antibodies initially found in paraneoplastic forms are now generally viewed as nonpathogenic, in part because they are directed against intracellular antigens. Neuronal injury in paraneo­plastic limbic encephalitis is believed to be mediated by cytotoxic T lymphocytes, with neuronal autoantibodies being produced after the injury.⁴ Recently defined antibodies, such as those targeting the N-methyl-d-aspartate (NMDA) receptor⁶ and the LGI1 protein,⁷ are now understood to be common causes of limbic encephalitis. 

Imaging usually shows limbic focal changes

Structural MRI or functional fluorodeoxyglucose (FDG)-PET imaging may show focal changes in limbic system structures, such as the mesial temporal lobes.  It is now recognized that other cortical areas may be involved, and the term “limbic encephalitis” may give way to “cortical” or “focal encephalitis.”

In about 60% of patients, MRI shows hyperintense fluid-attenuated inversion recovery (FLAIR) or T2 signal changes in the mesial temporal lobes, likely reflecting inflammatory changes.^4,10,11 On FDG-PET, hypermetabolism may be observed in the mesial temporal lobes early in the disease despite normal findings on MRI.¹² Hypometabolism, either diffuse or localized to the mesial temporal lobes, eventually sets in, likely reflecting cytotoxic injury in the aftermath of prolonged inflammation or seizures.

Consider other causes

Before diagnosing limbic encephalitis, it is essential to evaluate for infectious meningoencephalitis, especially herpes simplex viral encephalitis. Thiamine deficiency (Wernicke encephalopathy), drug intoxication, prion disease, Hashimoto encephalopathy, tumor, and subclinical status epilepticus should also be considered. Some of these conditions are associated with the same neuronal autoantibodies detected in limbic encephalitis. Further complicating the picture, case reports have shown the presence of serum neuronal autoantibodies—VGKC complex^13–15 and NMDA-receptor antibodies^16,17—in confirmed cases of prion disease. In addition, adequately treated herpes simplex viral encephalitis can precipitate the production of NMDA-receptor antibodies and their characteristic syndrome.^18–20

BRAINSTEM ENCEPHALITIS

The brainstem—the midbrain, pons, and medulla—can be affected, either in isolation or more commonly as part of a more widespread autoantibody-mediated encephalitis. Symptoms and signs include eye movement abnormalities, ptosis, dysphagia, dysarthria, ataxia, facial palsy, vertigo, hearing impairment, reduced consciousness, and hypoventilation.²¹

Anti-Hu, anti-Ri, and anti-Ma2 antibodies are most commonly associated with brainstem encephalitis (Table 2). Anti-Ma2-associated encephalitis may improve after a combination of immunotherapy and tumor removal²¹; the others have a poor prognosis.

Neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders most commonly involve demyelination affecting the optic nerves and spinal cord, leading to  unilateral or bilateral optic neuritis and transverse myelitis spanning three or more vertebral segments.²² The initial clinical manifestation may be an encephalitic pattern, affecting predominantly the brainstem in a restricted fashion,²² or the central nervous system in a more diffuse pattern, mimicking either acute disseminated encephalomyelitis or, in less severe cases, posterior reversible encephalopathy syndrome.²³

Testing for antiaquaporin-4 antibody, also known as neuromyelitis optica immunoglobulin G, is the single most decisive laboratory test for diagnosing neuromyelitis optica spectrum disorders, so serum and cerebrospinal fluid evaluation for this autoantibody should be considered when caring for a patient whose clinical picture suggests brainstem encephalitis.²²

Bickerstaff brainstem encephalitis

Bickerstaff brainstem encephalitis was first described more than half a century ago in patients with postinfectious ataxia, ophthalmoparesis, and altered consciousness. This rare disease was later found to be associated with antiganglioside GQ1b (anti-GQ1b) autoantibody. MRI is normal in about 90% of cases, so recognizing the clinical presentation and analyzing anti-GQ1b serum titers are critical to diagnosis.

Recovery is usually spontaneous and complete and can be hastened by immunotherapy, especially intravenous immunoglobulin.²⁴

Other causes of brainstem encephalitis

The differential diagnosis of a presentation of brainstem encephalitis includes:

• Infectious causes, the most common being Listeria species followed by enterovirus 71 and herpes simplex virus.²⁵ Tuberculosis, brucellosis, and Whipple disease should also be considered.
• Primary central nervous system inflammatory and demyelinating conditions, eg, multiple sclerosis and acute disseminated encephalomyelitis.
• Systemic inflammatory conditions, eg, Beh­çet disease, systemic lupus erythematosus, and sarcoidosis.
• Direct brainstem neoplastic involvement, as might occur in primary central nervous system lymphoma or leptomeningeal carcinomatosis.

CEREBELLAR SYNDROME

Patients with autoantibody-mediated encephalitis localized predominantly to the cerebellum typically present with dizziness, vertigo, and unsteady gait, progressing eventually to limb and gait ataxia.⁴ Symptoms are often subacute, progressing over weeks.

Multiple neuronal autoantibodies have been found to occur with cerebellar encephalitis (Table 2). In most cases, they are paraneo­plastic and considered not to be pathogenic, given the intracellular location of their target antigen.⁴ In such cases, the syndrome is more accurately described as autoantibody-associated rather than autoantibody-mediated. Only in a minority of cases have neuronal autoantibodies been demonstrated to be directly pathogenic, ie, antimetabotropic glutamate receptor type 1 (anti-mGluR1) antibody-associated cerebellitis²⁶ and antiglutamic acid decarboxylase (anti-GAD)-associated cerebellar ataxia.²⁷

Differential diagnosis of cerebellar syndromes

The differential diagnosis of autoantibody-associated cerebellar syndromes is broad and includes:

• Alcohol-induced atrophy
• Drug-induced cerebellar atrophy (eg, from lithium, phenytoin, gabapentin, metronidazole, amiodarone, carbamazepine)
• Vitamin B₁ and E deficiency
• Hypothyroidism, hypoparathyroidism
• Neurodegenerative disease (eg, prion disease, multiple system atrophy)
• Parainfectious causes (eg, after infection with Epstein-Barr virus)
• Immune-mediated diseases (Miller-Fisher syndrome, associated with anti-GQ1b antibodies, and antigliadin-associated ataxia, which can occur in isolation or as part of celiac disease).⁴

SYNDROMES ASSOCIATED WITH SPECIFIC ANTIBODIES

A few of the autoantibody-mediated encephalitic syndromes have specific antibody associations and characteristic clinical presentations. The most prominent of these syndromes are VGKC complex antibody encephalitis (as in the patient described at the beginning of this article) and anti-NMDA receptor encephalitis.

VGKC COMPLEX ANTIBODY-MEDIATED LIMBIC ENCEPHALITIS

VGKC complex antibodies, initially reported to be associated with the peripheral nerve hyperexcitability disorder neuromyotonia, were subsequently found in Morvan syndrome.^28,29 Patients with this syndrome often present with autonomic dysfunction and peripheral nerve hyperexcitability but also develop insomnia, confusion, hallucinations, and memory loss. Drawing on the clinical overlap between Morvan syndrome and limbic encephalitis, Buckley et al³⁰ were the first to report VGKC complex antibodies in two cases of limbic encephalitis.

VGKC complex antibodies are now understood to be associated with a wide variety of neurologic conditions, including chronic idiopathic pain, epilepsy,³¹ movement disorders, cranial nerve abnormalities, autonomic dysfunction,³² and gut dysmotility.³³ In contrast, these antibodies are rare in healthy people.³⁴ Limbic encephalitis associated with VGKC complex antibody usually lacks cerebellar and brainstem dysfunction, which may help distinguish it from other types of autoantibody-mediated limbic encephalitis.¹²

VGKC complex antibody does not bind to the potassium channel itself. Instead it recognizes other constituents of the channel complex, most notably LGI1 and contactin-associated protein 2 (CASPR2). LGI1 antibody is more commonly associated with limbic encephalitis—as illustrated in our case study—in addition to a distinctive type of seizure affecting the arm and face (faciobrachial dystonic seizure).³⁴ The CASPR2 antibody, on the other hand, more often correlates with peripheral nerve manifestations and Morvan syndrome.²⁹ Hyponatremia is commonly seen on serum chemical analysis and provides a clue that these syndromes are present.¹²

Good response to immunotherapy

A critical change in therapy came as clinicians realized that seizures were often refractory to standard antiepileptic drugs but responded well to immunotherapies. On the basis of these observations, sera of patients with long-standing epilepsy have been reanalyzed to look for neuronal autoantibodies.³¹ These antibodies should be checked in cases of new-onset refractory status epilepticus of unknown origin that does not respond to antiepileptic medications.

About half of patients with VGKC complex antibody-mediated limbic encephalitis have normal findings on brain MRI.⁵ Seven of 10 patients who were prospectively followed for VGKC complex antibody-mediated faciobrachial dystonic seizures had normal brain MRIs.³⁵

VGKC complex antibody-mediated limbic encephalitis does not usually recur.³⁶ Most cases are nonparaneoplastic, as evidenced by failure to detect a single active tumor in 64 patients after a median follow-up of 3 years. The prognosis is generally favorable except in cases with coexisting tumors.¹²

ANTI-NMDA RECEPTOR ENCEPHALITIS

Often associated with ovarian teratoma

Anti-NMDA receptor encephalitis typically affects women in their 20s and 30s, and about half of patients have an ovarian teratoma. It can also occur in younger patients and in men, in whom it is less likely to be associated with a neoplasm.³⁷

Typical initial symptoms include striking and often stereotyped neuropsychiatric disturbances manifesting as psychosis, confusion, seizures, and amnesia. After 1 to 2 weeks, new symptoms set in, including reduced consciousness, movement disorders (ranging from orolingualfacial dyskinesia to rigidity and choreoathetosis), autonomic dysfunction, and hypoventilation, often prompting admission to the intensive care unit.³⁸

Although the outcome is favorable in most cases, recovery, in contrast to VGKC complex antibody-mediated limbic encephalitis, is slow and may take longer than 1 year. Up to a quarter of patients have a relapse, underscoring the importance of maintenance immunotherapy.

It is important to undertake an intensive search for possible ovarian and extraovarian teratomas in young women with this syndrome—including CT of the pelvis, vaginal ultrasonography, and PET imaging—as removal of the teratoma may be curative.³⁷

DIAGNOSIS OF AUTOANTIBODY-MEDIATED ENCEPHALITIS

Critical to diagnosing autoantibody-mediated encephalitis is awareness of these disorders. Since antibody testing may be very specific and is not usually part of the standard batteries of tests, a high level of suspicion is needed. Patients may present to different specialists in different settings; therefore, clinicians in pediatrics, rheumatology, psychiatry, and intensive care medicine need to be aware of these syndromes to avoid delay and misdiagnosis.

Clinical features suggesting autoantibody-mediated encephalitis include:

• Acute or subacute onset of a neurologic syndrome
• New-onset refractory status epilepticus of unknown etiology
• Acute or subacute psychiatric illness with unexpected progression to neurologic symptoms or delirium
• Unusual movement disorders not conforming to standard syndromes
• Cognitive impairment, psychosis, or behavioral or language disorders with atypical findings on imaging or cerebrospinal fluid analysis.

Imaging. Diagnosis of autoantibody-mediated encephalitis focuses on evidence suggesting an inflammatory central nervous system syndrome. MRI may show hyperintense signals on T2, FLAIR, or diffusion-weighted imaging changes in various brain regions. In many cases, however, MRI is negative despite severe clinical symptoms. In a study of 72 patients suspected of having autoimmune dementia of various etiologies, including but not restricted to antineuronal surface antibody-mediated causes, Flanagan et al³⁹ identified atypical neuroimaging findings in only 29%. PET imaging may show hypermetabolism in certain brain areas correlating to clinical syndromes but is often difficult to obtain in a timely fashion.

Cerebrospinal fluid is often abnormal, showing elevated protein, increased immunoglobulin G synthesis, or oligoclonal banding. As with imaging studies, the cerebrospinal fluid may be normal despite severe clinical manifestations.

Electroencephalography may show focal slowing or seizure activity. Neuropsychologic testing may show different patterns of abnormalities.

Antibody testing. None of these tests can be used in isolation, and the diagnosis of autoantibody-mediated encephalitis hinges on recognizing a clinical syndrome and ordering supportive testing. Specific antibodies are more likely in different clinical syndromes and should be sought (Table 3).

Patients who have autoantibody-mediated encephalitis may test negative for autoantibodies for many possible reasons:

• Blood testing for antibodies may be less sensitive than cerebrospinal fluid testing
• Antibody titers may vary in the course of the disease
• The patient may be expressing an antibody that is less often tested for (eg, anti-AMPA receptor or antigamma-aminobutyric acid B) or one that has not yet been isolated.

Evaluating for malignancy is recommended in all cases of autoantibody-mediated encephalitis. The initial workup may involve CT of the chest, abdomen, and pelvis, as well as mammography in women and serum prostate-specific antigen testing and testicular ultrasonography in men. Ordering FDG-PET in cases in which CT is negative or inconclusive increases cancer detection.⁴⁰ If no cancer is found, close tumor surveillance—every 3 to 6 months—is recommended for at least 2 years.⁴¹

TREATMENT

Owing in large part to the rarity of autoantibody-mediated encephalitides, no randomized trials of therapy have been performed. Treatment at present is guided mostly by case series and expert consensus, which suggest first-line therapy with intravenous immunoglobulin, high-dose corticosteroids, plasmapheresis, or a combination.

Different syndromes and antibody-related disorders respond differently to therapy. Syndromes associated with antibodies against intracellular antigens tend to be more resistant to immune therapy than cell surface antigen-related syndromes.⁴

Tiered approach

Combined treatment with intravenous immunoglobulin and high-dose corticosteroids may be superior to treatment with steroids alone for LGI1-antibody mediated limbic encephalitis.⁴²

In cases refractory to first-line (“tier 1”) therapy, second-line immunotherapy with drugs affecting B-cell populations (eg, rituximab, cyclophosphamide, and mycophenolate mofetil) has been used.

A tiered approach has been most extensively studied for anti-NMDA-receptor encephalitis, with better outcomes found using second-line therapy.⁴³

Treatment strategies for these disorders will likely evolve over time with additional experience.

Outpatient management

Once the patient is discharged from the hospital, a multidisciplinary approach to care is recommended, including physical rehabilitation, speech therapy, neuropsychiatric and neuroimmunologic follow-up, and annual surveillance for malignancies.

A 79-year-old woman with a history of breast cancer in remission and hypertension presented to a local emergency department because of subacute memory loss and compulsive shopping. Her serum sodium concentration was 127 mmol/L (reference range 132–148). Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were normal, and she was sent home.

Three days later, she experienced a generalized tonic-clonic seizure that evolved into status epilepticus. She was intubated and admitted to the intensive care unit. Cerebrospinal fluid analysis was normal, and infectious causes of encephalitis were ruled out. MRI showed increased signal in both hippocampi (Figure 1). Her seizures were refractory to treatment, and she was given pentobarbital to induce a coma.

Serum evaluation of neuronal antibodies revealed elevated titers of the voltage-gated potassium channel (VGKC) complex antibody, with subsequent subtyping confirming the leucine-rich glioma-inactivated protein 1 (LGI1) protein as the antigenic target.

She received a 5-day course of intravenous immunoglobulin and methylprednisolone, pentobarbital was withdrawn, and the seizures did not recur, but weeks later she remained comatose. Positron emission tomography (PET) of the brain revealed hypermetabolism in the medial and anterior aspects of both temporal lobes. She underwent five sessions of plasma exchange, after which she began to improve and follow commands. She was ultimately discharged to an acute rehabilitation facility after a 4-week hospital stay.

She received infusions of intravenous immunoglobulin twice a month for 6 months.  At her last follow-up visit, she was seizure-free and neurologically intact except for mild inattention.

NEWLY RECOGNIZED DISEASES

Although autoantibody-mediated encephalitic syndromes were first described more than 50 years ago,^1,2 their autoimmune basis was not recognized until the early 1980s.³ In the past 10 years, a flood of novel clinical syndromes associated with neuronal autoantibodies has been described that may be markedly improved or even completely resolved with immunotherapy. In cases of unexplained seizure, encephalitis, or acute-onset psychiatric syndromes, suspecting these syndromes can lead to diagnosis, treatment, and a good outcome.

This review describes the key clinical autoantibody-mediated encephalitic syndromes, explains the better-characterized antibody associations, and discusses their diagnosis and treatment. 

CLASSIFIED ANATOMICALLY, IMMUNOLOGICALLY, OR EPONYMOUSLY

Autoantibody-mediated encephalitis is also known as autoimmune-mediated encephalitis, autoimmune-mediated limbic encephalitis, and autoimmune synaptic encephalitis.

How to categorize these syndromes is still in flux: they can be listed by the area of the brain affected, the antibody involved, or the name of the discoverer (eg, Morvan syndrome).

Autoantibodies identified in autoimmune encephalitis fall under two broad categories:

• Those targeting intracellular (intranuclear or intracytoplasmic) antigens; the syndromes they cause are more likely to be paraneoplastic and less responsive to immunotherapy
• Those targeting antigens on the neuronal surface: the syndromes they cause are less likely to be paraneoplastic and are more responsive to immunotherapy.⁴

SYNDROMES DEFINED BY BRAIN AREA AFFECTED

Below, we provide examples of neurologic syndromes of autoantibody-mediated encephalitis according to the region of the brain most affected, ie, the limbic system, the brainstem, or the cerebellum (Figure 2).

LIMBIC ENCEPHALITIS

Memory loss, behavioral changes, seizures

Patients with limbic encephalitis (such as the patient described in the vignette above) present with symptoms attributed to dysfunction of mesial temporal lobe structures, most notably the hippocampus. Prominent symptoms include short-term memory loss, behavioral disturbances such as agitation and confusion, and psychiatric problems such as depression and psychosis. Recurrent seizures are a salient feature and, not uncommonly, progress to status epilepticus.

Antibodies are not all cancer-associated

Cerebrospinal fluid analysis can be normal or show abnormalities suggesting immune activation, eg, slight pleocytosis, elevated protein, increased immunoglobulin G synthesis, and oligoclonal banding.⁵

In many cases, an autoantibody is found in the blood or in the cerebrospinal fluid. Some patients may express more than one autoantibody, so the traditional view of “one antibody, one syndrome” is incorrect.

Although initially identified as a rare paraneoplastic disorder, limbic encephalitis sometimes occurs in the absence of malignancy.

Multiple antibodies have been linked to the syndrome (Table 1).^6–9 The “classic” antibodies initially found in paraneoplastic forms are now generally viewed as nonpathogenic, in part because they are directed against intracellular antigens. Neuronal injury in paraneo­plastic limbic encephalitis is believed to be mediated by cytotoxic T lymphocytes, with neuronal autoantibodies being produced after the injury.⁴ Recently defined antibodies, such as those targeting the N-methyl-d-aspartate (NMDA) receptor⁶ and the LGI1 protein,⁷ are now understood to be common causes of limbic encephalitis. 

Imaging usually shows limbic focal changes

Structural MRI or functional fluorodeoxyglucose (FDG)-PET imaging may show focal changes in limbic system structures, such as the mesial temporal lobes.  It is now recognized that other cortical areas may be involved, and the term “limbic encephalitis” may give way to “cortical” or “focal encephalitis.”

In about 60% of patients, MRI shows hyperintense fluid-attenuated inversion recovery (FLAIR) or T2 signal changes in the mesial temporal lobes, likely reflecting inflammatory changes.^4,10,11 On FDG-PET, hypermetabolism may be observed in the mesial temporal lobes early in the disease despite normal findings on MRI.¹² Hypometabolism, either diffuse or localized to the mesial temporal lobes, eventually sets in, likely reflecting cytotoxic injury in the aftermath of prolonged inflammation or seizures.

Consider other causes

Before diagnosing limbic encephalitis, it is essential to evaluate for infectious meningoencephalitis, especially herpes simplex viral encephalitis. Thiamine deficiency (Wernicke encephalopathy), drug intoxication, prion disease, Hashimoto encephalopathy, tumor, and subclinical status epilepticus should also be considered. Some of these conditions are associated with the same neuronal autoantibodies detected in limbic encephalitis. Further complicating the picture, case reports have shown the presence of serum neuronal autoantibodies—VGKC complex^13–15 and NMDA-receptor antibodies^16,17—in confirmed cases of prion disease. In addition, adequately treated herpes simplex viral encephalitis can precipitate the production of NMDA-receptor antibodies and their characteristic syndrome.^18–20

BRAINSTEM ENCEPHALITIS

The brainstem—the midbrain, pons, and medulla—can be affected, either in isolation or more commonly as part of a more widespread autoantibody-mediated encephalitis. Symptoms and signs include eye movement abnormalities, ptosis, dysphagia, dysarthria, ataxia, facial palsy, vertigo, hearing impairment, reduced consciousness, and hypoventilation.²¹

Anti-Hu, anti-Ri, and anti-Ma2 antibodies are most commonly associated with brainstem encephalitis (Table 2). Anti-Ma2-associated encephalitis may improve after a combination of immunotherapy and tumor removal²¹; the others have a poor prognosis.

Neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders most commonly involve demyelination affecting the optic nerves and spinal cord, leading to  unilateral or bilateral optic neuritis and transverse myelitis spanning three or more vertebral segments.²² The initial clinical manifestation may be an encephalitic pattern, affecting predominantly the brainstem in a restricted fashion,²² or the central nervous system in a more diffuse pattern, mimicking either acute disseminated encephalomyelitis or, in less severe cases, posterior reversible encephalopathy syndrome.²³

Testing for antiaquaporin-4 antibody, also known as neuromyelitis optica immunoglobulin G, is the single most decisive laboratory test for diagnosing neuromyelitis optica spectrum disorders, so serum and cerebrospinal fluid evaluation for this autoantibody should be considered when caring for a patient whose clinical picture suggests brainstem encephalitis.²²

Bickerstaff brainstem encephalitis

Bickerstaff brainstem encephalitis was first described more than half a century ago in patients with postinfectious ataxia, ophthalmoparesis, and altered consciousness. This rare disease was later found to be associated with antiganglioside GQ1b (anti-GQ1b) autoantibody. MRI is normal in about 90% of cases, so recognizing the clinical presentation and analyzing anti-GQ1b serum titers are critical to diagnosis.

Recovery is usually spontaneous and complete and can be hastened by immunotherapy, especially intravenous immunoglobulin.²⁴

Other causes of brainstem encephalitis

The differential diagnosis of a presentation of brainstem encephalitis includes:

• Infectious causes, the most common being Listeria species followed by enterovirus 71 and herpes simplex virus.²⁵ Tuberculosis, brucellosis, and Whipple disease should also be considered.
• Primary central nervous system inflammatory and demyelinating conditions, eg, multiple sclerosis and acute disseminated encephalomyelitis.
• Systemic inflammatory conditions, eg, Beh­çet disease, systemic lupus erythematosus, and sarcoidosis.
• Direct brainstem neoplastic involvement, as might occur in primary central nervous system lymphoma or leptomeningeal carcinomatosis.

CEREBELLAR SYNDROME

Patients with autoantibody-mediated encephalitis localized predominantly to the cerebellum typically present with dizziness, vertigo, and unsteady gait, progressing eventually to limb and gait ataxia.⁴ Symptoms are often subacute, progressing over weeks.

Multiple neuronal autoantibodies have been found to occur with cerebellar encephalitis (Table 2). In most cases, they are paraneo­plastic and considered not to be pathogenic, given the intracellular location of their target antigen.⁴ In such cases, the syndrome is more accurately described as autoantibody-associated rather than autoantibody-mediated. Only in a minority of cases have neuronal autoantibodies been demonstrated to be directly pathogenic, ie, antimetabotropic glutamate receptor type 1 (anti-mGluR1) antibody-associated cerebellitis²⁶ and antiglutamic acid decarboxylase (anti-GAD)-associated cerebellar ataxia.²⁷

Differential diagnosis of cerebellar syndromes

The differential diagnosis of autoantibody-associated cerebellar syndromes is broad and includes:

• Alcohol-induced atrophy
• Drug-induced cerebellar atrophy (eg, from lithium, phenytoin, gabapentin, metronidazole, amiodarone, carbamazepine)
• Vitamin B₁ and E deficiency
• Hypothyroidism, hypoparathyroidism
• Neurodegenerative disease (eg, prion disease, multiple system atrophy)
• Parainfectious causes (eg, after infection with Epstein-Barr virus)
• Immune-mediated diseases (Miller-Fisher syndrome, associated with anti-GQ1b antibodies, and antigliadin-associated ataxia, which can occur in isolation or as part of celiac disease).⁴

SYNDROMES ASSOCIATED WITH SPECIFIC ANTIBODIES

A few of the autoantibody-mediated encephalitic syndromes have specific antibody associations and characteristic clinical presentations. The most prominent of these syndromes are VGKC complex antibody encephalitis (as in the patient described at the beginning of this article) and anti-NMDA receptor encephalitis.

VGKC COMPLEX ANTIBODY-MEDIATED LIMBIC ENCEPHALITIS

VGKC complex antibodies, initially reported to be associated with the peripheral nerve hyperexcitability disorder neuromyotonia, were subsequently found in Morvan syndrome.^28,29 Patients with this syndrome often present with autonomic dysfunction and peripheral nerve hyperexcitability but also develop insomnia, confusion, hallucinations, and memory loss. Drawing on the clinical overlap between Morvan syndrome and limbic encephalitis, Buckley et al³⁰ were the first to report VGKC complex antibodies in two cases of limbic encephalitis.

VGKC complex antibodies are now understood to be associated with a wide variety of neurologic conditions, including chronic idiopathic pain, epilepsy,³¹ movement disorders, cranial nerve abnormalities, autonomic dysfunction,³² and gut dysmotility.³³ In contrast, these antibodies are rare in healthy people.³⁴ Limbic encephalitis associated with VGKC complex antibody usually lacks cerebellar and brainstem dysfunction, which may help distinguish it from other types of autoantibody-mediated limbic encephalitis.¹²

VGKC complex antibody does not bind to the potassium channel itself. Instead it recognizes other constituents of the channel complex, most notably LGI1 and contactin-associated protein 2 (CASPR2). LGI1 antibody is more commonly associated with limbic encephalitis—as illustrated in our case study—in addition to a distinctive type of seizure affecting the arm and face (faciobrachial dystonic seizure).³⁴ The CASPR2 antibody, on the other hand, more often correlates with peripheral nerve manifestations and Morvan syndrome.²⁹ Hyponatremia is commonly seen on serum chemical analysis and provides a clue that these syndromes are present.¹²

Good response to immunotherapy

A critical change in therapy came as clinicians realized that seizures were often refractory to standard antiepileptic drugs but responded well to immunotherapies. On the basis of these observations, sera of patients with long-standing epilepsy have been reanalyzed to look for neuronal autoantibodies.³¹ These antibodies should be checked in cases of new-onset refractory status epilepticus of unknown origin that does not respond to antiepileptic medications.

About half of patients with VGKC complex antibody-mediated limbic encephalitis have normal findings on brain MRI.⁵ Seven of 10 patients who were prospectively followed for VGKC complex antibody-mediated faciobrachial dystonic seizures had normal brain MRIs.³⁵

VGKC complex antibody-mediated limbic encephalitis does not usually recur.³⁶ Most cases are nonparaneoplastic, as evidenced by failure to detect a single active tumor in 64 patients after a median follow-up of 3 years. The prognosis is generally favorable except in cases with coexisting tumors.¹²

ANTI-NMDA RECEPTOR ENCEPHALITIS

Often associated with ovarian teratoma

Anti-NMDA receptor encephalitis typically affects women in their 20s and 30s, and about half of patients have an ovarian teratoma. It can also occur in younger patients and in men, in whom it is less likely to be associated with a neoplasm.³⁷

Typical initial symptoms include striking and often stereotyped neuropsychiatric disturbances manifesting as psychosis, confusion, seizures, and amnesia. After 1 to 2 weeks, new symptoms set in, including reduced consciousness, movement disorders (ranging from orolingualfacial dyskinesia to rigidity and choreoathetosis), autonomic dysfunction, and hypoventilation, often prompting admission to the intensive care unit.³⁸

Although the outcome is favorable in most cases, recovery, in contrast to VGKC complex antibody-mediated limbic encephalitis, is slow and may take longer than 1 year. Up to a quarter of patients have a relapse, underscoring the importance of maintenance immunotherapy.

It is important to undertake an intensive search for possible ovarian and extraovarian teratomas in young women with this syndrome—including CT of the pelvis, vaginal ultrasonography, and PET imaging—as removal of the teratoma may be curative.³⁷

DIAGNOSIS OF AUTOANTIBODY-MEDIATED ENCEPHALITIS

Critical to diagnosing autoantibody-mediated encephalitis is awareness of these disorders. Since antibody testing may be very specific and is not usually part of the standard batteries of tests, a high level of suspicion is needed. Patients may present to different specialists in different settings; therefore, clinicians in pediatrics, rheumatology, psychiatry, and intensive care medicine need to be aware of these syndromes to avoid delay and misdiagnosis.

Clinical features suggesting autoantibody-mediated encephalitis include:

• Acute or subacute onset of a neurologic syndrome
• New-onset refractory status epilepticus of unknown etiology
• Acute or subacute psychiatric illness with unexpected progression to neurologic symptoms or delirium
• Unusual movement disorders not conforming to standard syndromes
• Cognitive impairment, psychosis, or behavioral or language disorders with atypical findings on imaging or cerebrospinal fluid analysis.

Imaging. Diagnosis of autoantibody-mediated encephalitis focuses on evidence suggesting an inflammatory central nervous system syndrome. MRI may show hyperintense signals on T2, FLAIR, or diffusion-weighted imaging changes in various brain regions. In many cases, however, MRI is negative despite severe clinical symptoms. In a study of 72 patients suspected of having autoimmune dementia of various etiologies, including but not restricted to antineuronal surface antibody-mediated causes, Flanagan et al³⁹ identified atypical neuroimaging findings in only 29%. PET imaging may show hypermetabolism in certain brain areas correlating to clinical syndromes but is often difficult to obtain in a timely fashion.

Cerebrospinal fluid is often abnormal, showing elevated protein, increased immunoglobulin G synthesis, or oligoclonal banding. As with imaging studies, the cerebrospinal fluid may be normal despite severe clinical manifestations.

Electroencephalography may show focal slowing or seizure activity. Neuropsychologic testing may show different patterns of abnormalities.

Antibody testing. None of these tests can be used in isolation, and the diagnosis of autoantibody-mediated encephalitis hinges on recognizing a clinical syndrome and ordering supportive testing. Specific antibodies are more likely in different clinical syndromes and should be sought (Table 3).

Patients who have autoantibody-mediated encephalitis may test negative for autoantibodies for many possible reasons:

• Blood testing for antibodies may be less sensitive than cerebrospinal fluid testing
• Antibody titers may vary in the course of the disease
• The patient may be expressing an antibody that is less often tested for (eg, anti-AMPA receptor or antigamma-aminobutyric acid B) or one that has not yet been isolated.

Evaluating for malignancy is recommended in all cases of autoantibody-mediated encephalitis. The initial workup may involve CT of the chest, abdomen, and pelvis, as well as mammography in women and serum prostate-specific antigen testing and testicular ultrasonography in men. Ordering FDG-PET in cases in which CT is negative or inconclusive increases cancer detection.⁴⁰ If no cancer is found, close tumor surveillance—every 3 to 6 months—is recommended for at least 2 years.⁴¹

TREATMENT

Owing in large part to the rarity of autoantibody-mediated encephalitides, no randomized trials of therapy have been performed. Treatment at present is guided mostly by case series and expert consensus, which suggest first-line therapy with intravenous immunoglobulin, high-dose corticosteroids, plasmapheresis, or a combination.

Different syndromes and antibody-related disorders respond differently to therapy. Syndromes associated with antibodies against intracellular antigens tend to be more resistant to immune therapy than cell surface antigen-related syndromes.⁴

Tiered approach

Combined treatment with intravenous immunoglobulin and high-dose corticosteroids may be superior to treatment with steroids alone for LGI1-antibody mediated limbic encephalitis.⁴²

In cases refractory to first-line (“tier 1”) therapy, second-line immunotherapy with drugs affecting B-cell populations (eg, rituximab, cyclophosphamide, and mycophenolate mofetil) has been used.

A tiered approach has been most extensively studied for anti-NMDA-receptor encephalitis, with better outcomes found using second-line therapy.⁴³

Treatment strategies for these disorders will likely evolve over time with additional experience.

Outpatient management

Once the patient is discharged from the hospital, a multidisciplinary approach to care is recommended, including physical rehabilitation, speech therapy, neuropsychiatric and neuroimmunologic follow-up, and annual surveillance for malignancies.

When the Affordable Care Act (ACA) was passed in 2010, it represented an intended shift from reactive medicine, with its focus on acute and urgent needs, to a model focused on disease prevention.

OBG Management readers know about the important women’s health services ensured by the ACA, including well-woman care, as well as the key role played by the American Congress of Obstetricians and Gynecologists (ACOG) in winning this coverage. ACOG worked closely with the Institute of Medicine (IOM) to help define this set of services. And the ACA ensured that women have access to these services, often without copays and deductibles.

ACOG and the National Women’s Law Center (NWLC) work closely on many issues. At first independently and then together, the 2 organizations set out to explore some fundamental issues:

• How does a woman experience the new well-woman benefit when she visits her doctor?
• Does she receive a consistent care set?
• Do some patients have copays while patients in other clinics do not for the same services?
• What does well-woman care mean from one doctor to another, from an ObGyn to an internist to a family physician?

This article explores these issues.

2 initiatives focused on components of women’s health care
During her tenure as president of ACOG, Jeanne Conry, MD, PhD, decided to tackle clinical issues associated with well-woman care. She convened a Well-Woman Task Force, led by Haywood Brown, MD, and included the NWLC among other partner organizations (TABLE).

Table. Partipating organizations of the ACOG Well-Woman Task Force
• American Academy of Family Physicians
• American Academy of Pediatrics
• American Academy of Physician Assistants
• American College of Nurse–Midwives
• American College of Osteopathic Obstetricians and Gynecologists
• Association of Reproductive Health Professionals
• Association of Women’s Health, Obstetric, and Neonatal Nurses
• National Association of Nurse Practitioners in Women’s Health
• National Medical Association
• National Women’s Law Center
• Planned Parenthood Federation of America
• Society for Maternal-Fetal Medicine
• Society of Academic Specialists in General Obstetrics and Gynecology
• Society of Gynecologic Oncology

The NWLC and Brigham and Women’s Hospital also partnered with ACOG and others to help ensure a consistent patient experience. These 2 closely related initiatives were designed to work together to help patients and physicians understand and benefit from new coverage under the ACA.

1. How does a woman experience well-woman care?
Experts associated with these 2 initiatives recognized that well-woman care includes attention to the history, physical examination, counseling, and screening intended to maintain physical, mental, and social wellbeing and general health throughout a woman’s lifespan. Experts also recognized that the ACA guarantees coverage of at least one annual well-woman visit, although not all of the recommended components necessarily would be performed at the same visit or by the same provider.

For many women who have gained insurance coverage under the ACA, the well-woman visit represents their entry into the insured health care system. These women may have limited understanding of the services they should receive during this visit.

To address this issue, the NWLC invited ACOG to participate in its initiative with Brigham and Women’s Hospital to understand the well-woman visit from the patient’s point of view. This effort yielded patient education materials in English and Spanish that help women understand:

• that their health insurance now covers a well-woman visit
• what care is included in that visit
• that there is no deductible or copay for this visit
• how to prepare for this visit
• what questions to ask during the visit.

These materials help women understand that the purpose of the well-woman visit is to provide them with a chance to:

• “receive care and counseling that is appropriate, based on age, cognitive development, and life experience
• review their current health and risks to their health with their health care professional
• ask any questions they may have about their health or risk factors
• talk about what they can do to prevent future health problems
• build a trusting relationship with their health care provider, with an emphasis on confidentiality
• receive appropriate preventive screenings and immunizations and make sure they know which screenings and immunizations they should receive in the future
• review their reproductive plan and contraceptive choices.”¹                 

The materials also advise patients that they may be asked about:

• current health concerns
• current medications, both prescription and over the counter
• family history on both the mother’s and father’s sides
• life management, including family relationships, work, and stress
• substance use habits, including alcohol and tobacco
• sexual activity
• eating habits and physical activity
• past reproductive health experience and any pregnancy complications
• any memory problems (older women)
• screening for depression, anxiety, substance use disorders, and interpersonal violence.

To view some of these materials, visit http://www.nwlc.org/sites/default/files/final_well-womanbrochure.pdf.

2. Does each woman receive consistent well-woman care?
ACOG’s Well-Woman Task Force was shaped by an awareness that many medical societies and government agencies provide recommendations and guidelines about the basic elements of women’s health. While these recommendations and guidelines all may be based on evidence and expert opinion, the recommendations vary. A goal of the task force was to work with providers across the women’s health spectrum to find consensus and provide guidance to women and clinicians with age-appropriate recommendations for a well-woman visit.

In the fall of 2015, the task force’s findings were published in an article entitled “Components of the well-woman visit” in the journal Obstetrics & Gynecology.² Those findings outline a core set of well-woman care practices across a woman’s lifespan, from adolescence through the reproductive years and into maturity, and they are usable by any provider who cares for adolescent girls or women.

ACOG has summarized its well-woman recommendations, by age, on its website,³ at http://www.acog.org/About-ACOG/ACOG-Departments/Annual-Womens-Health-Care/Well-Woman-Recommendations.

3. Do all women have a copay for the well-woman visit?
Because research has revealed that any type of copay or deductible for preventive care significantly lessens the likelihood that patients will seek out such care, the ACA sought to make basic preventive care available without cost sharing.⁴

The US Department of Health and Human Services notes that: “The Affordable Care Act requires most health plans to cover recommended preventive services without cost sharing. In 2011 and 2012, 71 million Americans with private health insurance gained access to preventive services with no cost sharing because of the law.”⁴

Grandfathered plans (those created or sold before March 23, 2010) are exempt from this requirement, as are Medicare, TRICARE, and traditional Medicaid plans.

4. What does well-woman care mean from one doctor to another?
Under the ACA, well-woman care can be provided by a “wide range of providers, including family physicians, internists, nurse–midwives, nurse practitioners, obstetrician-gynecologists, pediatricians, and physician assistants,” depending on the age of the patient, her particular needs and preferences, and access to health services.²

The ACOG Well-Woman Task Force “focused on delineating the well-woman visit throughout the lifespan, across all providers and health plans.”²

In determining the components of well-woman care, ACOG’s task force compiled existing guidelines from many sources, including the Department of Health and Human Services, the IOM, the US Preventive Services Task Force, and each member organization.

Members categorized guidelines as:

• single source (eg, abdominal examination)
• no agreement (breast cancer/mammography screening)
• limited agreement (pelvic examination)
• general agreement (hypertension, osteoporosis)
• sound agreement (screening for sexually transmitted infections)

The task force also agreed that final recommendations would rely on evidence-based guidelines, evidence-informed guidelines, and uniform expert agreement. Recommendations were considered “strong” if they relied primarily on evidence-based or evidence-informed guidelines and “qualified” if they relied primarily on expert consensus.

Guidelines were further separated into age bands:

• adolescents (13–18 years)
• reproductive-aged women (19–45 years)
• mature women (46–64 years)
• women older than 64 years.

The task force recommended that, during the well-woman visit, health care professionals educate patients about:

• healthy eating habits and maintenance of healthy weight
• exercise and physical activity
• seat belt use
• risk factors for certain types of cancer
• heart health
• breast health
• bone health
• safer sex practices and prevention of sexually transmitted infections
• healthy interpersonal relationships
• prevention and management of chronic disease
• resources for the patient (online, written, community, patient groups)
• medication use
• fall prevention.

Health care providers also should counsel patients regarding:

• recommended preventive screenings and immunizations
• any concerns about mood, such as prolonged periods of sadness, a failure to enjoy what they usually find pleasant, or anxiety or irritability that seems out of proportion to events
• what to expect in terms of effects on mood and anxiety at reproductive life transitions, including menarche, pregnancy, the postpartum period, and perimenopause
• body image issues
• what to expect in terms of the menstrual cycle during perimenopause and menopause
• reproductive health or fertility concerns
• reproductive life planning (contraception appropriate for life stage, reproductive plans, and risk factors, including risk factors for breast and ovarian cancer and cardiovascular disease)
• pregnancy planning, including attaining and maintaining a healthy weight and managing any chronic conditions before or during pregnancy
• what to expect during menopause, including signs and symptoms and options for addressing symptoms (midlife and older women)
• symptoms of cardiovascular disease
• urinary incontinence.

The task force acknowledged that not all of these recommendations can be carried out at a single well-woman visit or by a single provider.

See, again, ACOG’s specific well-woman recommendations, by age range, at http://www.acog.org/About-ACOG/ACOG-Departments/Annual-Womens-Health-Care/Well-Woman-Recommendations.³

How to winnow a long list of recommendations to determine the most pressing issues for a specific patient
In an editorial accompanying the ACOG Well-Woman Task Force report, entitled “Re-envisioning the annual well-woman visit: the task forward,” George F. Sawaya, MD, of the University of California, San Francisco, devised a plan to determine the most pressing well-woman needs for a specific patient.¹ He chose as an example a 41-year-old sexually active woman who does not smoke.

While Dr. Sawaya praised the Well-Woman Task Force recommendations for their “comprehensive scope,” he also noted that the sheer number of recommendations might be “overwhelming and difficult to navigate.”¹ One tool for winnowing the recommendations comes from the Agency for Healthcare Research and Quality, which offers an Electronic Preventive Services Selector (http://epss.ahrq.gov/PDA/index.jsp), available both online and as a smartphone app. Once the clinician plugs in the patient’s age and a few risk factors, the tool generates a list of recommended preventive services. This list of services has been evaluated by the US Preventive Services Task Force, with each recommendation graded “A” through “D,” based on benefits versus harms.

Back to that 41-year-old sexually active woman: Using the Electronic Preventive Services Selector, a list of as many as 20 grade A and B recommendations would be generated. However, only 3 of them would be grade A (screening for cervical cancer, HIV, and high blood pressure). An additional 2 grade B recommendations might apply to an average-risk patient such as this: screening for alcohol misuse and depression. All 5 services fall within the Well-Woman Task Force’s recommendations. They also have “good face validity with clinicians as being important, so it seems reasonable that these be prioritized above the others, at least at the first visit,” Dr. Sawaya says.¹

Clinicians can use a similar strategy for patients of various ages and risk factors.

Reference
1. Sawaya GF. Re-envisioning the annual well-woman visit: the task forward [editorial]. Obstet Gynecol. 2015;126(4):695–696.

The bottom line
By defining and implementing the foundational elements of women’s health, we can improve care for all women and ensure, as Dr. Conry emphasized during her tenure as ACOG president, “that every woman gets the care she needs, every time.”

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

When the Affordable Care Act (ACA) was passed in 2010, it represented an intended shift from reactive medicine, with its focus on acute and urgent needs, to a model focused on disease prevention.

OBG Management readers know about the important women’s health services ensured by the ACA, including well-woman care, as well as the key role played by the American Congress of Obstetricians and Gynecologists (ACOG) in winning this coverage. ACOG worked closely with the Institute of Medicine (IOM) to help define this set of services. And the ACA ensured that women have access to these services, often without copays and deductibles.

ACOG and the National Women’s Law Center (NWLC) work closely on many issues. At first independently and then together, the 2 organizations set out to explore some fundamental issues:

• How does a woman experience the new well-woman benefit when she visits her doctor?
• Does she receive a consistent care set?
• Do some patients have copays while patients in other clinics do not for the same services?
• What does well-woman care mean from one doctor to another, from an ObGyn to an internist to a family physician?

This article explores these issues.

2 initiatives focused on components of women’s health care
During her tenure as president of ACOG, Jeanne Conry, MD, PhD, decided to tackle clinical issues associated with well-woman care. She convened a Well-Woman Task Force, led by Haywood Brown, MD, and included the NWLC among other partner organizations (TABLE).

Table. Partipating organizations of the ACOG Well-Woman Task Force
• American Academy of Family Physicians
• American Academy of Pediatrics
• American Academy of Physician Assistants
• American College of Nurse–Midwives
• American College of Osteopathic Obstetricians and Gynecologists
• Association of Reproductive Health Professionals
• Association of Women’s Health, Obstetric, and Neonatal Nurses
• National Association of Nurse Practitioners in Women’s Health
• National Medical Association
• National Women’s Law Center
• Planned Parenthood Federation of America
• Society for Maternal-Fetal Medicine
• Society of Academic Specialists in General Obstetrics and Gynecology
• Society of Gynecologic Oncology

The NWLC and Brigham and Women’s Hospital also partnered with ACOG and others to help ensure a consistent patient experience. These 2 closely related initiatives were designed to work together to help patients and physicians understand and benefit from new coverage under the ACA.

1. How does a woman experience well-woman care?
Experts associated with these 2 initiatives recognized that well-woman care includes attention to the history, physical examination, counseling, and screening intended to maintain physical, mental, and social wellbeing and general health throughout a woman’s lifespan. Experts also recognized that the ACA guarantees coverage of at least one annual well-woman visit, although not all of the recommended components necessarily would be performed at the same visit or by the same provider.

For many women who have gained insurance coverage under the ACA, the well-woman visit represents their entry into the insured health care system. These women may have limited understanding of the services they should receive during this visit.

To address this issue, the NWLC invited ACOG to participate in its initiative with Brigham and Women’s Hospital to understand the well-woman visit from the patient’s point of view. This effort yielded patient education materials in English and Spanish that help women understand:

• that their health insurance now covers a well-woman visit
• what care is included in that visit
• that there is no deductible or copay for this visit
• how to prepare for this visit
• what questions to ask during the visit.

These materials help women understand that the purpose of the well-woman visit is to provide them with a chance to:

• “receive care and counseling that is appropriate, based on age, cognitive development, and life experience
• review their current health and risks to their health with their health care professional
• ask any questions they may have about their health or risk factors
• talk about what they can do to prevent future health problems
• build a trusting relationship with their health care provider, with an emphasis on confidentiality
• receive appropriate preventive screenings and immunizations and make sure they know which screenings and immunizations they should receive in the future
• review their reproductive plan and contraceptive choices.”¹                 

The materials also advise patients that they may be asked about:

• current health concerns
• current medications, both prescription and over the counter
• family history on both the mother’s and father’s sides
• life management, including family relationships, work, and stress
• substance use habits, including alcohol and tobacco
• sexual activity
• eating habits and physical activity
• past reproductive health experience and any pregnancy complications
• any memory problems (older women)
• screening for depression, anxiety, substance use disorders, and interpersonal violence.

To view some of these materials, visit http://www.nwlc.org/sites/default/files/final_well-womanbrochure.pdf.

2. Does each woman receive consistent well-woman care?
ACOG’s Well-Woman Task Force was shaped by an awareness that many medical societies and government agencies provide recommendations and guidelines about the basic elements of women’s health. While these recommendations and guidelines all may be based on evidence and expert opinion, the recommendations vary. A goal of the task force was to work with providers across the women’s health spectrum to find consensus and provide guidance to women and clinicians with age-appropriate recommendations for a well-woman visit.

In the fall of 2015, the task force’s findings were published in an article entitled “Components of the well-woman visit” in the journal Obstetrics & Gynecology.² Those findings outline a core set of well-woman care practices across a woman’s lifespan, from adolescence through the reproductive years and into maturity, and they are usable by any provider who cares for adolescent girls or women.

ACOG has summarized its well-woman recommendations, by age, on its website,³ at http://www.acog.org/About-ACOG/ACOG-Departments/Annual-Womens-Health-Care/Well-Woman-Recommendations.

3. Do all women have a copay for the well-woman visit?
Because research has revealed that any type of copay or deductible for preventive care significantly lessens the likelihood that patients will seek out such care, the ACA sought to make basic preventive care available without cost sharing.⁴

The US Department of Health and Human Services notes that: “The Affordable Care Act requires most health plans to cover recommended preventive services without cost sharing. In 2011 and 2012, 71 million Americans with private health insurance gained access to preventive services with no cost sharing because of the law.”⁴

Grandfathered plans (those created or sold before March 23, 2010) are exempt from this requirement, as are Medicare, TRICARE, and traditional Medicaid plans.

4. What does well-woman care mean from one doctor to another?
Under the ACA, well-woman care can be provided by a “wide range of providers, including family physicians, internists, nurse–midwives, nurse practitioners, obstetrician-gynecologists, pediatricians, and physician assistants,” depending on the age of the patient, her particular needs and preferences, and access to health services.²

The ACOG Well-Woman Task Force “focused on delineating the well-woman visit throughout the lifespan, across all providers and health plans.”²

In determining the components of well-woman care, ACOG’s task force compiled existing guidelines from many sources, including the Department of Health and Human Services, the IOM, the US Preventive Services Task Force, and each member organization.

Members categorized guidelines as:

• single source (eg, abdominal examination)
• no agreement (breast cancer/mammography screening)
• limited agreement (pelvic examination)
• general agreement (hypertension, osteoporosis)
• sound agreement (screening for sexually transmitted infections)

The task force also agreed that final recommendations would rely on evidence-based guidelines, evidence-informed guidelines, and uniform expert agreement. Recommendations were considered “strong” if they relied primarily on evidence-based or evidence-informed guidelines and “qualified” if they relied primarily on expert consensus.

Guidelines were further separated into age bands:

• adolescents (13–18 years)
• reproductive-aged women (19–45 years)
• mature women (46–64 years)
• women older than 64 years.

The task force recommended that, during the well-woman visit, health care professionals educate patients about:

• healthy eating habits and maintenance of healthy weight
• exercise and physical activity
• seat belt use
• risk factors for certain types of cancer
• heart health
• breast health
• bone health
• safer sex practices and prevention of sexually transmitted infections
• healthy interpersonal relationships
• prevention and management of chronic disease
• resources for the patient (online, written, community, patient groups)
• medication use
• fall prevention.

Health care providers also should counsel patients regarding:

• recommended preventive screenings and immunizations
• any concerns about mood, such as prolonged periods of sadness, a failure to enjoy what they usually find pleasant, or anxiety or irritability that seems out of proportion to events
• what to expect in terms of effects on mood and anxiety at reproductive life transitions, including menarche, pregnancy, the postpartum period, and perimenopause
• body image issues
• what to expect in terms of the menstrual cycle during perimenopause and menopause
• reproductive health or fertility concerns
• reproductive life planning (contraception appropriate for life stage, reproductive plans, and risk factors, including risk factors for breast and ovarian cancer and cardiovascular disease)
• pregnancy planning, including attaining and maintaining a healthy weight and managing any chronic conditions before or during pregnancy
• what to expect during menopause, including signs and symptoms and options for addressing symptoms (midlife and older women)
• symptoms of cardiovascular disease
• urinary incontinence.

The task force acknowledged that not all of these recommendations can be carried out at a single well-woman visit or by a single provider.

See, again, ACOG’s specific well-woman recommendations, by age range, at http://www.acog.org/About-ACOG/ACOG-Departments/Annual-Womens-Health-Care/Well-Woman-Recommendations.³

How to winnow a long list of recommendations to determine the most pressing issues for a specific patient
In an editorial accompanying the ACOG Well-Woman Task Force report, entitled “Re-envisioning the annual well-woman visit: the task forward,” George F. Sawaya, MD, of the University of California, San Francisco, devised a plan to determine the most pressing well-woman needs for a specific patient.¹ He chose as an example a 41-year-old sexually active woman who does not smoke.

While Dr. Sawaya praised the Well-Woman Task Force recommendations for their “comprehensive scope,” he also noted that the sheer number of recommendations might be “overwhelming and difficult to navigate.”¹ One tool for winnowing the recommendations comes from the Agency for Healthcare Research and Quality, which offers an Electronic Preventive Services Selector (http://epss.ahrq.gov/PDA/index.jsp), available both online and as a smartphone app. Once the clinician plugs in the patient’s age and a few risk factors, the tool generates a list of recommended preventive services. This list of services has been evaluated by the US Preventive Services Task Force, with each recommendation graded “A” through “D,” based on benefits versus harms.

Back to that 41-year-old sexually active woman: Using the Electronic Preventive Services Selector, a list of as many as 20 grade A and B recommendations would be generated. However, only 3 of them would be grade A (screening for cervical cancer, HIV, and high blood pressure). An additional 2 grade B recommendations might apply to an average-risk patient such as this: screening for alcohol misuse and depression. All 5 services fall within the Well-Woman Task Force’s recommendations. They also have “good face validity with clinicians as being important, so it seems reasonable that these be prioritized above the others, at least at the first visit,” Dr. Sawaya says.¹

Clinicians can use a similar strategy for patients of various ages and risk factors.

Reference
1. Sawaya GF. Re-envisioning the annual well-woman visit: the task forward [editorial]. Obstet Gynecol. 2015;126(4):695–696.

The bottom line
By defining and implementing the foundational elements of women’s health, we can improve care for all women and ensure, as Dr. Conry emphasized during her tenure as ACOG president, “that every woman gets the care she needs, every time.”

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

When the Affordable Care Act (ACA) was passed in 2010, it represented an intended shift from reactive medicine, with its focus on acute and urgent needs, to a model focused on disease prevention.

OBG Management readers know about the important women’s health services ensured by the ACA, including well-woman care, as well as the key role played by the American Congress of Obstetricians and Gynecologists (ACOG) in winning this coverage. ACOG worked closely with the Institute of Medicine (IOM) to help define this set of services. And the ACA ensured that women have access to these services, often without copays and deductibles.

ACOG and the National Women’s Law Center (NWLC) work closely on many issues. At first independently and then together, the 2 organizations set out to explore some fundamental issues:

• How does a woman experience the new well-woman benefit when she visits her doctor?
• Does she receive a consistent care set?
• Do some patients have copays while patients in other clinics do not for the same services?
• What does well-woman care mean from one doctor to another, from an ObGyn to an internist to a family physician?

This article explores these issues.

2 initiatives focused on components of women’s health care
During her tenure as president of ACOG, Jeanne Conry, MD, PhD, decided to tackle clinical issues associated with well-woman care. She convened a Well-Woman Task Force, led by Haywood Brown, MD, and included the NWLC among other partner organizations (TABLE).

Table. Partipating organizations of the ACOG Well-Woman Task Force
• American Academy of Family Physicians
• American Academy of Pediatrics
• American Academy of Physician Assistants
• American College of Nurse–Midwives
• American College of Osteopathic Obstetricians and Gynecologists
• Association of Reproductive Health Professionals
• Association of Women’s Health, Obstetric, and Neonatal Nurses
• National Association of Nurse Practitioners in Women’s Health
• National Medical Association
• National Women’s Law Center
• Planned Parenthood Federation of America
• Society for Maternal-Fetal Medicine
• Society of Academic Specialists in General Obstetrics and Gynecology
• Society of Gynecologic Oncology

The NWLC and Brigham and Women’s Hospital also partnered with ACOG and others to help ensure a consistent patient experience. These 2 closely related initiatives were designed to work together to help patients and physicians understand and benefit from new coverage under the ACA.

1. How does a woman experience well-woman care?
Experts associated with these 2 initiatives recognized that well-woman care includes attention to the history, physical examination, counseling, and screening intended to maintain physical, mental, and social wellbeing and general health throughout a woman’s lifespan. Experts also recognized that the ACA guarantees coverage of at least one annual well-woman visit, although not all of the recommended components necessarily would be performed at the same visit or by the same provider.

For many women who have gained insurance coverage under the ACA, the well-woman visit represents their entry into the insured health care system. These women may have limited understanding of the services they should receive during this visit.

To address this issue, the NWLC invited ACOG to participate in its initiative with Brigham and Women’s Hospital to understand the well-woman visit from the patient’s point of view. This effort yielded patient education materials in English and Spanish that help women understand:

• that their health insurance now covers a well-woman visit
• what care is included in that visit
• that there is no deductible or copay for this visit
• how to prepare for this visit
• what questions to ask during the visit.

These materials help women understand that the purpose of the well-woman visit is to provide them with a chance to:

• “receive care and counseling that is appropriate, based on age, cognitive development, and life experience
• review their current health and risks to their health with their health care professional
• ask any questions they may have about their health or risk factors
• talk about what they can do to prevent future health problems
• build a trusting relationship with their health care provider, with an emphasis on confidentiality
• receive appropriate preventive screenings and immunizations and make sure they know which screenings and immunizations they should receive in the future
• review their reproductive plan and contraceptive choices.”¹                 

The materials also advise patients that they may be asked about:

• current health concerns
• current medications, both prescription and over the counter
• family history on both the mother’s and father’s sides
• life management, including family relationships, work, and stress
• substance use habits, including alcohol and tobacco
• sexual activity
• eating habits and physical activity
• past reproductive health experience and any pregnancy complications
• any memory problems (older women)
• screening for depression, anxiety, substance use disorders, and interpersonal violence.

To view some of these materials, visit http://www.nwlc.org/sites/default/files/final_well-womanbrochure.pdf.

2. Does each woman receive consistent well-woman care?
ACOG’s Well-Woman Task Force was shaped by an awareness that many medical societies and government agencies provide recommendations and guidelines about the basic elements of women’s health. While these recommendations and guidelines all may be based on evidence and expert opinion, the recommendations vary. A goal of the task force was to work with providers across the women’s health spectrum to find consensus and provide guidance to women and clinicians with age-appropriate recommendations for a well-woman visit.

In the fall of 2015, the task force’s findings were published in an article entitled “Components of the well-woman visit” in the journal Obstetrics & Gynecology.² Those findings outline a core set of well-woman care practices across a woman’s lifespan, from adolescence through the reproductive years and into maturity, and they are usable by any provider who cares for adolescent girls or women.

ACOG has summarized its well-woman recommendations, by age, on its website,³ at http://www.acog.org/About-ACOG/ACOG-Departments/Annual-Womens-Health-Care/Well-Woman-Recommendations.

3. Do all women have a copay for the well-woman visit?
Because research has revealed that any type of copay or deductible for preventive care significantly lessens the likelihood that patients will seek out such care, the ACA sought to make basic preventive care available without cost sharing.⁴

The US Department of Health and Human Services notes that: “The Affordable Care Act requires most health plans to cover recommended preventive services without cost sharing. In 2011 and 2012, 71 million Americans with private health insurance gained access to preventive services with no cost sharing because of the law.”⁴

Grandfathered plans (those created or sold before March 23, 2010) are exempt from this requirement, as are Medicare, TRICARE, and traditional Medicaid plans.

4. What does well-woman care mean from one doctor to another?
Under the ACA, well-woman care can be provided by a “wide range of providers, including family physicians, internists, nurse–midwives, nurse practitioners, obstetrician-gynecologists, pediatricians, and physician assistants,” depending on the age of the patient, her particular needs and preferences, and access to health services.²

The ACOG Well-Woman Task Force “focused on delineating the well-woman visit throughout the lifespan, across all providers and health plans.”²

In determining the components of well-woman care, ACOG’s task force compiled existing guidelines from many sources, including the Department of Health and Human Services, the IOM, the US Preventive Services Task Force, and each member organization.

Members categorized guidelines as:

• single source (eg, abdominal examination)
• no agreement (breast cancer/mammography screening)
• limited agreement (pelvic examination)
• general agreement (hypertension, osteoporosis)
• sound agreement (screening for sexually transmitted infections)

The task force also agreed that final recommendations would rely on evidence-based guidelines, evidence-informed guidelines, and uniform expert agreement. Recommendations were considered “strong” if they relied primarily on evidence-based or evidence-informed guidelines and “qualified” if they relied primarily on expert consensus.

Guidelines were further separated into age bands:

• adolescents (13–18 years)
• reproductive-aged women (19–45 years)
• mature women (46–64 years)
• women older than 64 years.

The task force recommended that, during the well-woman visit, health care professionals educate patients about:

• healthy eating habits and maintenance of healthy weight
• exercise and physical activity
• seat belt use
• risk factors for certain types of cancer
• heart health
• breast health
• bone health
• safer sex practices and prevention of sexually transmitted infections
• healthy interpersonal relationships
• prevention and management of chronic disease
• resources for the patient (online, written, community, patient groups)
• medication use
• fall prevention.

Health care providers also should counsel patients regarding:

• recommended preventive screenings and immunizations
• any concerns about mood, such as prolonged periods of sadness, a failure to enjoy what they usually find pleasant, or anxiety or irritability that seems out of proportion to events
• what to expect in terms of effects on mood and anxiety at reproductive life transitions, including menarche, pregnancy, the postpartum period, and perimenopause
• body image issues
• what to expect in terms of the menstrual cycle during perimenopause and menopause
• reproductive health or fertility concerns
• reproductive life planning (contraception appropriate for life stage, reproductive plans, and risk factors, including risk factors for breast and ovarian cancer and cardiovascular disease)
• pregnancy planning, including attaining and maintaining a healthy weight and managing any chronic conditions before or during pregnancy
• what to expect during menopause, including signs and symptoms and options for addressing symptoms (midlife and older women)
• symptoms of cardiovascular disease
• urinary incontinence.

The task force acknowledged that not all of these recommendations can be carried out at a single well-woman visit or by a single provider.

See, again, ACOG’s specific well-woman recommendations, by age range, at http://www.acog.org/About-ACOG/ACOG-Departments/Annual-Womens-Health-Care/Well-Woman-Recommendations.³

How to winnow a long list of recommendations to determine the most pressing issues for a specific patient
In an editorial accompanying the ACOG Well-Woman Task Force report, entitled “Re-envisioning the annual well-woman visit: the task forward,” George F. Sawaya, MD, of the University of California, San Francisco, devised a plan to determine the most pressing well-woman needs for a specific patient.¹ He chose as an example a 41-year-old sexually active woman who does not smoke.

While Dr. Sawaya praised the Well-Woman Task Force recommendations for their “comprehensive scope,” he also noted that the sheer number of recommendations might be “overwhelming and difficult to navigate.”¹ One tool for winnowing the recommendations comes from the Agency for Healthcare Research and Quality, which offers an Electronic Preventive Services Selector (http://epss.ahrq.gov/PDA/index.jsp), available both online and as a smartphone app. Once the clinician plugs in the patient’s age and a few risk factors, the tool generates a list of recommended preventive services. This list of services has been evaluated by the US Preventive Services Task Force, with each recommendation graded “A” through “D,” based on benefits versus harms.

Back to that 41-year-old sexually active woman: Using the Electronic Preventive Services Selector, a list of as many as 20 grade A and B recommendations would be generated. However, only 3 of them would be grade A (screening for cervical cancer, HIV, and high blood pressure). An additional 2 grade B recommendations might apply to an average-risk patient such as this: screening for alcohol misuse and depression. All 5 services fall within the Well-Woman Task Force’s recommendations. They also have “good face validity with clinicians as being important, so it seems reasonable that these be prioritized above the others, at least at the first visit,” Dr. Sawaya says.¹

Clinicians can use a similar strategy for patients of various ages and risk factors.

Reference
1. Sawaya GF. Re-envisioning the annual well-woman visit: the task forward [editorial]. Obstet Gynecol. 2015;126(4):695–696.

The bottom line
By defining and implementing the foundational elements of women’s health, we can improve care for all women and ensure, as Dr. Conry emphasized during her tenure as ACOG president, “that every woman gets the care she needs, every time.”

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Screening for and treating high blood pressure (HBP) to prevent cardiovascular and renal disease is a tried-and-true preventive intervention that is supported by strong evidence. And not surprisingly, when the US Preventive Services Task Force (USPSTF) recently updated its 2007 recommendation for blood pressure screening for adults, it once again gave an A recommendation for those ages 18 years and older. What is noteworthy, however, is that this update concentrates on the accuracy of blood pressure measurement methods and optimal frequency of screening.¹

The most significant modification of past recommendations is that HBP found with office measurement of blood pressure (OMBP) should be confirmed with either ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) before starting treatment. (For its recommendation, the USPSTF used the HBP definition from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [TABLE 1].^2,3)

Ensuring accurate blood-pressure measurements. More than 30% of adults in the United States have HBP, with prevalence increasing with age (TABLE 2).² Only about half of this population has HBP under control.⁴ This modifiable condition contributes to more than 360,000 deaths annually.² However, while treatment of true HBP results in substantial benefits, it is important not to over-diagnose HBP and over-treat it.

Studies have shown that 15% to 30% of individuals diagnosed with HBP in a clinical setting will have blood pressure in the normal range when measurements are taken outside of the doctor’s office.¹ This discrepancy can be due to measurement error, regression to the mean, recent caffeine ingestion by the patient, or isolated clinical hypertension wherein the stress and anxiety caused by clinic visits elevates blood pressure transiently.

With this in mind, the USPSTF recommends that OMBP-detected HBP be confirmed with either ABPM or HBPM. Of these 2 follow-up methods, ABPM is supported by stronger evidence and is preferred. The USPSTF includes HBPM as an alternative because ABPM equipment may not always be available—or affordable—and using the equipment may present logistical challenges.

Starting off on the right foot

Screening for HBP in a clinical setting is more accurate if conducted according to recommended procedures: use an appropriately sized cuff; take the measurement at least 5 minutes after the patient’s arrival while he or she is seated with legs uncrossed and the cuffed arm is at the level of the heart; and record the mean of 2 separate measurements. There appears to be no real difference in the accuracy of automated vs manual sphygmomanometers.

Optimal frequency of screening varies. While the USPSTF found little evidence to support any particular overall screening frequency, it recommends annual screening for those who are 40 years of age or older and those ages 18 to 39 who are obese or overweight, are African American, or who have high-normal blood pressure (TABLE 3).¹ Screening every 3 to 5 years is recommended for individuals not in these categories.

Initial steps in treating HBP. The Task Force also commented on which medications to use when initiating HBP treatment (after lifestyle and dietary interventions). Non-African Americans should receive a thiazide diuretic, calcium channel blocker, angiotensin-converting enzyme inhibitor, or angiotensin-receptor blocker. African Americans should begin treatment with a thiazide diuretic or calcium channel blocker. These recommendations appear to have been adopted from the Eighth Joint National Committee, since the accompanying evidence report for the USPSTF’s update did not address this issue.⁵

Don't forget patient support

Patient support is key. As of June 2015, the Community Preventive Services Task Force (CPSTF) recommends self-measured blood pressure monitoring combined with additional support as a means of improving blood pressure control in those with HBP.⁴

Supportive measures include things such as patient counseling on medications and health behavior changes (eg, diet and exercise); education on HBP and blood pressure self-management; and use of secure electronic or Web-based tools such as text or e-mail reminders to measure blood pressure, show up for appointments, or communicate blood pressure readings to healthcare providers. Patients who participate in home self-measurement of blood pressure with additional support lower their systolic blood pressure, on average, 1.4 mm Hg more than those who do not.⁴

Remaining questions

The new USPSTF recommendation leaves several issues unaddressed. For one thing, the Affordable Care Act mandates that commercial health insurance plans provide services with an A or B Task Force recommendation to patients with no copayments. So does the new HBP recommendation mean payers have to make ABPM and HBPM available to patients at no charge?

Up to 30% of individuals diagnosed with high BP in a clinical setting will have BP in the normal range when measurements are taken outside of the doctor's office.

There are other questions, too. If HBP detected by OMBP is not confirmed when ABPM is performed, should ABPM be repeated, and if so, at what interval? What is the role of emerging technologies that use devices other than arm cuffs to measure blood pressure?

Despite these uncertainties, the new USPSTF and CPSTF recommendations refine the longstanding in-office–only approach to diagnosing and monitoring HBP and advocate newer technologies that could help improve diagnostic accuracy, avoid over-diagnosis and over-treatment, and improve patient adherence to treatment goals.

Screening for and treating high blood pressure (HBP) to prevent cardiovascular and renal disease is a tried-and-true preventive intervention that is supported by strong evidence. And not surprisingly, when the US Preventive Services Task Force (USPSTF) recently updated its 2007 recommendation for blood pressure screening for adults, it once again gave an A recommendation for those ages 18 years and older. What is noteworthy, however, is that this update concentrates on the accuracy of blood pressure measurement methods and optimal frequency of screening.¹

The most significant modification of past recommendations is that HBP found with office measurement of blood pressure (OMBP) should be confirmed with either ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) before starting treatment. (For its recommendation, the USPSTF used the HBP definition from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [TABLE 1].^2,3)

Ensuring accurate blood-pressure measurements. More than 30% of adults in the United States have HBP, with prevalence increasing with age (TABLE 2).² Only about half of this population has HBP under control.⁴ This modifiable condition contributes to more than 360,000 deaths annually.² However, while treatment of true HBP results in substantial benefits, it is important not to over-diagnose HBP and over-treat it.

Studies have shown that 15% to 30% of individuals diagnosed with HBP in a clinical setting will have blood pressure in the normal range when measurements are taken outside of the doctor’s office.¹ This discrepancy can be due to measurement error, regression to the mean, recent caffeine ingestion by the patient, or isolated clinical hypertension wherein the stress and anxiety caused by clinic visits elevates blood pressure transiently.

With this in mind, the USPSTF recommends that OMBP-detected HBP be confirmed with either ABPM or HBPM. Of these 2 follow-up methods, ABPM is supported by stronger evidence and is preferred. The USPSTF includes HBPM as an alternative because ABPM equipment may not always be available—or affordable—and using the equipment may present logistical challenges.

Starting off on the right foot

Screening for HBP in a clinical setting is more accurate if conducted according to recommended procedures: use an appropriately sized cuff; take the measurement at least 5 minutes after the patient’s arrival while he or she is seated with legs uncrossed and the cuffed arm is at the level of the heart; and record the mean of 2 separate measurements. There appears to be no real difference in the accuracy of automated vs manual sphygmomanometers.

Optimal frequency of screening varies. While the USPSTF found little evidence to support any particular overall screening frequency, it recommends annual screening for those who are 40 years of age or older and those ages 18 to 39 who are obese or overweight, are African American, or who have high-normal blood pressure (TABLE 3).¹ Screening every 3 to 5 years is recommended for individuals not in these categories.

Initial steps in treating HBP. The Task Force also commented on which medications to use when initiating HBP treatment (after lifestyle and dietary interventions). Non-African Americans should receive a thiazide diuretic, calcium channel blocker, angiotensin-converting enzyme inhibitor, or angiotensin-receptor blocker. African Americans should begin treatment with a thiazide diuretic or calcium channel blocker. These recommendations appear to have been adopted from the Eighth Joint National Committee, since the accompanying evidence report for the USPSTF’s update did not address this issue.⁵

Don't forget patient support

Patient support is key. As of June 2015, the Community Preventive Services Task Force (CPSTF) recommends self-measured blood pressure monitoring combined with additional support as a means of improving blood pressure control in those with HBP.⁴

Supportive measures include things such as patient counseling on medications and health behavior changes (eg, diet and exercise); education on HBP and blood pressure self-management; and use of secure electronic or Web-based tools such as text or e-mail reminders to measure blood pressure, show up for appointments, or communicate blood pressure readings to healthcare providers. Patients who participate in home self-measurement of blood pressure with additional support lower their systolic blood pressure, on average, 1.4 mm Hg more than those who do not.⁴

Remaining questions

The new USPSTF recommendation leaves several issues unaddressed. For one thing, the Affordable Care Act mandates that commercial health insurance plans provide services with an A or B Task Force recommendation to patients with no copayments. So does the new HBP recommendation mean payers have to make ABPM and HBPM available to patients at no charge?

Up to 30% of individuals diagnosed with high BP in a clinical setting will have BP in the normal range when measurements are taken outside of the doctor's office.

There are other questions, too. If HBP detected by OMBP is not confirmed when ABPM is performed, should ABPM be repeated, and if so, at what interval? What is the role of emerging technologies that use devices other than arm cuffs to measure blood pressure?

Despite these uncertainties, the new USPSTF and CPSTF recommendations refine the longstanding in-office–only approach to diagnosing and monitoring HBP and advocate newer technologies that could help improve diagnostic accuracy, avoid over-diagnosis and over-treatment, and improve patient adherence to treatment goals.

Screening for and treating high blood pressure (HBP) to prevent cardiovascular and renal disease is a tried-and-true preventive intervention that is supported by strong evidence. And not surprisingly, when the US Preventive Services Task Force (USPSTF) recently updated its 2007 recommendation for blood pressure screening for adults, it once again gave an A recommendation for those ages 18 years and older. What is noteworthy, however, is that this update concentrates on the accuracy of blood pressure measurement methods and optimal frequency of screening.¹

The most significant modification of past recommendations is that HBP found with office measurement of blood pressure (OMBP) should be confirmed with either ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) before starting treatment. (For its recommendation, the USPSTF used the HBP definition from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [TABLE 1].^2,3)

Ensuring accurate blood-pressure measurements. More than 30% of adults in the United States have HBP, with prevalence increasing with age (TABLE 2).² Only about half of this population has HBP under control.⁴ This modifiable condition contributes to more than 360,000 deaths annually.² However, while treatment of true HBP results in substantial benefits, it is important not to over-diagnose HBP and over-treat it.

Studies have shown that 15% to 30% of individuals diagnosed with HBP in a clinical setting will have blood pressure in the normal range when measurements are taken outside of the doctor’s office.¹ This discrepancy can be due to measurement error, regression to the mean, recent caffeine ingestion by the patient, or isolated clinical hypertension wherein the stress and anxiety caused by clinic visits elevates blood pressure transiently.

With this in mind, the USPSTF recommends that OMBP-detected HBP be confirmed with either ABPM or HBPM. Of these 2 follow-up methods, ABPM is supported by stronger evidence and is preferred. The USPSTF includes HBPM as an alternative because ABPM equipment may not always be available—or affordable—and using the equipment may present logistical challenges.

Starting off on the right foot

Screening for HBP in a clinical setting is more accurate if conducted according to recommended procedures: use an appropriately sized cuff; take the measurement at least 5 minutes after the patient’s arrival while he or she is seated with legs uncrossed and the cuffed arm is at the level of the heart; and record the mean of 2 separate measurements. There appears to be no real difference in the accuracy of automated vs manual sphygmomanometers.

Optimal frequency of screening varies. While the USPSTF found little evidence to support any particular overall screening frequency, it recommends annual screening for those who are 40 years of age or older and those ages 18 to 39 who are obese or overweight, are African American, or who have high-normal blood pressure (TABLE 3).¹ Screening every 3 to 5 years is recommended for individuals not in these categories.

Initial steps in treating HBP. The Task Force also commented on which medications to use when initiating HBP treatment (after lifestyle and dietary interventions). Non-African Americans should receive a thiazide diuretic, calcium channel blocker, angiotensin-converting enzyme inhibitor, or angiotensin-receptor blocker. African Americans should begin treatment with a thiazide diuretic or calcium channel blocker. These recommendations appear to have been adopted from the Eighth Joint National Committee, since the accompanying evidence report for the USPSTF’s update did not address this issue.⁵

Don't forget patient support

Patient support is key. As of June 2015, the Community Preventive Services Task Force (CPSTF) recommends self-measured blood pressure monitoring combined with additional support as a means of improving blood pressure control in those with HBP.⁴

Supportive measures include things such as patient counseling on medications and health behavior changes (eg, diet and exercise); education on HBP and blood pressure self-management; and use of secure electronic or Web-based tools such as text or e-mail reminders to measure blood pressure, show up for appointments, or communicate blood pressure readings to healthcare providers. Patients who participate in home self-measurement of blood pressure with additional support lower their systolic blood pressure, on average, 1.4 mm Hg more than those who do not.⁴

Remaining questions

The new USPSTF recommendation leaves several issues unaddressed. For one thing, the Affordable Care Act mandates that commercial health insurance plans provide services with an A or B Task Force recommendation to patients with no copayments. So does the new HBP recommendation mean payers have to make ABPM and HBPM available to patients at no charge?

Up to 30% of individuals diagnosed with high BP in a clinical setting will have BP in the normal range when measurements are taken outside of the doctor's office.

There are other questions, too. If HBP detected by OMBP is not confirmed when ABPM is performed, should ABPM be repeated, and if so, at what interval? What is the role of emerging technologies that use devices other than arm cuffs to measure blood pressure?

Despite these uncertainties, the new USPSTF and CPSTF recommendations refine the longstanding in-office–only approach to diagnosing and monitoring HBP and advocate newer technologies that could help improve diagnostic accuracy, avoid over-diagnosis and over-treatment, and improve patient adherence to treatment goals.

Just as psychiatrists are adapting to DSM-5, they have to cope with implementation of the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). This challenge raises questions: What is the importance of understanding ICD-10? How will it affect the practice of psychiatry?

Furthermore, how does ICD-10 relate to DSM-5 and Current Procedural Terminology (CPT)? How does it differ from ICD-9? What are the ICD-10-Clinical Modification (CM) and ICD-10-Procedures (PCS)?Learning the essence of the changes, and understanding what impact they have on your clinical work, are necessary to ensure that your practice keeps pace with professional and legal standards of care. The effort involved is not onerous, however, and can improve the quality and efficiency of your care and how you document it.

In this article, we provide you with an overview of ICD-10; highlight major changes of the new classification; explain its relevance to clinical practice; and offer guidelines for implementing it effectively. We also emphasize that a good understanding of DSM-5 facilitates appreciation of ICD-10 and makes its implementation fairly easy and straightforward.

To begin, we provide a glossary of ICD-related terms and a review of additional definitions, distinctions, and dates (Box).^1-6

Major changes from ICD-9
No question: ICD-10 is going to significantly influence your practice and your reimbursement. Furthermore, a number of revisions in ICD-10 have the potential to meaningfully improve clinical documentation and communication and to enhance your ability to precisely describe the complexity of your patients—with implications for billing.

ICD-10 differs from ICD-9 in organization, structure, code composition, and level of detail. In addition, ICD-10 makes some changes in terminology and definitions, with the goal of improving precision.

ICD-10 also is much larger than ICD-9.The total number of medical diagnostic codes has increased more than 5-fold—from approximately 13,000 to 69,000. This expansion allows for greater specificity in diagnosis and enables differentiation of an initial clinical encounter from a subsequent encounter.

To accommodate the expansion in the number of codes, the 5-digit numeric codes used in ICD-9 have been replaced in ICD-10 by 7-digit alphanumeric codes:

• the first digit always is a letter
• the second and third digits are numbers followed by a decimal point
• the fourth though seventh digits can be letters or numbers
• the first 3 digits denote the diagnostic category
• the fourth through sixth digits provide diagnostic detail
• the seventh digit provides information about the nature of the encounter (eg, initial, subsequent, or sequel, denoted respectively by “A,” “D,” and “S” in the seventh digit).

The number of 3-digit categories for psychiatric disorders has increased from 30 in ICD-9 (290-319) to 100 in ICD-10 (F00-F99). Only the first 5 digits are used for the section on mental disorders in ICD-10, with the first digit always “F” and the second digit a number denoting the broad type of disorders. The second and third digits in conjunction define the major category of the disorder; the fourth and fifth digits provide additional descriptive detail about the disorder (Table).

Examples of “Z” codes relevant to psychiatry are:

Z00 General psychiatric examination (eg, of a person who does not have a complaint or diagnosis)

Z03 Examination for suspected mental and behavioral disorder

Z04 Examination for medicolegal or other purposes; Z04.8 is relevant laboratory testing, such as drug testing of urine or blood

Z50 Care involving rehabilitation (substance use disorder, etc.)

Z60 Problem related to social environment

Z61 Problem related to negative life events in childhood

Z63 Problem related to primary support group, including family circumstances

Z64-Z65 Problem related to other psychosocial circumstances

Z70-Z71 Condition requiring counseling, not elsewhere classified

Z73 Problem related to difficulty with life management (burnout, stress, role conflict, etc.)

Z75 Problem related to medical facilities and other aspects of health care (eg, awaiting admission)

Z81 Family history of mental or behavioral disorders

Z85-Z91 Personal history of various disorders (must be absent or in full remission at the moment); Z86.51, for example, refers to a history of combat and operational stress reaction.

Greater precision is now possible when coding for treatment-related adverse effects. A particular adverse effect now is coded under the relevant system, along with its attribution to the specific substance. Obesity attributable to antipsychotic treatment,^7,8 for example, is coded as E66.1.

Integrating DSM-5 and ICD-10
Because DSM-5 lists corresponding ICD-10-CM codes for all disorders, you will find it much easier than other physicians to implement ICD-10. DSM-5 includes ICD-9-CM and ICD-10-CM codes for each DSM-5 disorder (for example, the ICD-9-CM code for schizophrenia is 295.x; the ICD-10-CM code is F20.9).⁹

Furthermore, a number of changes from ICD-9-CM to ICD-10-CM enable documentation of greater diagnostic specificity; for example, DSM-5 schizoaffective disorder, bipolar type, and schizoaffective disorder, depressive type, are distinctly coded as F25.0 and F25.1, respectively, in ICD-10-CM, whereas both were coded as 295.7 in ICD-9-CM.¹⁰

You will continue to use DSM-5 criteria to guide your diagnostic process, translating the DSM-5 diagnosis (diagnoses) into corresponding ICD-10-CM codes. Experience with DSM-5 substantially simplifies the transition to ICD-10.

Key differences between DSM-5 and ICD-10
There are notable differences in organization and content between DSM-5 and ICD-10.

The 20 chapters in DSM-5 begin with neuro­developmental disorders; neurocognitive disorders are toward the end (ie, childhood to late life). In contrast, neurocognitive disorders (ie, “dementia”) appear at the beginning of ICD-10; neurodevelopmental disorders are at the end.

Elimination of schizophrenia subtypes in DSM-5 necessitates coding of all schizophrenia as F20.9 in ICD-10-CM because F20.0-F20.8 are specific subtypes. DSM-5 schizophreniform disorder is coded F20.81.

Substance abuse and substance dependence continue to be separate in ICD-10-CM, but they are combined in a single category of substance use disorders in DSM-5. The correct ICD-10-CM code (ie, abuse vs dependence) is determined by the severity of the substance use disorder: “Mild” coding as abuse (F1x.1) and “moderate” and “severe” coding as dependence (F2x.2), with x denoting the substance abused.

There can be multiple applicable diagnoses associated with a clinical encounter, as there was with ICD-9-CM. Give precedence to the diagnosis that best represents the nature of the presenting problem; list other diagnoses in the order of their relevance. DSM-5 and ICD-10-CM are similar in this regard.

ICD-10-CM uses only subtypes, in contrast to the use of subtypes and specifiers in DSM-5 to describe variability in disorders across patients. It is possible, however, to code certain DSM-5 specifiers in ICD-10-CM. (This is discussed in the “Recording Procedures” section of the DSM-5 text and summarized at the beginning of the manual, and appears in the “Appendix.”) To code the catatonia specifier in the context of schizoaffective disorder, depressive type, for example, use ICD-10-CM code F25.1 for the disorder and add code F06.1 for the catatonia specifier.¹¹

How will ICD-10 affect your practice?
As of October 1, 2015, all health care facilities were to have become ICD-10 compliant. Furthermore, any Health Insurance Portability and Accountability Act-covered entity must use ICD-10-CM codes if it expects to be reimbursed for health care services.

Mental health practitioners might think that the transition from ICD-9-CM to ICD-10-CM involves only billers and coders, not them. They are wrong. All clinicians are responsible for documenting their diagnostic and treatment services properly. Medical records must contain adequate information to support any diagnostic (ICD-10-CM) and treatment (CPT) codes that are applied to a given clinical encounter.

The greater detail and specificity that are provided by ICD-10-CM allow more accurate recording of clinical complexity, which, in turn, influences reimbursement. However, good documentation is necessary for proper coding. Because clinicians are ultimately responsible for proper diagnostic coding, good understanding of ICD-10-CM is essential to be able to code properly.

Similar to the expansion of ICD-10-CM (from volumes 1 and 2 of ICD-9-CM), ICD-10-PCS has undergone similar expansion (from volume 3 of ICD-9-CM), with a corresponding increase in specificity. For example, there are now 5 distinct codes for electroconvulsive therapy (GZB0ZZZ-GZB4ZZZ) that distinguish unilateral from bilateral electrode placement and single from multiple stimulations.

DSM-5 will continue to be the frameworkfor psychiatric assessment and diagnosis. ICD-10-CM will be the coding system to accurately denote DSM-5 diagnoses. The Centers for Medicare and Medicaid Services (CMS) and the National Center for Health Statistics recognize DSM-5 as the means to identify proper ICD-10-CM codes for mental disorders. CMS also has announced that, although ICD-10-CM codes are necessary for reimbursement, use of an incorrect code will not be the basis for denying a Medicare claim for 1 year.

Making ICD-10 part of practice
Here are several keys to implementing ICD-10 with minimum pain and maximum benefit.

Multiple diagnosis codes should be listed in the order of their relevance to the clinical encounter.

Visit type. The seventh character of the ICD-10-CM code denotes the type of visit (initial, subsequent, or sequela) and must be provided:

• An initial encounter is one in which the patient first receives active treatment.
• A subsequent encounter refers to a follow-up visit in which the patient receives routine care during the healing or recovery phase.
• A sequel encounter is one in which a patient receives treatment for complications or conditions that arise as a direct result of the initial condition.

The transition to ICD-10 should be facilitated by adoption of DSM-5. Continue using DSM-5 to determine the correct diagnosis or diagnoses of the mental disorder, then apply the corresponding ICD-10-CM code(s). The better you understand and apply DSM-5, the more precise you can be in utilizing the greater specificity and accuracy afforded by ICD-10-CM coding.

Document well. Good understanding of the structure and organization of ICD-10-CM facilitates efficient, comprehensive documentation. This, in turn, will foster better clinical communication and appropriate reimbursement.

Know your payers—in particular, their policies regarding differential reimbursement for clinical complexity (based on ICD-10-CM/PCS). Medical practices that are part of an accountable care organization, and those that have risk-adjusted contracts must pay special attention to documenting clinical complexity when coding.

Know your electronic health care record, understand what tools it offers to efficiently translate DSM-5 diagnoses into appropriate ICD-10-CM codes, and use those tools efficiently.

Review your medical record documentation for the top 20 conditions in your practice, in the context of their definition in ICD-10-CM.

If you have coders who do ICD-10-CM coding for you, review a few patient charts with them to compare your sense of the patient’s clinical complexity and their coding based on your documentation.

Changes in DSM-5 have encouraged clinicians to improve their assessment of patients and provide measurement-based care. The significant changes in ICD-10-CM should provide the impetus for you to hone your ability to provide documentation. Sufficient flexibility exists within guidelines to permit individualization of the style of documentation.

Because all DSM-5 diagnoses map to appropriate ICD-10-CM codes, effective use of DSM-5 should make the transition to ICD-10 easy.

Bottom Line
Compared with ICD-9, definitions of mental health diagnoses have been improved in ICD-10, and more elaborate code descriptions in ICD-10-CM provide for greater precision when you report a diagnosis. The result? More accurate and efficient documentation of the care you provide and better reimbursement. Understanding what impact the changes in ICD-10 will have on your clinical work will ensure that your practice keeps pace with professional and legal standards of care.

Related Resources
• Blue Cross Blue Shield of Michigan ICD-10 update: mental and behavioral health ICD-10-CM codes. http://www.bcbsm.com/content/dam/public/Providers/Documents/help/faqs/icd10-update-mentalhealth.pdf.
• American Psychiatric Association ICD-10 tutorial. http://www.psychiatry.org/psychiatrists/practice/dsm/icd-10.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Just as psychiatrists are adapting to DSM-5, they have to cope with implementation of the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). This challenge raises questions: What is the importance of understanding ICD-10? How will it affect the practice of psychiatry?

Furthermore, how does ICD-10 relate to DSM-5 and Current Procedural Terminology (CPT)? How does it differ from ICD-9? What are the ICD-10-Clinical Modification (CM) and ICD-10-Procedures (PCS)?Learning the essence of the changes, and understanding what impact they have on your clinical work, are necessary to ensure that your practice keeps pace with professional and legal standards of care. The effort involved is not onerous, however, and can improve the quality and efficiency of your care and how you document it.

In this article, we provide you with an overview of ICD-10; highlight major changes of the new classification; explain its relevance to clinical practice; and offer guidelines for implementing it effectively. We also emphasize that a good understanding of DSM-5 facilitates appreciation of ICD-10 and makes its implementation fairly easy and straightforward.

To begin, we provide a glossary of ICD-related terms and a review of additional definitions, distinctions, and dates (Box).^1-6

Major changes from ICD-9
No question: ICD-10 is going to significantly influence your practice and your reimbursement. Furthermore, a number of revisions in ICD-10 have the potential to meaningfully improve clinical documentation and communication and to enhance your ability to precisely describe the complexity of your patients—with implications for billing.

ICD-10 differs from ICD-9 in organization, structure, code composition, and level of detail. In addition, ICD-10 makes some changes in terminology and definitions, with the goal of improving precision.

ICD-10 also is much larger than ICD-9.The total number of medical diagnostic codes has increased more than 5-fold—from approximately 13,000 to 69,000. This expansion allows for greater specificity in diagnosis and enables differentiation of an initial clinical encounter from a subsequent encounter.

To accommodate the expansion in the number of codes, the 5-digit numeric codes used in ICD-9 have been replaced in ICD-10 by 7-digit alphanumeric codes:

• the first digit always is a letter
• the second and third digits are numbers followed by a decimal point
• the fourth though seventh digits can be letters or numbers
• the first 3 digits denote the diagnostic category
• the fourth through sixth digits provide diagnostic detail
• the seventh digit provides information about the nature of the encounter (eg, initial, subsequent, or sequel, denoted respectively by “A,” “D,” and “S” in the seventh digit).

The number of 3-digit categories for psychiatric disorders has increased from 30 in ICD-9 (290-319) to 100 in ICD-10 (F00-F99). Only the first 5 digits are used for the section on mental disorders in ICD-10, with the first digit always “F” and the second digit a number denoting the broad type of disorders. The second and third digits in conjunction define the major category of the disorder; the fourth and fifth digits provide additional descriptive detail about the disorder (Table).

Examples of “Z” codes relevant to psychiatry are:

Z00 General psychiatric examination (eg, of a person who does not have a complaint or diagnosis)

Z03 Examination for suspected mental and behavioral disorder

Z04 Examination for medicolegal or other purposes; Z04.8 is relevant laboratory testing, such as drug testing of urine or blood

Z50 Care involving rehabilitation (substance use disorder, etc.)

Z60 Problem related to social environment

Z61 Problem related to negative life events in childhood

Z63 Problem related to primary support group, including family circumstances

Z64-Z65 Problem related to other psychosocial circumstances

Z70-Z71 Condition requiring counseling, not elsewhere classified

Z73 Problem related to difficulty with life management (burnout, stress, role conflict, etc.)

Z75 Problem related to medical facilities and other aspects of health care (eg, awaiting admission)

Z81 Family history of mental or behavioral disorders

Z85-Z91 Personal history of various disorders (must be absent or in full remission at the moment); Z86.51, for example, refers to a history of combat and operational stress reaction.

Greater precision is now possible when coding for treatment-related adverse effects. A particular adverse effect now is coded under the relevant system, along with its attribution to the specific substance. Obesity attributable to antipsychotic treatment,^7,8 for example, is coded as E66.1.

Integrating DSM-5 and ICD-10
Because DSM-5 lists corresponding ICD-10-CM codes for all disorders, you will find it much easier than other physicians to implement ICD-10. DSM-5 includes ICD-9-CM and ICD-10-CM codes for each DSM-5 disorder (for example, the ICD-9-CM code for schizophrenia is 295.x; the ICD-10-CM code is F20.9).⁹

Furthermore, a number of changes from ICD-9-CM to ICD-10-CM enable documentation of greater diagnostic specificity; for example, DSM-5 schizoaffective disorder, bipolar type, and schizoaffective disorder, depressive type, are distinctly coded as F25.0 and F25.1, respectively, in ICD-10-CM, whereas both were coded as 295.7 in ICD-9-CM.¹⁰

You will continue to use DSM-5 criteria to guide your diagnostic process, translating the DSM-5 diagnosis (diagnoses) into corresponding ICD-10-CM codes. Experience with DSM-5 substantially simplifies the transition to ICD-10.

Key differences between DSM-5 and ICD-10
There are notable differences in organization and content between DSM-5 and ICD-10.

The 20 chapters in DSM-5 begin with neuro­developmental disorders; neurocognitive disorders are toward the end (ie, childhood to late life). In contrast, neurocognitive disorders (ie, “dementia”) appear at the beginning of ICD-10; neurodevelopmental disorders are at the end.

Elimination of schizophrenia subtypes in DSM-5 necessitates coding of all schizophrenia as F20.9 in ICD-10-CM because F20.0-F20.8 are specific subtypes. DSM-5 schizophreniform disorder is coded F20.81.

Substance abuse and substance dependence continue to be separate in ICD-10-CM, but they are combined in a single category of substance use disorders in DSM-5. The correct ICD-10-CM code (ie, abuse vs dependence) is determined by the severity of the substance use disorder: “Mild” coding as abuse (F1x.1) and “moderate” and “severe” coding as dependence (F2x.2), with x denoting the substance abused.

There can be multiple applicable diagnoses associated with a clinical encounter, as there was with ICD-9-CM. Give precedence to the diagnosis that best represents the nature of the presenting problem; list other diagnoses in the order of their relevance. DSM-5 and ICD-10-CM are similar in this regard.

ICD-10-CM uses only subtypes, in contrast to the use of subtypes and specifiers in DSM-5 to describe variability in disorders across patients. It is possible, however, to code certain DSM-5 specifiers in ICD-10-CM. (This is discussed in the “Recording Procedures” section of the DSM-5 text and summarized at the beginning of the manual, and appears in the “Appendix.”) To code the catatonia specifier in the context of schizoaffective disorder, depressive type, for example, use ICD-10-CM code F25.1 for the disorder and add code F06.1 for the catatonia specifier.¹¹

How will ICD-10 affect your practice?
As of October 1, 2015, all health care facilities were to have become ICD-10 compliant. Furthermore, any Health Insurance Portability and Accountability Act-covered entity must use ICD-10-CM codes if it expects to be reimbursed for health care services.

Mental health practitioners might think that the transition from ICD-9-CM to ICD-10-CM involves only billers and coders, not them. They are wrong. All clinicians are responsible for documenting their diagnostic and treatment services properly. Medical records must contain adequate information to support any diagnostic (ICD-10-CM) and treatment (CPT) codes that are applied to a given clinical encounter.

The greater detail and specificity that are provided by ICD-10-CM allow more accurate recording of clinical complexity, which, in turn, influences reimbursement. However, good documentation is necessary for proper coding. Because clinicians are ultimately responsible for proper diagnostic coding, good understanding of ICD-10-CM is essential to be able to code properly.

Similar to the expansion of ICD-10-CM (from volumes 1 and 2 of ICD-9-CM), ICD-10-PCS has undergone similar expansion (from volume 3 of ICD-9-CM), with a corresponding increase in specificity. For example, there are now 5 distinct codes for electroconvulsive therapy (GZB0ZZZ-GZB4ZZZ) that distinguish unilateral from bilateral electrode placement and single from multiple stimulations.

DSM-5 will continue to be the frameworkfor psychiatric assessment and diagnosis. ICD-10-CM will be the coding system to accurately denote DSM-5 diagnoses. The Centers for Medicare and Medicaid Services (CMS) and the National Center for Health Statistics recognize DSM-5 as the means to identify proper ICD-10-CM codes for mental disorders. CMS also has announced that, although ICD-10-CM codes are necessary for reimbursement, use of an incorrect code will not be the basis for denying a Medicare claim for 1 year.

Making ICD-10 part of practice
Here are several keys to implementing ICD-10 with minimum pain and maximum benefit.

Multiple diagnosis codes should be listed in the order of their relevance to the clinical encounter.

Visit type. The seventh character of the ICD-10-CM code denotes the type of visit (initial, subsequent, or sequela) and must be provided:

• An initial encounter is one in which the patient first receives active treatment.
• A subsequent encounter refers to a follow-up visit in which the patient receives routine care during the healing or recovery phase.
• A sequel encounter is one in which a patient receives treatment for complications or conditions that arise as a direct result of the initial condition.

The transition to ICD-10 should be facilitated by adoption of DSM-5. Continue using DSM-5 to determine the correct diagnosis or diagnoses of the mental disorder, then apply the corresponding ICD-10-CM code(s). The better you understand and apply DSM-5, the more precise you can be in utilizing the greater specificity and accuracy afforded by ICD-10-CM coding.

Document well. Good understanding of the structure and organization of ICD-10-CM facilitates efficient, comprehensive documentation. This, in turn, will foster better clinical communication and appropriate reimbursement.

Know your payers—in particular, their policies regarding differential reimbursement for clinical complexity (based on ICD-10-CM/PCS). Medical practices that are part of an accountable care organization, and those that have risk-adjusted contracts must pay special attention to documenting clinical complexity when coding.

Know your electronic health care record, understand what tools it offers to efficiently translate DSM-5 diagnoses into appropriate ICD-10-CM codes, and use those tools efficiently.

Review your medical record documentation for the top 20 conditions in your practice, in the context of their definition in ICD-10-CM.

If you have coders who do ICD-10-CM coding for you, review a few patient charts with them to compare your sense of the patient’s clinical complexity and their coding based on your documentation.

Changes in DSM-5 have encouraged clinicians to improve their assessment of patients and provide measurement-based care. The significant changes in ICD-10-CM should provide the impetus for you to hone your ability to provide documentation. Sufficient flexibility exists within guidelines to permit individualization of the style of documentation.

Because all DSM-5 diagnoses map to appropriate ICD-10-CM codes, effective use of DSM-5 should make the transition to ICD-10 easy.

Bottom Line
Compared with ICD-9, definitions of mental health diagnoses have been improved in ICD-10, and more elaborate code descriptions in ICD-10-CM provide for greater precision when you report a diagnosis. The result? More accurate and efficient documentation of the care you provide and better reimbursement. Understanding what impact the changes in ICD-10 will have on your clinical work will ensure that your practice keeps pace with professional and legal standards of care.

Related Resources
• Blue Cross Blue Shield of Michigan ICD-10 update: mental and behavioral health ICD-10-CM codes. http://www.bcbsm.com/content/dam/public/Providers/Documents/help/faqs/icd10-update-mentalhealth.pdf.
• American Psychiatric Association ICD-10 tutorial. http://www.psychiatry.org/psychiatrists/practice/dsm/icd-10.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Just as psychiatrists are adapting to DSM-5, they have to cope with implementation of the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). This challenge raises questions: What is the importance of understanding ICD-10? How will it affect the practice of psychiatry?

Furthermore, how does ICD-10 relate to DSM-5 and Current Procedural Terminology (CPT)? How does it differ from ICD-9? What are the ICD-10-Clinical Modification (CM) and ICD-10-Procedures (PCS)?Learning the essence of the changes, and understanding what impact they have on your clinical work, are necessary to ensure that your practice keeps pace with professional and legal standards of care. The effort involved is not onerous, however, and can improve the quality and efficiency of your care and how you document it.

In this article, we provide you with an overview of ICD-10; highlight major changes of the new classification; explain its relevance to clinical practice; and offer guidelines for implementing it effectively. We also emphasize that a good understanding of DSM-5 facilitates appreciation of ICD-10 and makes its implementation fairly easy and straightforward.

To begin, we provide a glossary of ICD-related terms and a review of additional definitions, distinctions, and dates (Box).^1-6

Major changes from ICD-9
No question: ICD-10 is going to significantly influence your practice and your reimbursement. Furthermore, a number of revisions in ICD-10 have the potential to meaningfully improve clinical documentation and communication and to enhance your ability to precisely describe the complexity of your patients—with implications for billing.

ICD-10 differs from ICD-9 in organization, structure, code composition, and level of detail. In addition, ICD-10 makes some changes in terminology and definitions, with the goal of improving precision.

ICD-10 also is much larger than ICD-9.The total number of medical diagnostic codes has increased more than 5-fold—from approximately 13,000 to 69,000. This expansion allows for greater specificity in diagnosis and enables differentiation of an initial clinical encounter from a subsequent encounter.

To accommodate the expansion in the number of codes, the 5-digit numeric codes used in ICD-9 have been replaced in ICD-10 by 7-digit alphanumeric codes:

• the first digit always is a letter
• the second and third digits are numbers followed by a decimal point
• the fourth though seventh digits can be letters or numbers
• the first 3 digits denote the diagnostic category
• the fourth through sixth digits provide diagnostic detail
• the seventh digit provides information about the nature of the encounter (eg, initial, subsequent, or sequel, denoted respectively by “A,” “D,” and “S” in the seventh digit).

The number of 3-digit categories for psychiatric disorders has increased from 30 in ICD-9 (290-319) to 100 in ICD-10 (F00-F99). Only the first 5 digits are used for the section on mental disorders in ICD-10, with the first digit always “F” and the second digit a number denoting the broad type of disorders. The second and third digits in conjunction define the major category of the disorder; the fourth and fifth digits provide additional descriptive detail about the disorder (Table).

Examples of “Z” codes relevant to psychiatry are:

Z00 General psychiatric examination (eg, of a person who does not have a complaint or diagnosis)

Z03 Examination for suspected mental and behavioral disorder

Z04 Examination for medicolegal or other purposes; Z04.8 is relevant laboratory testing, such as drug testing of urine or blood

Z50 Care involving rehabilitation (substance use disorder, etc.)

Z60 Problem related to social environment

Z61 Problem related to negative life events in childhood

Z63 Problem related to primary support group, including family circumstances

Z64-Z65 Problem related to other psychosocial circumstances

Z70-Z71 Condition requiring counseling, not elsewhere classified

Z73 Problem related to difficulty with life management (burnout, stress, role conflict, etc.)

Z75 Problem related to medical facilities and other aspects of health care (eg, awaiting admission)

Z81 Family history of mental or behavioral disorders

Z85-Z91 Personal history of various disorders (must be absent or in full remission at the moment); Z86.51, for example, refers to a history of combat and operational stress reaction.

Greater precision is now possible when coding for treatment-related adverse effects. A particular adverse effect now is coded under the relevant system, along with its attribution to the specific substance. Obesity attributable to antipsychotic treatment,^7,8 for example, is coded as E66.1.

Integrating DSM-5 and ICD-10
Because DSM-5 lists corresponding ICD-10-CM codes for all disorders, you will find it much easier than other physicians to implement ICD-10. DSM-5 includes ICD-9-CM and ICD-10-CM codes for each DSM-5 disorder (for example, the ICD-9-CM code for schizophrenia is 295.x; the ICD-10-CM code is F20.9).⁹

Furthermore, a number of changes from ICD-9-CM to ICD-10-CM enable documentation of greater diagnostic specificity; for example, DSM-5 schizoaffective disorder, bipolar type, and schizoaffective disorder, depressive type, are distinctly coded as F25.0 and F25.1, respectively, in ICD-10-CM, whereas both were coded as 295.7 in ICD-9-CM.¹⁰

You will continue to use DSM-5 criteria to guide your diagnostic process, translating the DSM-5 diagnosis (diagnoses) into corresponding ICD-10-CM codes. Experience with DSM-5 substantially simplifies the transition to ICD-10.

Key differences between DSM-5 and ICD-10
There are notable differences in organization and content between DSM-5 and ICD-10.

The 20 chapters in DSM-5 begin with neuro­developmental disorders; neurocognitive disorders are toward the end (ie, childhood to late life). In contrast, neurocognitive disorders (ie, “dementia”) appear at the beginning of ICD-10; neurodevelopmental disorders are at the end.

Elimination of schizophrenia subtypes in DSM-5 necessitates coding of all schizophrenia as F20.9 in ICD-10-CM because F20.0-F20.8 are specific subtypes. DSM-5 schizophreniform disorder is coded F20.81.

Substance abuse and substance dependence continue to be separate in ICD-10-CM, but they are combined in a single category of substance use disorders in DSM-5. The correct ICD-10-CM code (ie, abuse vs dependence) is determined by the severity of the substance use disorder: “Mild” coding as abuse (F1x.1) and “moderate” and “severe” coding as dependence (F2x.2), with x denoting the substance abused.

There can be multiple applicable diagnoses associated with a clinical encounter, as there was with ICD-9-CM. Give precedence to the diagnosis that best represents the nature of the presenting problem; list other diagnoses in the order of their relevance. DSM-5 and ICD-10-CM are similar in this regard.

ICD-10-CM uses only subtypes, in contrast to the use of subtypes and specifiers in DSM-5 to describe variability in disorders across patients. It is possible, however, to code certain DSM-5 specifiers in ICD-10-CM. (This is discussed in the “Recording Procedures” section of the DSM-5 text and summarized at the beginning of the manual, and appears in the “Appendix.”) To code the catatonia specifier in the context of schizoaffective disorder, depressive type, for example, use ICD-10-CM code F25.1 for the disorder and add code F06.1 for the catatonia specifier.¹¹

How will ICD-10 affect your practice?
As of October 1, 2015, all health care facilities were to have become ICD-10 compliant. Furthermore, any Health Insurance Portability and Accountability Act-covered entity must use ICD-10-CM codes if it expects to be reimbursed for health care services.

Mental health practitioners might think that the transition from ICD-9-CM to ICD-10-CM involves only billers and coders, not them. They are wrong. All clinicians are responsible for documenting their diagnostic and treatment services properly. Medical records must contain adequate information to support any diagnostic (ICD-10-CM) and treatment (CPT) codes that are applied to a given clinical encounter.

The greater detail and specificity that are provided by ICD-10-CM allow more accurate recording of clinical complexity, which, in turn, influences reimbursement. However, good documentation is necessary for proper coding. Because clinicians are ultimately responsible for proper diagnostic coding, good understanding of ICD-10-CM is essential to be able to code properly.

Similar to the expansion of ICD-10-CM (from volumes 1 and 2 of ICD-9-CM), ICD-10-PCS has undergone similar expansion (from volume 3 of ICD-9-CM), with a corresponding increase in specificity. For example, there are now 5 distinct codes for electroconvulsive therapy (GZB0ZZZ-GZB4ZZZ) that distinguish unilateral from bilateral electrode placement and single from multiple stimulations.

DSM-5 will continue to be the frameworkfor psychiatric assessment and diagnosis. ICD-10-CM will be the coding system to accurately denote DSM-5 diagnoses. The Centers for Medicare and Medicaid Services (CMS) and the National Center for Health Statistics recognize DSM-5 as the means to identify proper ICD-10-CM codes for mental disorders. CMS also has announced that, although ICD-10-CM codes are necessary for reimbursement, use of an incorrect code will not be the basis for denying a Medicare claim for 1 year.

Making ICD-10 part of practice
Here are several keys to implementing ICD-10 with minimum pain and maximum benefit.

Multiple diagnosis codes should be listed in the order of their relevance to the clinical encounter.

Visit type. The seventh character of the ICD-10-CM code denotes the type of visit (initial, subsequent, or sequela) and must be provided:

• An initial encounter is one in which the patient first receives active treatment.
• A subsequent encounter refers to a follow-up visit in which the patient receives routine care during the healing or recovery phase.
• A sequel encounter is one in which a patient receives treatment for complications or conditions that arise as a direct result of the initial condition.

The transition to ICD-10 should be facilitated by adoption of DSM-5. Continue using DSM-5 to determine the correct diagnosis or diagnoses of the mental disorder, then apply the corresponding ICD-10-CM code(s). The better you understand and apply DSM-5, the more precise you can be in utilizing the greater specificity and accuracy afforded by ICD-10-CM coding.

Document well. Good understanding of the structure and organization of ICD-10-CM facilitates efficient, comprehensive documentation. This, in turn, will foster better clinical communication and appropriate reimbursement.

Know your payers—in particular, their policies regarding differential reimbursement for clinical complexity (based on ICD-10-CM/PCS). Medical practices that are part of an accountable care organization, and those that have risk-adjusted contracts must pay special attention to documenting clinical complexity when coding.

Know your electronic health care record, understand what tools it offers to efficiently translate DSM-5 diagnoses into appropriate ICD-10-CM codes, and use those tools efficiently.

Review your medical record documentation for the top 20 conditions in your practice, in the context of their definition in ICD-10-CM.

If you have coders who do ICD-10-CM coding for you, review a few patient charts with them to compare your sense of the patient’s clinical complexity and their coding based on your documentation.

Changes in DSM-5 have encouraged clinicians to improve their assessment of patients and provide measurement-based care. The significant changes in ICD-10-CM should provide the impetus for you to hone your ability to provide documentation. Sufficient flexibility exists within guidelines to permit individualization of the style of documentation.

Because all DSM-5 diagnoses map to appropriate ICD-10-CM codes, effective use of DSM-5 should make the transition to ICD-10 easy.

Bottom Line
Compared with ICD-9, definitions of mental health diagnoses have been improved in ICD-10, and more elaborate code descriptions in ICD-10-CM provide for greater precision when you report a diagnosis. The result? More accurate and efficient documentation of the care you provide and better reimbursement. Understanding what impact the changes in ICD-10 will have on your clinical work will ensure that your practice keeps pace with professional and legal standards of care.

Related Resources
• Blue Cross Blue Shield of Michigan ICD-10 update: mental and behavioral health ICD-10-CM codes. http://www.bcbsm.com/content/dam/public/Providers/Documents/help/faqs/icd10-update-mentalhealth.pdf.
• American Psychiatric Association ICD-10 tutorial. http://www.psychiatry.org/psychiatrists/practice/dsm/icd-10.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dementia—“major neurocognitive disorder” in DSM-5—manifests as progressive decline in cognitive function.In tandem with that decline, approximately 80% of nursing home patients with dementia exhibit behavioral disturbances,¹ including irritability, insomnia, wandering, and repetitive questioning.^1,2 These disturbances can erode their quality of life and can frustrate caregivers and providers.³

Causative pathology
Before designing a therapeutic intervention for cognitively impaired people with behavioral disturbances, a precise diagnosis of the causative pathology must be determined. This affords therapies that specifically address the patient’s problems. Other related and unrelated somatic or mental health concerns should be identified to specify the optimal approach.

Patients in whom dementia is suspected require that a thorough medical, psychiatric, substance use, and family history be taken to identify predisposing factors for their illness²; exhaustive review of the history might reveal drug interactions or polypharmacy that can cause or exacerbate symptoms, including behavioral manifestations. Physical examination, cognitive function testing, laboratory tests, and neuroimaging also help reveal the etiologic diagnosis of the dementia.^1,3

Identifying the diagnosis directs the treatment; for example, a behaviorally discontrolled person with a cognitive, stroke-induced encephalopathy requires an entirely different regimen than a comparatively compromised individual with Alzheimer’s disease or frontotemporal dementia. Early detection of dementia also is helpful for managing its cognitive and behavioral problems more effectively.¹Once a diagnosis of dementia is established, it might be behavioral symptoms and poor insight that become more worrisome to the patient’s caregivers and providers than cognitive deficits. Your task is then to apply behavioral approaches to management, with consistency, to maximize, at all times, the patient’s safety and comfort.⁴

How you approach behavioral management is important
Consider these interventions:

• Ensure that you appropriately treat associated depression, pain, and somatic illness—whether related or unrelated to dementia.
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.
• Provide family and caregivers with disease education, social support, and management tips^1,2; be respectful to family members in all interactions.³
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.

Minimize psychosocial and environmental stressors

• Avoid unnecessary environmental changes, such as rearranging or refurbishing the patient’s living space.¹
• As noted, ensure that the patient is comfortable and safe in his (her) surroundings, such as providing wall-mounted handrails and other aids for ambulation.
• Provide access to television, proper lighting, and other indicated life-enhancing devices.^1,2
• Consider a pet for the patient; pets can be an important adjunct in providing comfort.
• Provide music to reduce agitation and anxiety.⁴
• Appeal to institutional administration to provide a higher staff−patient ratio for comfort and security.^2,5
• Because social contact is helpful to build a pleasant environment, preserve opportunities for the patient to communicate with others, and facilitate socialization by encouraging friendly interactions.¹
• Provide stimulation and diversion with social activities, support programs, and physical exercise—sources of interaction that can promote health and improve sleep.
• Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.^2,5
• Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.¹
• Provide access to television, proper lighting, and other indicated life-enhancing devices.Provide music to reduce agitation and anxiety.Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.

Other considerations

• Identify and treat primary and secondary causes of the underlying major neurocognitive disorder.
• Use an integrative, multidisciplinary approach to manage behavioral problems in dementia.
• Utilize a social worker’s expertise to faciliate family, financial, or related social issues and better cooperation. This promotes comfort for patients, families, and staff.
• Physical therapy aids in maintaining physical function, especially preservation of gait, balance, and range of motion. Thus, with greater stability avoiding a fall can be a life-saving event.
• Socialization, mental outlook, and emotional health are improved by occupational therapist interventions.
• Individual psychotherapy helps to improve self-esteem and personal adjustment. Group activities reinforces interpersonal connections.
• Refer the family and caregivers for supportive therapy and education on dementia; such resources help minimize deleterious effects of the patient’s behavioral problems on those key people.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dementia—“major neurocognitive disorder” in DSM-5—manifests as progressive decline in cognitive function.In tandem with that decline, approximately 80% of nursing home patients with dementia exhibit behavioral disturbances,¹ including irritability, insomnia, wandering, and repetitive questioning.^1,2 These disturbances can erode their quality of life and can frustrate caregivers and providers.³

Causative pathology
Before designing a therapeutic intervention for cognitively impaired people with behavioral disturbances, a precise diagnosis of the causative pathology must be determined. This affords therapies that specifically address the patient’s problems. Other related and unrelated somatic or mental health concerns should be identified to specify the optimal approach.

Patients in whom dementia is suspected require that a thorough medical, psychiatric, substance use, and family history be taken to identify predisposing factors for their illness²; exhaustive review of the history might reveal drug interactions or polypharmacy that can cause or exacerbate symptoms, including behavioral manifestations. Physical examination, cognitive function testing, laboratory tests, and neuroimaging also help reveal the etiologic diagnosis of the dementia.^1,3

Identifying the diagnosis directs the treatment; for example, a behaviorally discontrolled person with a cognitive, stroke-induced encephalopathy requires an entirely different regimen than a comparatively compromised individual with Alzheimer’s disease or frontotemporal dementia. Early detection of dementia also is helpful for managing its cognitive and behavioral problems more effectively.¹Once a diagnosis of dementia is established, it might be behavioral symptoms and poor insight that become more worrisome to the patient’s caregivers and providers than cognitive deficits. Your task is then to apply behavioral approaches to management, with consistency, to maximize, at all times, the patient’s safety and comfort.⁴

How you approach behavioral management is important
Consider these interventions:

• Ensure that you appropriately treat associated depression, pain, and somatic illness—whether related or unrelated to dementia.
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.
• Provide family and caregivers with disease education, social support, and management tips^1,2; be respectful to family members in all interactions.³
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.

Minimize psychosocial and environmental stressors

• Avoid unnecessary environmental changes, such as rearranging or refurbishing the patient’s living space.¹
• As noted, ensure that the patient is comfortable and safe in his (her) surroundings, such as providing wall-mounted handrails and other aids for ambulation.
• Provide access to television, proper lighting, and other indicated life-enhancing devices.^1,2
• Consider a pet for the patient; pets can be an important adjunct in providing comfort.
• Provide music to reduce agitation and anxiety.⁴
• Appeal to institutional administration to provide a higher staff−patient ratio for comfort and security.^2,5
• Because social contact is helpful to build a pleasant environment, preserve opportunities for the patient to communicate with others, and facilitate socialization by encouraging friendly interactions.¹
• Provide stimulation and diversion with social activities, support programs, and physical exercise—sources of interaction that can promote health and improve sleep.
• Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.^2,5
• Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.¹
• Provide access to television, proper lighting, and other indicated life-enhancing devices.Provide music to reduce agitation and anxiety.Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.

Other considerations

• Identify and treat primary and secondary causes of the underlying major neurocognitive disorder.
• Use an integrative, multidisciplinary approach to manage behavioral problems in dementia.
• Utilize a social worker’s expertise to faciliate family, financial, or related social issues and better cooperation. This promotes comfort for patients, families, and staff.
• Physical therapy aids in maintaining physical function, especially preservation of gait, balance, and range of motion. Thus, with greater stability avoiding a fall can be a life-saving event.
• Socialization, mental outlook, and emotional health are improved by occupational therapist interventions.
• Individual psychotherapy helps to improve self-esteem and personal adjustment. Group activities reinforces interpersonal connections.
• Refer the family and caregivers for supportive therapy and education on dementia; such resources help minimize deleterious effects of the patient’s behavioral problems on those key people.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dementia—“major neurocognitive disorder” in DSM-5—manifests as progressive decline in cognitive function.In tandem with that decline, approximately 80% of nursing home patients with dementia exhibit behavioral disturbances,¹ including irritability, insomnia, wandering, and repetitive questioning.^1,2 These disturbances can erode their quality of life and can frustrate caregivers and providers.³

Causative pathology
Before designing a therapeutic intervention for cognitively impaired people with behavioral disturbances, a precise diagnosis of the causative pathology must be determined. This affords therapies that specifically address the patient’s problems. Other related and unrelated somatic or mental health concerns should be identified to specify the optimal approach.

Patients in whom dementia is suspected require that a thorough medical, psychiatric, substance use, and family history be taken to identify predisposing factors for their illness²; exhaustive review of the history might reveal drug interactions or polypharmacy that can cause or exacerbate symptoms, including behavioral manifestations. Physical examination, cognitive function testing, laboratory tests, and neuroimaging also help reveal the etiologic diagnosis of the dementia.^1,3

Identifying the diagnosis directs the treatment; for example, a behaviorally discontrolled person with a cognitive, stroke-induced encephalopathy requires an entirely different regimen than a comparatively compromised individual with Alzheimer’s disease or frontotemporal dementia. Early detection of dementia also is helpful for managing its cognitive and behavioral problems more effectively.¹Once a diagnosis of dementia is established, it might be behavioral symptoms and poor insight that become more worrisome to the patient’s caregivers and providers than cognitive deficits. Your task is then to apply behavioral approaches to management, with consistency, to maximize, at all times, the patient’s safety and comfort.⁴

How you approach behavioral management is important
Consider these interventions:

• Ensure that you appropriately treat associated depression, pain, and somatic illness—whether related or unrelated to dementia.
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.
• Provide family and caregivers with disease education, social support, and management tips^1,2; be respectful to family members in all interactions.³
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.

Minimize psychosocial and environmental stressors

• Avoid unnecessary environmental changes, such as rearranging or refurbishing the patient’s living space.¹
• As noted, ensure that the patient is comfortable and safe in his (her) surroundings, such as providing wall-mounted handrails and other aids for ambulation.
• Provide access to television, proper lighting, and other indicated life-enhancing devices.^1,2
• Consider a pet for the patient; pets can be an important adjunct in providing comfort.
• Provide music to reduce agitation and anxiety.⁴
• Appeal to institutional administration to provide a higher staff−patient ratio for comfort and security.^2,5
• Because social contact is helpful to build a pleasant environment, preserve opportunities for the patient to communicate with others, and facilitate socialization by encouraging friendly interactions.¹
• Provide stimulation and diversion with social activities, support programs, and physical exercise—sources of interaction that can promote health and improve sleep.
• Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.^2,5
• Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.¹
• Provide access to television, proper lighting, and other indicated life-enhancing devices.Provide music to reduce agitation and anxiety.Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.

Other considerations

• Identify and treat primary and secondary causes of the underlying major neurocognitive disorder.
• Use an integrative, multidisciplinary approach to manage behavioral problems in dementia.
• Utilize a social worker’s expertise to faciliate family, financial, or related social issues and better cooperation. This promotes comfort for patients, families, and staff.
• Physical therapy aids in maintaining physical function, especially preservation of gait, balance, and range of motion. Thus, with greater stability avoiding a fall can be a life-saving event.
• Socialization, mental outlook, and emotional health are improved by occupational therapist interventions.
• Individual psychotherapy helps to improve self-esteem and personal adjustment. Group activities reinforces interpersonal connections.
• Refer the family and caregivers for supportive therapy and education on dementia; such resources help minimize deleterious effects of the patient’s behavioral problems on those key people.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Since 2005, I’ve had the opportunity to review “Pearls” articles submitted for publication in Current Psychiatry. In that time, I have read many worthwhile papers written by authors who may not be entirely clear about what constitutes a “Pearl." The mnemonic PEARL could help authors:

• decide if their article or idea is appropriate for “Pearls”
• construct the article to conform to the “Pearls” format.

Easy to remember. Lengthy, highly detailed articles may be helpful and informative but are not consistent with the purpose of “Pearls.

Alert. A “Pearl” should alert a physician to identify a problem, diagnosis, or adverse effect that they might otherwise miss or take unnecessary time to identify. Classic examples are the “handshake diagnosis” of hyperthyroidism,¹ or the “3 little words that can diagnose mild cognitive impairment.”²

References. A professional article of any length should include references. References add immediate credibility to the information presented. For a “Pearl,” even 1 reference is acceptable. A writer can easily search PubMed and the Internet to find references to confirm or support their ideas.
 

Less is more. Architect Mies van der Rohe’s minimalist concept applies to “Pearls.” A “Pearl”—like its namesake—is small, polished, and valuable. Simplicity is its essence.

I hope this mnemonic is useful for clinicians interested in sharing their ideas or experiences to help others in the field. I look forward to reviewing many more “Pearls.”

Since 2005, I’ve had the opportunity to review “Pearls” articles submitted for publication in Current Psychiatry. In that time, I have read many worthwhile papers written by authors who may not be entirely clear about what constitutes a “Pearl." The mnemonic PEARL could help authors:

• decide if their article or idea is appropriate for “Pearls”
• construct the article to conform to the “Pearls” format.

Easy to remember. Lengthy, highly detailed articles may be helpful and informative but are not consistent with the purpose of “Pearls.

Alert. A “Pearl” should alert a physician to identify a problem, diagnosis, or adverse effect that they might otherwise miss or take unnecessary time to identify. Classic examples are the “handshake diagnosis” of hyperthyroidism,¹ or the “3 little words that can diagnose mild cognitive impairment.”²

References. A professional article of any length should include references. References add immediate credibility to the information presented. For a “Pearl,” even 1 reference is acceptable. A writer can easily search PubMed and the Internet to find references to confirm or support their ideas.
 

Less is more. Architect Mies van der Rohe’s minimalist concept applies to “Pearls.” A “Pearl”—like its namesake—is small, polished, and valuable. Simplicity is its essence.

I hope this mnemonic is useful for clinicians interested in sharing their ideas or experiences to help others in the field. I look forward to reviewing many more “Pearls.”

Since 2005, I’ve had the opportunity to review “Pearls” articles submitted for publication in Current Psychiatry. In that time, I have read many worthwhile papers written by authors who may not be entirely clear about what constitutes a “Pearl." The mnemonic PEARL could help authors:

• decide if their article or idea is appropriate for “Pearls”
• construct the article to conform to the “Pearls” format.

Easy to remember. Lengthy, highly detailed articles may be helpful and informative but are not consistent with the purpose of “Pearls.

Alert. A “Pearl” should alert a physician to identify a problem, diagnosis, or adverse effect that they might otherwise miss or take unnecessary time to identify. Classic examples are the “handshake diagnosis” of hyperthyroidism,¹ or the “3 little words that can diagnose mild cognitive impairment.”²

References. A professional article of any length should include references. References add immediate credibility to the information presented. For a “Pearl,” even 1 reference is acceptable. A writer can easily search PubMed and the Internet to find references to confirm or support their ideas.
 

Less is more. Architect Mies van der Rohe’s minimalist concept applies to “Pearls.” A “Pearl”—like its namesake—is small, polished, and valuable. Simplicity is its essence.

I hope this mnemonic is useful for clinicians interested in sharing their ideas or experiences to help others in the field. I look forward to reviewing many more “Pearls.”