Doctor and patient

Credit: NIH

In a study comparing healthcare in 11 industrialized countries, the US ranked last on measures of health system quality, efficiency, access to care, equity, and healthy lives.

The other countries included in this study were Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, and the UK.

While the results revealed room for improvement in every country, the US stood out for having the highest costs and lowest performance.

For instance, the US spent $8508 per person on healthcare in 2011, compared with $3406 in the UK, which ranked first overall.

Details on expenditures and rankings derived from this study are available in the Commonwealth Fund report, Mirror, Mirror on the Wall: How the Performance of the U.S. Health Care System Compares Internationally, 2014 Update.

“It is disappointing, but not surprising, that, despite our significant investment in healthcare, the US has continued to lag behind other countries,” said lead report author Karen Davis, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

The report was also produced in 2004, 2006, 2007, and 2010, with the US ranking last in each of those years. Four countries were added to this year’s report: Switzerland and Sweden, which followed the UK at the top of the rankings, and Norway and France, which were in the middle of the pack.

Australia, Germany, the Netherlands, New Zealand, and Norway also placed in the middle, and Canada ranked just above the US.

In addition to ranking last overall, the US ranked last on infant mortality and on deaths that were potentially preventable with timely access to effective healthcare. The country ranked second-to-last on healthy life expectancy at age 60.

The US also ranked last on every measure of cost-related access. More than one-third (37%) of US adults reported forgoing a recommended test, treatment, or follow-up care because of cost.

With regard to healthcare quality, the US fell somewhere in the middle. On 2 of 4 measures of quality—effective care and patient-centered care—the US ranked near the top (3rd and 4th of 11 countries, respectively). But it did not perform as well with regard to providing safe or coordinated care.

The US ranked last in efficiency, due to low marks on the time and dollars spent dealing with insurance administration, lack of communication among healthcare providers, and duplicative medical testing.

Forty percent of US adults who had visited an emergency room reported they could have been treated by a regular doctor if one had been available. This is more than double the rate of patients in the UK (16%).

The US also ranked last in healthcare equity. About 4 of 10 (39%) adults with below-average incomes in the US reported a medical problem but did not visit a doctor in the past year because of costs, compared with less than 1 of 10 in the UK, Sweden, Canada, and Norway.

There were also large discrepancies in the length of time US adults waited for specialist, emergency, and after-hours care. And wait times were associated with patient income.

The data for this research were drawn from the Commonwealth Fund 2011 International Health Policy Survey of Sicker Adults, the Commonwealth Fund 2012 International Health Policy Survey of Primary Care Physicians, and the Commonwealth Fund 2013 International Health Policy Survey.

The 2011 survey targeted a representative sample of “sicker adults,” defined as those who rated their health status as fair or poor, received medical care for a serious chronic illness, serious injury, or disability in the past year, or were hospitalized or underwent surgery in the previous 2 years.

The 2012 survey looked at the experiences of primary care physicians. The 2013 survey focused on the experiences of nationally representative samples of adults ages 18 and older.

Additional data on health outcomes were drawn from the Organization for Economic Cooperation and Development and the World Health Organization.

Doctor and patient

Credit: NIH

In a study comparing healthcare in 11 industrialized countries, the US ranked last on measures of health system quality, efficiency, access to care, equity, and healthy lives.

The other countries included in this study were Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, and the UK.

While the results revealed room for improvement in every country, the US stood out for having the highest costs and lowest performance.

For instance, the US spent $8508 per person on healthcare in 2011, compared with $3406 in the UK, which ranked first overall.

Details on expenditures and rankings derived from this study are available in the Commonwealth Fund report, Mirror, Mirror on the Wall: How the Performance of the U.S. Health Care System Compares Internationally, 2014 Update.

“It is disappointing, but not surprising, that, despite our significant investment in healthcare, the US has continued to lag behind other countries,” said lead report author Karen Davis, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

The report was also produced in 2004, 2006, 2007, and 2010, with the US ranking last in each of those years. Four countries were added to this year’s report: Switzerland and Sweden, which followed the UK at the top of the rankings, and Norway and France, which were in the middle of the pack.

Australia, Germany, the Netherlands, New Zealand, and Norway also placed in the middle, and Canada ranked just above the US.

In addition to ranking last overall, the US ranked last on infant mortality and on deaths that were potentially preventable with timely access to effective healthcare. The country ranked second-to-last on healthy life expectancy at age 60.

The US also ranked last on every measure of cost-related access. More than one-third (37%) of US adults reported forgoing a recommended test, treatment, or follow-up care because of cost.

With regard to healthcare quality, the US fell somewhere in the middle. On 2 of 4 measures of quality—effective care and patient-centered care—the US ranked near the top (3rd and 4th of 11 countries, respectively). But it did not perform as well with regard to providing safe or coordinated care.

The US ranked last in efficiency, due to low marks on the time and dollars spent dealing with insurance administration, lack of communication among healthcare providers, and duplicative medical testing.

Forty percent of US adults who had visited an emergency room reported they could have been treated by a regular doctor if one had been available. This is more than double the rate of patients in the UK (16%).

The US also ranked last in healthcare equity. About 4 of 10 (39%) adults with below-average incomes in the US reported a medical problem but did not visit a doctor in the past year because of costs, compared with less than 1 of 10 in the UK, Sweden, Canada, and Norway.

There were also large discrepancies in the length of time US adults waited for specialist, emergency, and after-hours care. And wait times were associated with patient income.

The data for this research were drawn from the Commonwealth Fund 2011 International Health Policy Survey of Sicker Adults, the Commonwealth Fund 2012 International Health Policy Survey of Primary Care Physicians, and the Commonwealth Fund 2013 International Health Policy Survey.

The 2011 survey targeted a representative sample of “sicker adults,” defined as those who rated their health status as fair or poor, received medical care for a serious chronic illness, serious injury, or disability in the past year, or were hospitalized or underwent surgery in the previous 2 years.

The 2012 survey looked at the experiences of primary care physicians. The 2013 survey focused on the experiences of nationally representative samples of adults ages 18 and older.

Additional data on health outcomes were drawn from the Organization for Economic Cooperation and Development and the World Health Organization.

Doctor and patient

Credit: NIH

In a study comparing healthcare in 11 industrialized countries, the US ranked last on measures of health system quality, efficiency, access to care, equity, and healthy lives.

The other countries included in this study were Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, and the UK.

While the results revealed room for improvement in every country, the US stood out for having the highest costs and lowest performance.

For instance, the US spent $8508 per person on healthcare in 2011, compared with $3406 in the UK, which ranked first overall.

Details on expenditures and rankings derived from this study are available in the Commonwealth Fund report, Mirror, Mirror on the Wall: How the Performance of the U.S. Health Care System Compares Internationally, 2014 Update.

“It is disappointing, but not surprising, that, despite our significant investment in healthcare, the US has continued to lag behind other countries,” said lead report author Karen Davis, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

The report was also produced in 2004, 2006, 2007, and 2010, with the US ranking last in each of those years. Four countries were added to this year’s report: Switzerland and Sweden, which followed the UK at the top of the rankings, and Norway and France, which were in the middle of the pack.

Australia, Germany, the Netherlands, New Zealand, and Norway also placed in the middle, and Canada ranked just above the US.

In addition to ranking last overall, the US ranked last on infant mortality and on deaths that were potentially preventable with timely access to effective healthcare. The country ranked second-to-last on healthy life expectancy at age 60.

The US also ranked last on every measure of cost-related access. More than one-third (37%) of US adults reported forgoing a recommended test, treatment, or follow-up care because of cost.

With regard to healthcare quality, the US fell somewhere in the middle. On 2 of 4 measures of quality—effective care and patient-centered care—the US ranked near the top (3rd and 4th of 11 countries, respectively). But it did not perform as well with regard to providing safe or coordinated care.

The US ranked last in efficiency, due to low marks on the time and dollars spent dealing with insurance administration, lack of communication among healthcare providers, and duplicative medical testing.

Forty percent of US adults who had visited an emergency room reported they could have been treated by a regular doctor if one had been available. This is more than double the rate of patients in the UK (16%).

The US also ranked last in healthcare equity. About 4 of 10 (39%) adults with below-average incomes in the US reported a medical problem but did not visit a doctor in the past year because of costs, compared with less than 1 of 10 in the UK, Sweden, Canada, and Norway.

There were also large discrepancies in the length of time US adults waited for specialist, emergency, and after-hours care. And wait times were associated with patient income.

The data for this research were drawn from the Commonwealth Fund 2011 International Health Policy Survey of Sicker Adults, the Commonwealth Fund 2012 International Health Policy Survey of Primary Care Physicians, and the Commonwealth Fund 2013 International Health Policy Survey.

The 2011 survey targeted a representative sample of “sicker adults,” defined as those who rated their health status as fair or poor, received medical care for a serious chronic illness, serious injury, or disability in the past year, or were hospitalized or underwent surgery in the previous 2 years.

The 2012 survey looked at the experiences of primary care physicians. The 2013 survey focused on the experiences of nationally representative samples of adults ages 18 and older.

Additional data on health outcomes were drawn from the Organization for Economic Cooperation and Development and the World Health Organization.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Malaria-transmitting mosquito

Credit: James Gathany

A genetic “barcode” for malaria parasites could be used to track and contain the spread of the disease, according to research published in Nature Communications.

Investigators analyzed the DNA of more than 700 Plasmodium falciparum parasites taken from patients in East and West Africa, South East Asia, Oceania, and South America.

And this revealed several short genetic sequences that were distinct in the DNA of parasites from certain geographic regions.

The team used this information to design a genetic barcode of 23 single-nucleotide polymorphisms that can be used to identify the source of new malaria infections.

“Being able to determine the geographic origin of malaria parasites has enormous potential in containing drug-resistance and eliminating malaria,” said study author Taane Clark, DPhil, of the London School of Hygiene & Tropical Medicine in the UK.

“Our work represents a breakthrough in the genetic barcoding of P falciparum, as it reveals very specific and accurate sequences for different geographic settings. We are currently extending the barcode to include other populations, such as India, Central America, southern Africa, and the Caribbean, and plan to include genetic markers for other types malaria, such as P vivax.”

Previous candidates for malaria genetic barcodes have relied on identifying DNA markers found in the parasite’s cell nucleus, which shows too much genetic variation between individual parasites to be used accurately.

But Dr Clark and his colleagues studied the DNA found in 2 parts of the parasite’s cells outside of the nucleus—the mitochondria and the apicolasts, which are only inherited through maternal lines, so their genes remain much more stable over generations.

By identifying short sequences in the DNA of the parasite’s mitochondria and apicoplasts that were specific for different geographic locations, the investigators were able to design a genetic barcode that is 92% predictive, stable, and geographically informative over time.

“By taking finger-prick bloodspots from malaria patients and using rapid gene sequencing technologies on small amounts of parasite material, local agencies could use this new barcode to quickly and accurately identify where a form of the parasite may have come from and help in programs of malaria elimination and resistance containment,” said study author Cally Roper, PhD, also of the London School of Hygiene & Tropical Medicine.

The investigators noted, however, that this barcode is limited because their study lacks representation of the Indian sub-continent, Central America, southern Africa, and the Caribbean, owing to the scarcity of sequence data from these regions.

Additionally, there’s a need to study more samples from East Africa, a region of high genetic diversity, high migration, and poor predictive ability.

Malaria-transmitting mosquito

Credit: James Gathany

A genetic “barcode” for malaria parasites could be used to track and contain the spread of the disease, according to research published in Nature Communications.

Investigators analyzed the DNA of more than 700 Plasmodium falciparum parasites taken from patients in East and West Africa, South East Asia, Oceania, and South America.

And this revealed several short genetic sequences that were distinct in the DNA of parasites from certain geographic regions.

The team used this information to design a genetic barcode of 23 single-nucleotide polymorphisms that can be used to identify the source of new malaria infections.

“Being able to determine the geographic origin of malaria parasites has enormous potential in containing drug-resistance and eliminating malaria,” said study author Taane Clark, DPhil, of the London School of Hygiene & Tropical Medicine in the UK.

“Our work represents a breakthrough in the genetic barcoding of P falciparum, as it reveals very specific and accurate sequences for different geographic settings. We are currently extending the barcode to include other populations, such as India, Central America, southern Africa, and the Caribbean, and plan to include genetic markers for other types malaria, such as P vivax.”

Previous candidates for malaria genetic barcodes have relied on identifying DNA markers found in the parasite’s cell nucleus, which shows too much genetic variation between individual parasites to be used accurately.

But Dr Clark and his colleagues studied the DNA found in 2 parts of the parasite’s cells outside of the nucleus—the mitochondria and the apicolasts, which are only inherited through maternal lines, so their genes remain much more stable over generations.

By identifying short sequences in the DNA of the parasite’s mitochondria and apicoplasts that were specific for different geographic locations, the investigators were able to design a genetic barcode that is 92% predictive, stable, and geographically informative over time.

“By taking finger-prick bloodspots from malaria patients and using rapid gene sequencing technologies on small amounts of parasite material, local agencies could use this new barcode to quickly and accurately identify where a form of the parasite may have come from and help in programs of malaria elimination and resistance containment,” said study author Cally Roper, PhD, also of the London School of Hygiene & Tropical Medicine.

The investigators noted, however, that this barcode is limited because their study lacks representation of the Indian sub-continent, Central America, southern Africa, and the Caribbean, owing to the scarcity of sequence data from these regions.

Additionally, there’s a need to study more samples from East Africa, a region of high genetic diversity, high migration, and poor predictive ability.

Malaria-transmitting mosquito

Credit: James Gathany

A genetic “barcode” for malaria parasites could be used to track and contain the spread of the disease, according to research published in Nature Communications.

Investigators analyzed the DNA of more than 700 Plasmodium falciparum parasites taken from patients in East and West Africa, South East Asia, Oceania, and South America.

And this revealed several short genetic sequences that were distinct in the DNA of parasites from certain geographic regions.

The team used this information to design a genetic barcode of 23 single-nucleotide polymorphisms that can be used to identify the source of new malaria infections.

“Being able to determine the geographic origin of malaria parasites has enormous potential in containing drug-resistance and eliminating malaria,” said study author Taane Clark, DPhil, of the London School of Hygiene & Tropical Medicine in the UK.

“Our work represents a breakthrough in the genetic barcoding of P falciparum, as it reveals very specific and accurate sequences for different geographic settings. We are currently extending the barcode to include other populations, such as India, Central America, southern Africa, and the Caribbean, and plan to include genetic markers for other types malaria, such as P vivax.”

Previous candidates for malaria genetic barcodes have relied on identifying DNA markers found in the parasite’s cell nucleus, which shows too much genetic variation between individual parasites to be used accurately.

But Dr Clark and his colleagues studied the DNA found in 2 parts of the parasite’s cells outside of the nucleus—the mitochondria and the apicolasts, which are only inherited through maternal lines, so their genes remain much more stable over generations.

By identifying short sequences in the DNA of the parasite’s mitochondria and apicoplasts that were specific for different geographic locations, the investigators were able to design a genetic barcode that is 92% predictive, stable, and geographically informative over time.

“By taking finger-prick bloodspots from malaria patients and using rapid gene sequencing technologies on small amounts of parasite material, local agencies could use this new barcode to quickly and accurately identify where a form of the parasite may have come from and help in programs of malaria elimination and resistance containment,” said study author Cally Roper, PhD, also of the London School of Hygiene & Tropical Medicine.

The investigators noted, however, that this barcode is limited because their study lacks representation of the Indian sub-continent, Central America, southern Africa, and the Caribbean, owing to the scarcity of sequence data from these regions.

Additionally, there’s a need to study more samples from East Africa, a region of high genetic diversity, high migration, and poor predictive ability.

This study by Sinyor et al. reviewed 56 studies of antidepressants versus placebo and found that active drugs physiologically generated more neurological, sexual and anticholinergic side effects. No differences between drug and placebo were found for generating more psychic symptoms, pain symptoms, or weight gain suggesting that if remarkable complaints exist post dosing that these may be nocebo in origin. A nocebo effect occurs when negative expectations in the patient’s mindset creates artificial or psychic-based side effects.

Interestingly in large psychotropic trials, up to a quarter of subject will discontinue the placebo treatment due to side effects. In clinical practice, this also means that many of our patients may quit their medications early or we may discontinue them early allowing for poor dosing and likely poor outcomes. More interventional research about anti-nocebo interventions (identifying those at nocebo risk, tailoring information during informed consent, positive framing of side effect percentages, etc.) are warranted and could lead to more days on drug per patient and ideally better outcomes for them as well.

Thomas L. Schwartz, MD

Senior Associate Dean of Education

Interim Chair/Professor of Psychiatry

SUNY Upstate Medical University

This study by Sinyor et al. reviewed 56 studies of antidepressants versus placebo and found that active drugs physiologically generated more neurological, sexual and anticholinergic side effects. No differences between drug and placebo were found for generating more psychic symptoms, pain symptoms, or weight gain suggesting that if remarkable complaints exist post dosing that these may be nocebo in origin. A nocebo effect occurs when negative expectations in the patient’s mindset creates artificial or psychic-based side effects.

Interestingly in large psychotropic trials, up to a quarter of subject will discontinue the placebo treatment due to side effects. In clinical practice, this also means that many of our patients may quit their medications early or we may discontinue them early allowing for poor dosing and likely poor outcomes. More interventional research about anti-nocebo interventions (identifying those at nocebo risk, tailoring information during informed consent, positive framing of side effect percentages, etc.) are warranted and could lead to more days on drug per patient and ideally better outcomes for them as well.

Thomas L. Schwartz, MD

Senior Associate Dean of Education

Interim Chair/Professor of Psychiatry

SUNY Upstate Medical University

This study by Sinyor et al. reviewed 56 studies of antidepressants versus placebo and found that active drugs physiologically generated more neurological, sexual and anticholinergic side effects. No differences between drug and placebo were found for generating more psychic symptoms, pain symptoms, or weight gain suggesting that if remarkable complaints exist post dosing that these may be nocebo in origin. A nocebo effect occurs when negative expectations in the patient’s mindset creates artificial or psychic-based side effects.

Interestingly in large psychotropic trials, up to a quarter of subject will discontinue the placebo treatment due to side effects. In clinical practice, this also means that many of our patients may quit their medications early or we may discontinue them early allowing for poor dosing and likely poor outcomes. More interventional research about anti-nocebo interventions (identifying those at nocebo risk, tailoring information during informed consent, positive framing of side effect percentages, etc.) are warranted and could lead to more days on drug per patient and ideally better outcomes for them as well.

Thomas L. Schwartz, MD

Senior Associate Dean of Education

Interim Chair/Professor of Psychiatry

SUNY Upstate Medical University

Coronary artery disease (CAD) continues to have a significant impact on society. The latest update by the American Heart Association estimates that 83.6 million American adults have some form of cardiovascular disease (CVD) with an anticipated 15.4 million attributed to CAD.¹ A portion of patients with CAD experience predictable chest pain, which occurs as a result of physical, emotional, or mental stress, more commonly referred to as chronic stable angina (CSA). Based on the most recent estimates, the incidence of patients who experience CSA is about 565,000 and increases in the male population through the eighth decade of life.¹

Although it may be common, treatment options for patients with CSA are limited, as these patients may not be ideal candidates for coronary artery bypass graft or percutaneous coronary intervention (PCI) and may often prefer less invasive treatments. It has also been demonstrated that optimal medical management results in similar cardiovascular outcomes when compared with optimal medical management combined with PCI.^2,3 Therefore, optimizing medical management is a reasonable alternative for these individuals.

Pharmacists have been successful in implementing collaborative practices for the management of various conditions, including anticoagulation, diabetes, hypertension, and hyperlipidemia.^4-7 Pharmacists are heavily involved with cardiovascular risk reduction and management, so it seems opportune that they also treat CSA.⁸ The latest estimated direct and indirect costs for CVD and stroke were well over $315 billion for 2010, and it is anticipated that the costs will continue to rise.¹ Because CSA is typically a medically managed disease and due to its huge medical expense, the development of a pharmacist-managed collaborative practice for treating CSA may prove to be beneficial for both clinical and pharmacoeconomic outcomes.

Clinic Development and Practices

In June 2007, following the approval of ranolazine by the FDA, the VA adopted nonformulary criteria for ranolazine use (Appendix).^9,10 In order for patients to receive ranolazine, health care providers (HCPs) within the North Florida/South Georgia Veterans Health System (NFSGVHS) network were required to submit an electronic nonformulary consult using the computerized patient record system (CPRS). Select clinical pharmacists who had knowledge of the health system’s nonformulary criteria and who were granted access to the electronic consults responded to the requests.

The consults primarily consisted of an automated template that required providers to fill out their contact information and the name of the requested nonformulary medication, dose, and clinical rationale for requesting the specified medication, including any previous treatments that the patient could not tolerate or on which the patient failed to achieve an adequate response. It was highly recommended but not required that the HCPs include other supporting information regarding the patient’s cardiovascular status, such as results from diagnostic cardiac catheterization, stress tests, electrocardiograms (ECGs), or echocardiograms if not readily available from the CPRS. If procedures or tests were conducted at outside facilities, then this information was supplied in the request or obtained with the patient’s consent. However, this information was not necessarily required in order to complete the nonformulary consult. Nonformulary requests for ranolazine were typically forwarded to the clinical pharmacists who specialized in cardiology.

A pharmacist-oriented collaborative practice was established to increase cost-effective use, improve monitoring by a HCP because of the drug’s ability to prolong the corrected QT (QTc) interval, and to more firmly establish its safety and efficacy in a veteran population. This practice operated in a clinic, which was staffed by a nurse, postdoctoral pharmacy fellow, clinical pharmacy specialist in cardiology, and a cardiologist. The nurse was responsible for obtaining the patient’s vitals and ECG and documenting them in the CPRS. The pharmacy fellow interviewed the patient and obtained pertinent medical and historical information before discussing any clinical recommendations with the clinical pharmacy specialist.

The recommendations consisted of drug initiation/discontinuation, dose adjustments, and assessing and ordering of pertinent laboratory values and ECGs, which took place under the scope of the clinical pharmacy specialist. The focus of the ECG was to assess for any evidence of excessive QTc prolongation. Due to the variable and subjective nature of CAD, a cardiologist was available at any time and was used to review any relevant information and further discuss any treatment recommendations.

Based in the NFSGVHS Malcom Randall Veterans Affairs Medical Center (VAMC) in Gainesville, Florida, clinic services were primarily offered to patients of that facility due to the limited number of cardiology providers and services offered at other NFSGVHS locations. Despite being driven by requests for ranolazine, especially after cardiac catheterization when further cardiac intervention may not have been feasible, all patients were allowed to enroll in the clinic at the discretion of their primary care provider (PCP) for optimization of their CSA regimen with the intent of adding ranolazine when appropriate.

Patients in outlying regions who met the criteria were supplied with ranolazine and continued to follow up with their HCPs as recommended by the criteria for use. Conversely, if patients from outside areas failed to meet the criteria, their PCPs were supplied with appropriate, alternative guideline-based recommendations for improving CSA with the option to resubmit the nonformulary consult.¹¹ Recommendations regarding cardiovascular risk reduction were also sent to HCPs at that time, which included optimal endpoints for managing other conditions, such as diabetes, hypertension, and hyperlipidemia when necesary.^8,11

Regardless of whether ranolazine was initiated at baseline, all patients enrolled in the clinic underwent appropriate labs and tests, including a basic metabolic panel, magnesium level, and an ECG, if not otherwise available from the CPRS or documented from outside facilities. A thorough history and description of the patient’s anginal symptoms were also taken at baseline and during follow-up visits. Once it was confirmed that the patients’ electrolytes were within normal limits and there was no evidence of prolongation in the Bazett’s QTc interval or major drug interactions, all patients who met criteria for ranolazine were initiated at 500 mg twice daily.^9,12 The Seattle Angina Questionnaire (SAQ) was also completed by patients at the initiation of ranolazine and then again at follow-up visits. The SAQ is an 11-question, self-administered survey that measures functional status of patients with angina.¹³

All patients initiated on or ensuing dose changes with ranolazine followed up with the clinic at 1 and 3 months with labs and ECGs obtained prior to ensure that there were no electrolyte imbalances or excessive QTc prolongation. Excessive QTc prolongation was defined as an increase of ≥ 60 milliseconds (msec) from baseline or > 500 msec.¹⁴ If this boundary was exceeded, ranolazine was discontinued, or for those taking higher doses, it was reduced to the initial 500 mg twice daily as long as there was no previous excessive QTc prolongation. In cases where ranolazine was not added at baseline, doses of antianginal medications were titrated over appropriate intervals to improve angina symptoms with ranolazine subsequently added in conjunction with the nonformulary criteria.

A generalized treatment algorithm was followed by the clinic for the management of CSA (Figure). It was highly recommended that all referred patients have an active prescription in the CPRS for short-acting sublingual nitroglycerin 0.4 mg in case of any acute episodes. Although other forms of short-acting nitroglycerin were available, sublingual nitroglycerin 0.4 mg was the preferred formulary medication at the time of the study.

Depending on whether the patients met nonformulary inclusion or exclusion criteria, they were either initiated or optimized on ranolazine or other traditional antianginals, such as beta-blockers (BBs), dihydropyridine calcium channel blockers (DHP-CCBs), or long-acting nitrates (LANs). Beta-blockers were recommended as first-line treatment for patients with previous myocardial infarction (MI) and left ventricular dysfunction, in accordance with treatment guidelines and because of their benefits in treating patients with CSA.^12,15

Once patients were optimized on BBs and/or DHP-CCBs, LANs were added if patients experienced ≥ 3 bothersome episodes of chest pain weekly. Optimization for BBs meant an ideal heart rate of at least about 60 bpm without symptoms suggestive of excessive bradycardia, whereas optimization for all 3 classes (BBs, DHP-CCBs, and LANs) consisted of dose titration until the presence of drug-related adverse effects (AEs) or symptoms suggestive of hypotension. Because LANs have lesser effects on blood pressure (BP) compared with DHP-CCBs, they were preferred in patients with persistent anginal symptoms whose BPs were considered low or normal, according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.¹⁶

If patients with normal or controlled BP continued to have symptoms of angina despite optimal doses of BBs and LANs, an appropriate dose of a DHP-CCB was administered and titrated for as long as the patients tolerated the treatment. If titration of antianginal agents was limited due to the presence of other antihypertensives, then the patient’s medication regimen was modified as necessary to allow for an increased dose of the BB or DHP-CCB due to these medications’ abilities to improve angina symptoms while also lowering BP. If patients achieved an acceptable reduction in their angina symptoms, they were discharged from the clinic, whereas those with contraindications to other classes were referred to their PCP or cardiologist.

Patients successfully treated with ranolazine (defined as a noticeable reduction in angina symptoms in the absence of intolerable AEs and excessive QTc prolongation after 3 months) were discharged from the clinic and instructed to follow up with their PCP at least annually. If the patient was discharged from the clinic at the baseline dose, it was recommended to the HCP that he or she follow up within 3 months after any dose increases. Any patient whose symptoms were consistent with unstable angina (described as occurring in an unpredictable manner, as determined by the clinical pharmacy specialist, lasting longer in duration and/or increasing in frequency, and those who experience symptoms at rest) were immediately evaluated and referred to a cardiologist. Patients who continued to have unacceptable rates or episodes of angina despite an optimal medical regimen were referred to Cardiology for consideration of other treatment modalities.

Results

The initial report of this study population was described by Reeder and colleagues.¹⁷ Fifty-seven patients were evaluated for study inclusion, of which 22 were excluded due to ranolazine being managed by an outside HCP or because an SAQ was not obtained at baseline. All study participants were males with an average age of 68 years and were predominantly white (86%). All patients had a past medical history significant for hypertension and hyperlipidemia. More than half (57%) had a prior MI and multivessel disease, although only 1 patient had an ejection fraction of < 35%. The majority of patients enrolled were being treated with BBs (97%) and LANs (94%) with a little more than half prescribed CCBs (60%). A large percentage (97%) of patients were also taking aspirin and a statin.

Improvements in angina symptoms as measured by the SAQ and safety measures, which included details of AEs and discontinuation rates following the initiation of ranolazine within the clinic, have previously been published.¹⁷ In summary, it was found that the addition of ranolazine to an optimal medical regimen for CSA improved all dimensions of the SAQ scores at 1 and 3 months compared with baseline (Table). Additionally, it was noted that higher doses may not have been as well tolerated in the veteran population, despite that only a small number of eligible patients were captured. This was because 5 of 7 patients whose dose was increased to 1,000 mg twice daily after 1 month required withdrawal as a result of AEs or lack of efficacy. The AEs reported included dizziness, abdominal pain, blurry vision, nausea and vomiting, dry mouth, and dyspnea.

The pharmacists were able to ensure that relevant electrolytes were replaced during the treatment period and also minimized the number of clinically significant drug interactions. Twenty-one patients received medications at baseline that had known interactions with ranolazine. Two patients required discontinuation of other medications: sotalol and diltiazem. At the time this study was conducted, diltiazem was contraindicated when given concomitantly but has since been allowed per manufacturer recommendations as long as the dose of ranolazine does not exceed 500 mg twice daily. Electrolyte replacement was also required in 3 patients, 2 of whom had hypomagnesemia.

Conclusion

Pharmacists have been influential in managing a variety of chronic diseases. When instituted into collaborative practice agreements, CSA is another unique condition that pharmacists can play a role in treating. Given that pharmacists are heavily involved with cardiovascular risk reduction, combined with the higher cost of ranolazine and the need for monitoring due to its AEs, QTc interval prolongation, and significant drug interactions, the benefits of having pharmacist-oriented clinics can ensure the safe and effective use of medications in the treatment of CSA.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Coronary artery disease (CAD) continues to have a significant impact on society. The latest update by the American Heart Association estimates that 83.6 million American adults have some form of cardiovascular disease (CVD) with an anticipated 15.4 million attributed to CAD.¹ A portion of patients with CAD experience predictable chest pain, which occurs as a result of physical, emotional, or mental stress, more commonly referred to as chronic stable angina (CSA). Based on the most recent estimates, the incidence of patients who experience CSA is about 565,000 and increases in the male population through the eighth decade of life.¹

Although it may be common, treatment options for patients with CSA are limited, as these patients may not be ideal candidates for coronary artery bypass graft or percutaneous coronary intervention (PCI) and may often prefer less invasive treatments. It has also been demonstrated that optimal medical management results in similar cardiovascular outcomes when compared with optimal medical management combined with PCI.^2,3 Therefore, optimizing medical management is a reasonable alternative for these individuals.

Pharmacists have been successful in implementing collaborative practices for the management of various conditions, including anticoagulation, diabetes, hypertension, and hyperlipidemia.^4-7 Pharmacists are heavily involved with cardiovascular risk reduction and management, so it seems opportune that they also treat CSA.⁸ The latest estimated direct and indirect costs for CVD and stroke were well over $315 billion for 2010, and it is anticipated that the costs will continue to rise.¹ Because CSA is typically a medically managed disease and due to its huge medical expense, the development of a pharmacist-managed collaborative practice for treating CSA may prove to be beneficial for both clinical and pharmacoeconomic outcomes.

Clinic Development and Practices

In June 2007, following the approval of ranolazine by the FDA, the VA adopted nonformulary criteria for ranolazine use (Appendix).^9,10 In order for patients to receive ranolazine, health care providers (HCPs) within the North Florida/South Georgia Veterans Health System (NFSGVHS) network were required to submit an electronic nonformulary consult using the computerized patient record system (CPRS). Select clinical pharmacists who had knowledge of the health system’s nonformulary criteria and who were granted access to the electronic consults responded to the requests.

The consults primarily consisted of an automated template that required providers to fill out their contact information and the name of the requested nonformulary medication, dose, and clinical rationale for requesting the specified medication, including any previous treatments that the patient could not tolerate or on which the patient failed to achieve an adequate response. It was highly recommended but not required that the HCPs include other supporting information regarding the patient’s cardiovascular status, such as results from diagnostic cardiac catheterization, stress tests, electrocardiograms (ECGs), or echocardiograms if not readily available from the CPRS. If procedures or tests were conducted at outside facilities, then this information was supplied in the request or obtained with the patient’s consent. However, this information was not necessarily required in order to complete the nonformulary consult. Nonformulary requests for ranolazine were typically forwarded to the clinical pharmacists who specialized in cardiology.

A pharmacist-oriented collaborative practice was established to increase cost-effective use, improve monitoring by a HCP because of the drug’s ability to prolong the corrected QT (QTc) interval, and to more firmly establish its safety and efficacy in a veteran population. This practice operated in a clinic, which was staffed by a nurse, postdoctoral pharmacy fellow, clinical pharmacy specialist in cardiology, and a cardiologist. The nurse was responsible for obtaining the patient’s vitals and ECG and documenting them in the CPRS. The pharmacy fellow interviewed the patient and obtained pertinent medical and historical information before discussing any clinical recommendations with the clinical pharmacy specialist.

The recommendations consisted of drug initiation/discontinuation, dose adjustments, and assessing and ordering of pertinent laboratory values and ECGs, which took place under the scope of the clinical pharmacy specialist. The focus of the ECG was to assess for any evidence of excessive QTc prolongation. Due to the variable and subjective nature of CAD, a cardiologist was available at any time and was used to review any relevant information and further discuss any treatment recommendations.

Based in the NFSGVHS Malcom Randall Veterans Affairs Medical Center (VAMC) in Gainesville, Florida, clinic services were primarily offered to patients of that facility due to the limited number of cardiology providers and services offered at other NFSGVHS locations. Despite being driven by requests for ranolazine, especially after cardiac catheterization when further cardiac intervention may not have been feasible, all patients were allowed to enroll in the clinic at the discretion of their primary care provider (PCP) for optimization of their CSA regimen with the intent of adding ranolazine when appropriate.

Patients in outlying regions who met the criteria were supplied with ranolazine and continued to follow up with their HCPs as recommended by the criteria for use. Conversely, if patients from outside areas failed to meet the criteria, their PCPs were supplied with appropriate, alternative guideline-based recommendations for improving CSA with the option to resubmit the nonformulary consult.¹¹ Recommendations regarding cardiovascular risk reduction were also sent to HCPs at that time, which included optimal endpoints for managing other conditions, such as diabetes, hypertension, and hyperlipidemia when necesary.^8,11

Regardless of whether ranolazine was initiated at baseline, all patients enrolled in the clinic underwent appropriate labs and tests, including a basic metabolic panel, magnesium level, and an ECG, if not otherwise available from the CPRS or documented from outside facilities. A thorough history and description of the patient’s anginal symptoms were also taken at baseline and during follow-up visits. Once it was confirmed that the patients’ electrolytes were within normal limits and there was no evidence of prolongation in the Bazett’s QTc interval or major drug interactions, all patients who met criteria for ranolazine were initiated at 500 mg twice daily.^9,12 The Seattle Angina Questionnaire (SAQ) was also completed by patients at the initiation of ranolazine and then again at follow-up visits. The SAQ is an 11-question, self-administered survey that measures functional status of patients with angina.¹³

All patients initiated on or ensuing dose changes with ranolazine followed up with the clinic at 1 and 3 months with labs and ECGs obtained prior to ensure that there were no electrolyte imbalances or excessive QTc prolongation. Excessive QTc prolongation was defined as an increase of ≥ 60 milliseconds (msec) from baseline or > 500 msec.¹⁴ If this boundary was exceeded, ranolazine was discontinued, or for those taking higher doses, it was reduced to the initial 500 mg twice daily as long as there was no previous excessive QTc prolongation. In cases where ranolazine was not added at baseline, doses of antianginal medications were titrated over appropriate intervals to improve angina symptoms with ranolazine subsequently added in conjunction with the nonformulary criteria.

A generalized treatment algorithm was followed by the clinic for the management of CSA (Figure). It was highly recommended that all referred patients have an active prescription in the CPRS for short-acting sublingual nitroglycerin 0.4 mg in case of any acute episodes. Although other forms of short-acting nitroglycerin were available, sublingual nitroglycerin 0.4 mg was the preferred formulary medication at the time of the study.

Depending on whether the patients met nonformulary inclusion or exclusion criteria, they were either initiated or optimized on ranolazine or other traditional antianginals, such as beta-blockers (BBs), dihydropyridine calcium channel blockers (DHP-CCBs), or long-acting nitrates (LANs). Beta-blockers were recommended as first-line treatment for patients with previous myocardial infarction (MI) and left ventricular dysfunction, in accordance with treatment guidelines and because of their benefits in treating patients with CSA.^12,15

Once patients were optimized on BBs and/or DHP-CCBs, LANs were added if patients experienced ≥ 3 bothersome episodes of chest pain weekly. Optimization for BBs meant an ideal heart rate of at least about 60 bpm without symptoms suggestive of excessive bradycardia, whereas optimization for all 3 classes (BBs, DHP-CCBs, and LANs) consisted of dose titration until the presence of drug-related adverse effects (AEs) or symptoms suggestive of hypotension. Because LANs have lesser effects on blood pressure (BP) compared with DHP-CCBs, they were preferred in patients with persistent anginal symptoms whose BPs were considered low or normal, according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.¹⁶

If patients with normal or controlled BP continued to have symptoms of angina despite optimal doses of BBs and LANs, an appropriate dose of a DHP-CCB was administered and titrated for as long as the patients tolerated the treatment. If titration of antianginal agents was limited due to the presence of other antihypertensives, then the patient’s medication regimen was modified as necessary to allow for an increased dose of the BB or DHP-CCB due to these medications’ abilities to improve angina symptoms while also lowering BP. If patients achieved an acceptable reduction in their angina symptoms, they were discharged from the clinic, whereas those with contraindications to other classes were referred to their PCP or cardiologist.

Patients successfully treated with ranolazine (defined as a noticeable reduction in angina symptoms in the absence of intolerable AEs and excessive QTc prolongation after 3 months) were discharged from the clinic and instructed to follow up with their PCP at least annually. If the patient was discharged from the clinic at the baseline dose, it was recommended to the HCP that he or she follow up within 3 months after any dose increases. Any patient whose symptoms were consistent with unstable angina (described as occurring in an unpredictable manner, as determined by the clinical pharmacy specialist, lasting longer in duration and/or increasing in frequency, and those who experience symptoms at rest) were immediately evaluated and referred to a cardiologist. Patients who continued to have unacceptable rates or episodes of angina despite an optimal medical regimen were referred to Cardiology for consideration of other treatment modalities.

Results

The initial report of this study population was described by Reeder and colleagues.¹⁷ Fifty-seven patients were evaluated for study inclusion, of which 22 were excluded due to ranolazine being managed by an outside HCP or because an SAQ was not obtained at baseline. All study participants were males with an average age of 68 years and were predominantly white (86%). All patients had a past medical history significant for hypertension and hyperlipidemia. More than half (57%) had a prior MI and multivessel disease, although only 1 patient had an ejection fraction of < 35%. The majority of patients enrolled were being treated with BBs (97%) and LANs (94%) with a little more than half prescribed CCBs (60%). A large percentage (97%) of patients were also taking aspirin and a statin.

Improvements in angina symptoms as measured by the SAQ and safety measures, which included details of AEs and discontinuation rates following the initiation of ranolazine within the clinic, have previously been published.¹⁷ In summary, it was found that the addition of ranolazine to an optimal medical regimen for CSA improved all dimensions of the SAQ scores at 1 and 3 months compared with baseline (Table). Additionally, it was noted that higher doses may not have been as well tolerated in the veteran population, despite that only a small number of eligible patients were captured. This was because 5 of 7 patients whose dose was increased to 1,000 mg twice daily after 1 month required withdrawal as a result of AEs or lack of efficacy. The AEs reported included dizziness, abdominal pain, blurry vision, nausea and vomiting, dry mouth, and dyspnea.

The pharmacists were able to ensure that relevant electrolytes were replaced during the treatment period and also minimized the number of clinically significant drug interactions. Twenty-one patients received medications at baseline that had known interactions with ranolazine. Two patients required discontinuation of other medications: sotalol and diltiazem. At the time this study was conducted, diltiazem was contraindicated when given concomitantly but has since been allowed per manufacturer recommendations as long as the dose of ranolazine does not exceed 500 mg twice daily. Electrolyte replacement was also required in 3 patients, 2 of whom had hypomagnesemia.

Conclusion

Pharmacists have been influential in managing a variety of chronic diseases. When instituted into collaborative practice agreements, CSA is another unique condition that pharmacists can play a role in treating. Given that pharmacists are heavily involved with cardiovascular risk reduction, combined with the higher cost of ranolazine and the need for monitoring due to its AEs, QTc interval prolongation, and significant drug interactions, the benefits of having pharmacist-oriented clinics can ensure the safe and effective use of medications in the treatment of CSA.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Coronary artery disease (CAD) continues to have a significant impact on society. The latest update by the American Heart Association estimates that 83.6 million American adults have some form of cardiovascular disease (CVD) with an anticipated 15.4 million attributed to CAD.¹ A portion of patients with CAD experience predictable chest pain, which occurs as a result of physical, emotional, or mental stress, more commonly referred to as chronic stable angina (CSA). Based on the most recent estimates, the incidence of patients who experience CSA is about 565,000 and increases in the male population through the eighth decade of life.¹

Although it may be common, treatment options for patients with CSA are limited, as these patients may not be ideal candidates for coronary artery bypass graft or percutaneous coronary intervention (PCI) and may often prefer less invasive treatments. It has also been demonstrated that optimal medical management results in similar cardiovascular outcomes when compared with optimal medical management combined with PCI.^2,3 Therefore, optimizing medical management is a reasonable alternative for these individuals.

Pharmacists have been successful in implementing collaborative practices for the management of various conditions, including anticoagulation, diabetes, hypertension, and hyperlipidemia.^4-7 Pharmacists are heavily involved with cardiovascular risk reduction and management, so it seems opportune that they also treat CSA.⁸ The latest estimated direct and indirect costs for CVD and stroke were well over $315 billion for 2010, and it is anticipated that the costs will continue to rise.¹ Because CSA is typically a medically managed disease and due to its huge medical expense, the development of a pharmacist-managed collaborative practice for treating CSA may prove to be beneficial for both clinical and pharmacoeconomic outcomes.

Clinic Development and Practices

In June 2007, following the approval of ranolazine by the FDA, the VA adopted nonformulary criteria for ranolazine use (Appendix).^9,10 In order for patients to receive ranolazine, health care providers (HCPs) within the North Florida/South Georgia Veterans Health System (NFSGVHS) network were required to submit an electronic nonformulary consult using the computerized patient record system (CPRS). Select clinical pharmacists who had knowledge of the health system’s nonformulary criteria and who were granted access to the electronic consults responded to the requests.

The consults primarily consisted of an automated template that required providers to fill out their contact information and the name of the requested nonformulary medication, dose, and clinical rationale for requesting the specified medication, including any previous treatments that the patient could not tolerate or on which the patient failed to achieve an adequate response. It was highly recommended but not required that the HCPs include other supporting information regarding the patient’s cardiovascular status, such as results from diagnostic cardiac catheterization, stress tests, electrocardiograms (ECGs), or echocardiograms if not readily available from the CPRS. If procedures or tests were conducted at outside facilities, then this information was supplied in the request or obtained with the patient’s consent. However, this information was not necessarily required in order to complete the nonformulary consult. Nonformulary requests for ranolazine were typically forwarded to the clinical pharmacists who specialized in cardiology.

A pharmacist-oriented collaborative practice was established to increase cost-effective use, improve monitoring by a HCP because of the drug’s ability to prolong the corrected QT (QTc) interval, and to more firmly establish its safety and efficacy in a veteran population. This practice operated in a clinic, which was staffed by a nurse, postdoctoral pharmacy fellow, clinical pharmacy specialist in cardiology, and a cardiologist. The nurse was responsible for obtaining the patient’s vitals and ECG and documenting them in the CPRS. The pharmacy fellow interviewed the patient and obtained pertinent medical and historical information before discussing any clinical recommendations with the clinical pharmacy specialist.

The recommendations consisted of drug initiation/discontinuation, dose adjustments, and assessing and ordering of pertinent laboratory values and ECGs, which took place under the scope of the clinical pharmacy specialist. The focus of the ECG was to assess for any evidence of excessive QTc prolongation. Due to the variable and subjective nature of CAD, a cardiologist was available at any time and was used to review any relevant information and further discuss any treatment recommendations.

Based in the NFSGVHS Malcom Randall Veterans Affairs Medical Center (VAMC) in Gainesville, Florida, clinic services were primarily offered to patients of that facility due to the limited number of cardiology providers and services offered at other NFSGVHS locations. Despite being driven by requests for ranolazine, especially after cardiac catheterization when further cardiac intervention may not have been feasible, all patients were allowed to enroll in the clinic at the discretion of their primary care provider (PCP) for optimization of their CSA regimen with the intent of adding ranolazine when appropriate.

Patients in outlying regions who met the criteria were supplied with ranolazine and continued to follow up with their HCPs as recommended by the criteria for use. Conversely, if patients from outside areas failed to meet the criteria, their PCPs were supplied with appropriate, alternative guideline-based recommendations for improving CSA with the option to resubmit the nonformulary consult.¹¹ Recommendations regarding cardiovascular risk reduction were also sent to HCPs at that time, which included optimal endpoints for managing other conditions, such as diabetes, hypertension, and hyperlipidemia when necesary.^8,11

Regardless of whether ranolazine was initiated at baseline, all patients enrolled in the clinic underwent appropriate labs and tests, including a basic metabolic panel, magnesium level, and an ECG, if not otherwise available from the CPRS or documented from outside facilities. A thorough history and description of the patient’s anginal symptoms were also taken at baseline and during follow-up visits. Once it was confirmed that the patients’ electrolytes were within normal limits and there was no evidence of prolongation in the Bazett’s QTc interval or major drug interactions, all patients who met criteria for ranolazine were initiated at 500 mg twice daily.^9,12 The Seattle Angina Questionnaire (SAQ) was also completed by patients at the initiation of ranolazine and then again at follow-up visits. The SAQ is an 11-question, self-administered survey that measures functional status of patients with angina.¹³

All patients initiated on or ensuing dose changes with ranolazine followed up with the clinic at 1 and 3 months with labs and ECGs obtained prior to ensure that there were no electrolyte imbalances or excessive QTc prolongation. Excessive QTc prolongation was defined as an increase of ≥ 60 milliseconds (msec) from baseline or > 500 msec.¹⁴ If this boundary was exceeded, ranolazine was discontinued, or for those taking higher doses, it was reduced to the initial 500 mg twice daily as long as there was no previous excessive QTc prolongation. In cases where ranolazine was not added at baseline, doses of antianginal medications were titrated over appropriate intervals to improve angina symptoms with ranolazine subsequently added in conjunction with the nonformulary criteria.

A generalized treatment algorithm was followed by the clinic for the management of CSA (Figure). It was highly recommended that all referred patients have an active prescription in the CPRS for short-acting sublingual nitroglycerin 0.4 mg in case of any acute episodes. Although other forms of short-acting nitroglycerin were available, sublingual nitroglycerin 0.4 mg was the preferred formulary medication at the time of the study.

Depending on whether the patients met nonformulary inclusion or exclusion criteria, they were either initiated or optimized on ranolazine or other traditional antianginals, such as beta-blockers (BBs), dihydropyridine calcium channel blockers (DHP-CCBs), or long-acting nitrates (LANs). Beta-blockers were recommended as first-line treatment for patients with previous myocardial infarction (MI) and left ventricular dysfunction, in accordance with treatment guidelines and because of their benefits in treating patients with CSA.^12,15

Once patients were optimized on BBs and/or DHP-CCBs, LANs were added if patients experienced ≥ 3 bothersome episodes of chest pain weekly. Optimization for BBs meant an ideal heart rate of at least about 60 bpm without symptoms suggestive of excessive bradycardia, whereas optimization for all 3 classes (BBs, DHP-CCBs, and LANs) consisted of dose titration until the presence of drug-related adverse effects (AEs) or symptoms suggestive of hypotension. Because LANs have lesser effects on blood pressure (BP) compared with DHP-CCBs, they were preferred in patients with persistent anginal symptoms whose BPs were considered low or normal, according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.¹⁶

If patients with normal or controlled BP continued to have symptoms of angina despite optimal doses of BBs and LANs, an appropriate dose of a DHP-CCB was administered and titrated for as long as the patients tolerated the treatment. If titration of antianginal agents was limited due to the presence of other antihypertensives, then the patient’s medication regimen was modified as necessary to allow for an increased dose of the BB or DHP-CCB due to these medications’ abilities to improve angina symptoms while also lowering BP. If patients achieved an acceptable reduction in their angina symptoms, they were discharged from the clinic, whereas those with contraindications to other classes were referred to their PCP or cardiologist.

Patients successfully treated with ranolazine (defined as a noticeable reduction in angina symptoms in the absence of intolerable AEs and excessive QTc prolongation after 3 months) were discharged from the clinic and instructed to follow up with their PCP at least annually. If the patient was discharged from the clinic at the baseline dose, it was recommended to the HCP that he or she follow up within 3 months after any dose increases. Any patient whose symptoms were consistent with unstable angina (described as occurring in an unpredictable manner, as determined by the clinical pharmacy specialist, lasting longer in duration and/or increasing in frequency, and those who experience symptoms at rest) were immediately evaluated and referred to a cardiologist. Patients who continued to have unacceptable rates or episodes of angina despite an optimal medical regimen were referred to Cardiology for consideration of other treatment modalities.

Results

The initial report of this study population was described by Reeder and colleagues.¹⁷ Fifty-seven patients were evaluated for study inclusion, of which 22 were excluded due to ranolazine being managed by an outside HCP or because an SAQ was not obtained at baseline. All study participants were males with an average age of 68 years and were predominantly white (86%). All patients had a past medical history significant for hypertension and hyperlipidemia. More than half (57%) had a prior MI and multivessel disease, although only 1 patient had an ejection fraction of < 35%. The majority of patients enrolled were being treated with BBs (97%) and LANs (94%) with a little more than half prescribed CCBs (60%). A large percentage (97%) of patients were also taking aspirin and a statin.

Improvements in angina symptoms as measured by the SAQ and safety measures, which included details of AEs and discontinuation rates following the initiation of ranolazine within the clinic, have previously been published.¹⁷ In summary, it was found that the addition of ranolazine to an optimal medical regimen for CSA improved all dimensions of the SAQ scores at 1 and 3 months compared with baseline (Table). Additionally, it was noted that higher doses may not have been as well tolerated in the veteran population, despite that only a small number of eligible patients were captured. This was because 5 of 7 patients whose dose was increased to 1,000 mg twice daily after 1 month required withdrawal as a result of AEs or lack of efficacy. The AEs reported included dizziness, abdominal pain, blurry vision, nausea and vomiting, dry mouth, and dyspnea.

The pharmacists were able to ensure that relevant electrolytes were replaced during the treatment period and also minimized the number of clinically significant drug interactions. Twenty-one patients received medications at baseline that had known interactions with ranolazine. Two patients required discontinuation of other medications: sotalol and diltiazem. At the time this study was conducted, diltiazem was contraindicated when given concomitantly but has since been allowed per manufacturer recommendations as long as the dose of ranolazine does not exceed 500 mg twice daily. Electrolyte replacement was also required in 3 patients, 2 of whom had hypomagnesemia.

Conclusion

Pharmacists have been influential in managing a variety of chronic diseases. When instituted into collaborative practice agreements, CSA is another unique condition that pharmacists can play a role in treating. Given that pharmacists are heavily involved with cardiovascular risk reduction, combined with the higher cost of ranolazine and the need for monitoring due to its AEs, QTc interval prolongation, and significant drug interactions, the benefits of having pharmacist-oriented clinics can ensure the safe and effective use of medications in the treatment of CSA.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
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Micrograph of erythroblasts,

which secrete erythroferrone

Credit: Leon Kautz/UCLA

Researchers have discovered a new hormone, called erythroferrone, which regulates hepcidin, the main iron hormone that controls iron absorption and distribution in the body.

Using a mouse model, reseachers determined that erythroferrone is made by red blood-cell progenitors in the bone marrow, and its levels vary according to the demand for red blood cells.

“Modulating the activity of erythroferrone,” said study author Tomas Ganz, MD, PhD, of the David Geffen School of Medicine at UCLA, “could be a viable strategy for the treatment of iron disorders of both overabundance and scarcity.”

Higher levels of erythroferrone suppress hepcidin, thereby allowing more iron to be made available for red blood-cell production. Erythroferrone, or drugs acting like it, could suppress hepcidin and make more iron available for red blood-cell production.

The team began their inquiry by studying the impact of hemorrhage on the bone marrow. That led them to focus on a specific protein that was secreted in the blood. The protein belonged to a family of proteins involved in cell-to-cell communication.

They used recombinant DNA technology and found that the hormone suppressed the production of hepcidin, which affected iron metabolism.

Erythroferrone-deficient mice do not suppress hepcidin quickly after hemorrhage and consequently have delayed recovery from blood loss.

The investigators also found that erythroferrone expression is greatly increased in Hbb^th3/+ mice with thalassemia intermedia, indicating that the hormone contributes to the suppression of hepcidin and iron overload characteristic of the disease.

“Overproduction of erythroferrone may be a major cause of iron overload in untransfused patients and may contribute to iron overload in transfused patients,” said study author Elizabeta Nemeth, PhD, also of the David Geffen School of Medicine at UCLA.

“The identification of erythroferrone can potentially allow researchers and drug developers to target the hormone for specific treatment to prevent iron overload in Cooley’s anemia,” she said.

The investigators reported their findings recently in Nature Genetics.

They noted that further research is needed to understand the role of the new hormone in various blood diseases and to study the mechanisms through which erythroferrone regulates hepcidin.

Micrograph of erythroblasts,

which secrete erythroferrone

Credit: Leon Kautz/UCLA

Researchers have discovered a new hormone, called erythroferrone, which regulates hepcidin, the main iron hormone that controls iron absorption and distribution in the body.

Using a mouse model, reseachers determined that erythroferrone is made by red blood-cell progenitors in the bone marrow, and its levels vary according to the demand for red blood cells.

“Modulating the activity of erythroferrone,” said study author Tomas Ganz, MD, PhD, of the David Geffen School of Medicine at UCLA, “could be a viable strategy for the treatment of iron disorders of both overabundance and scarcity.”

Higher levels of erythroferrone suppress hepcidin, thereby allowing more iron to be made available for red blood-cell production. Erythroferrone, or drugs acting like it, could suppress hepcidin and make more iron available for red blood-cell production.

The team began their inquiry by studying the impact of hemorrhage on the bone marrow. That led them to focus on a specific protein that was secreted in the blood. The protein belonged to a family of proteins involved in cell-to-cell communication.

They used recombinant DNA technology and found that the hormone suppressed the production of hepcidin, which affected iron metabolism.

Erythroferrone-deficient mice do not suppress hepcidin quickly after hemorrhage and consequently have delayed recovery from blood loss.

The investigators also found that erythroferrone expression is greatly increased in Hbb^th3/+ mice with thalassemia intermedia, indicating that the hormone contributes to the suppression of hepcidin and iron overload characteristic of the disease.

“Overproduction of erythroferrone may be a major cause of iron overload in untransfused patients and may contribute to iron overload in transfused patients,” said study author Elizabeta Nemeth, PhD, also of the David Geffen School of Medicine at UCLA.

“The identification of erythroferrone can potentially allow researchers and drug developers to target the hormone for specific treatment to prevent iron overload in Cooley’s anemia,” she said.

The investigators reported their findings recently in Nature Genetics.

They noted that further research is needed to understand the role of the new hormone in various blood diseases and to study the mechanisms through which erythroferrone regulates hepcidin.

Micrograph of erythroblasts,

which secrete erythroferrone

Credit: Leon Kautz/UCLA

Researchers have discovered a new hormone, called erythroferrone, which regulates hepcidin, the main iron hormone that controls iron absorption and distribution in the body.

Using a mouse model, reseachers determined that erythroferrone is made by red blood-cell progenitors in the bone marrow, and its levels vary according to the demand for red blood cells.

“Modulating the activity of erythroferrone,” said study author Tomas Ganz, MD, PhD, of the David Geffen School of Medicine at UCLA, “could be a viable strategy for the treatment of iron disorders of both overabundance and scarcity.”

Higher levels of erythroferrone suppress hepcidin, thereby allowing more iron to be made available for red blood-cell production. Erythroferrone, or drugs acting like it, could suppress hepcidin and make more iron available for red blood-cell production.

The team began their inquiry by studying the impact of hemorrhage on the bone marrow. That led them to focus on a specific protein that was secreted in the blood. The protein belonged to a family of proteins involved in cell-to-cell communication.

They used recombinant DNA technology and found that the hormone suppressed the production of hepcidin, which affected iron metabolism.

Erythroferrone-deficient mice do not suppress hepcidin quickly after hemorrhage and consequently have delayed recovery from blood loss.

The investigators also found that erythroferrone expression is greatly increased in Hbb^th3/+ mice with thalassemia intermedia, indicating that the hormone contributes to the suppression of hepcidin and iron overload characteristic of the disease.

“Overproduction of erythroferrone may be a major cause of iron overload in untransfused patients and may contribute to iron overload in transfused patients,” said study author Elizabeta Nemeth, PhD, also of the David Geffen School of Medicine at UCLA.

“The identification of erythroferrone can potentially allow researchers and drug developers to target the hormone for specific treatment to prevent iron overload in Cooley’s anemia,” she said.

The investigators reported their findings recently in Nature Genetics.

They noted that further research is needed to understand the role of the new hormone in various blood diseases and to study the mechanisms through which erythroferrone regulates hepcidin.

From the Department of Neurology, University of Maryland School of Medicine, Baltimore, MD.

Abstracts

• Objective: To provide a review of psychogenic nonepileptic seizures, including a discussion of the diagnosis, treatment, and clinical significance of the disorder.
• Methods: Review of the relevant literature.
• Results: Psychogenic nonepileptic seizures are a common and potentially disabling neurologic disorder. They are most prevalent in young adults, and more commonly seen in women versus men. Certain psychosocial variables may impact the development of the condition. The diagnosis is made through a detailed history and observation of clinical events in conjunction with video EEG monitoring. Neuropsychological testing is an important component in the evaluation. Treatment includes establishment of an accurate diagnosis, management of any underlying psychiatric diagnoses, and regular follow-up with a neurologist or trained care provider.
• Conclusion: Psychogenic nonepileptic seizures represent a complex interaction between neurologic and psychological factors. Obtaining an accurate diagnosis through the use of video EEG monitoring and clinical observation is an important initial step in treatment and improved quality of life in this patient population.

Psychogenic nonepileptic seizures (PNES) are commonly encountered in outpatient specialty epilepsy clinics as well as inpatient epilepsy monitoring units. They comprise approximately 20% of all refractory seizure disorders referred to specialty epilepsy centers [1–4]. PNES are thought to be psychological in origin as opposed to arising from abnormal electrical discharges as in epileptic seizures. PNES may be more frequent and disabling than epileptic seizures, and patients with PNES may report worse outcomes [5,6]. Increased utilization of long-term video EEG monitoring along with greater recognition of psychogenic neurologic disorders has allowed for improved diagnosis of PNES. However, many diagnostic and therapeutic challenges remain. There are often delays in obtaining an accurate diagnosis, and optimal management remains challenging, often leading to inappropriate, ineffective, and costly treatment, sometimes for many years [6–8].

Epidemiology

PNES are seen across the spectrum of age-groups, from children [9,10] to elderly persons, but they most often occur in young adults between the ages of 15 to 35 years [1,8]. Caution should be used when considering this diagnosis in infants or young children, in whom it is more common to see physiologic events that may mimic epileptic seizures, including gastroesophageal reflux, shuddering, night terrors, or breath holding spells [1,9,10].

PNES are prevalent within epilepsy practices. Patients with PNES comprise approximately 5% to 20% patients thought to have intractable epilepsy seen in outpatient centers, and within epilepsy monitoring units they account for 10% to 40% of patients [1,2,6,8]. A population-based study approximates the incidence of PNES at 1.4 per 100,000 people and 3.4 per 100,000 people between the ages of 15 to 24 years [4].

There is a female preponderance in PNES, which is similar to other conversion and somatoform disorders. Overall, women comprise approximately 70% to 80% of patients with the PNES diagnosis [1,2,6]. There are psychosocial variables that are seen in some patients with this disorder. An important factor that has been described is past history of sexual or physical abuse. In one series, there was a history of sexual abuse in almost 25% of patients with PNES, and history of either sexual abuse, physical abuse, or both in 32% of patients [11]. A history of sexual and/or physical abuse is not exclusive to these patients, and can certainly be seen in patients with epilepsy as well. For example, in a control population of epilepsy patients, there was a reported rate of past sexual or physical abuse approaching 9% [12].

A prior history of head trauma, often of a relatively mild degree, has been described as a potential inciting factor for some cases of PNES [6,13]. In the literature, studies report that as many as 20% of PNES patients attributed their seizures to head trauma, often rather mild head trauma [6,14].

Historcial Context

Historically, what today are called PNES originate with the concept of hysteria, a medical diagnosis in women that can be traced to antiquity [15,16]. By the late 1800s, one of the founders of neurology, Jean Charcot, established hysterical seizures as an important clinical entity with his detailed, elegant descriptions of patients. Charcot formulated clinical methods for distinguishing hysteria and particularly hysterical seizures from epilepsy. He presumed that hysteria and epilepsy were closely related, and he termed seizures due to hysteria as “hysteroepilepsy” or “epileptiform” hysteria. Charcot proposed that hysterical seizures were organic disorders of the brain, like other forms of seizures and epilepsy, and emphasized their relation to disturbance of the female reproductive system [17,18]. Charcot utilized techniques such as manipulation of “hysterogenic zones” and ovarian compression as well as suggestion to both treat and provoke hysteria and hysterical seizures, which he described and documented [17,18]. One of Charcot’s most celebrated students, Sigmund Freud, observed Charcot’s demonstrations but drew different conclusions. He theorized that hysteria and hysterical seizures were not organic disorders of the brain as Charcot proposed, but were rather emotional disorders of the unconscious mind due to repressed energies or drives. Based largely the theories of Freud and Charcot, individuals with hysteria were distinguished from those with epilepsy, with hysterical seizures related to psychological dysfunction while epileptic seizures were associated with physical or organic brain disorders [15,16].

With the introduction of EEG recording in the 1930s, it became possible to characterize epilepsy as an electrical disorder of the brain with associated EEG changes and more effectively distinguish it from hysterical seizures, which did not have such abnormalities. In addition, in the first half of the 20th century, the nature of hysteria as seen and diagnosed by physicians seemed to change. The dramatic, theatrical convulsions described by Charcot and his contemporaries appeared less commonly, while disorders such as chronic pain seemed to increase [1,19].

However, by the 1960s, several reports confirmed that hysterical seizures were actually still prevalent. Newer terms like “pseudoseizures” were used to describe these disorders because the term “hysteria” was thought to be somewhat derogatory, anti-feminist, and antiquated [20,21]. In the 1970s and thereafter, with the increasing availability of video EEG monitoring and growth of inpatient epilepsy monitoring units, it was discovered that these hysterical, pseudo-, or what were also by then termed psychogenic seizures, were actually still common [1,22].

More recently, it has been recognized that the pendulum in some cases may have swung too far in regard to the diagnosis of this disorder. Some rare patients with seizures initially diagnosed as PNES may actually have forms of epileptic seizures such as frontal lobe epilepsy or related physiological disorders rather than psychogenic causes for their episodes [1,23]. These types of epileptic seizures can be very difficult to diagnose properly unless one appreciates how they present and manifest and remains vigilant for them during evaluation [1,23].

Terminology

There is an ongoing debate regarding the appropriate terminology for psychogenic events, and there is no uniform standardized definition or classification at this time. The term that is currently preferred within the epilepsy community for seizures of psychological origin that are thought to be associated with conversion, somatization, or dissociative disorders is “psychogenic nonepileptic seizures” (PNES). This terminology is felt to be non-disparaging and more neutral as compared with other terms such as pseudoseizures, which were previously favored. Nonepileptic seizures or nonepileptic events are broader terms meant to incorporate both physiologic and psychological causes for disorders that are mistaken for epilepsy. PNES are widely defined as paroxysmal events that appear similar to epileptic seizures but are not due to abnormal electrical discharges in the brain and as noted, are typically thought to be related or caused by conversion, somatization, or dissociative disorders.

Physiologic nonepileptic events are another category of physical disorders that may be mistaken for epilepsy. The underlying causes differ between age-groups, and can include conditions such as cardiac arrhythmias, migraine variants, syncope, or metabolic abnormalities. Physiologic nonepileptic seizures account for only a small proportion of all patients with nonepileptic seizures or events [1]. In general, any patient with a psychological disorder that causes symptoms that are mistaken for epilepsy can be said to have PNES.

Clinical Characteristics And Presentation

The duration of PNES is often significantly longer than that seen in epileptic seizures, which usually last less than 3 minutes, excluding the postictal period. PNES may also exhibit waxing and waning convulsive activity, although this finding can certainly be seen in epileptic seizures as well. PNES may be shown to have distractibility with external stimuli. Additionally, the movements in PNES may appear asymmetric, asynchronous, or purposeful, although this is not diagnostic for this disorder. This may contrast with the well-defined, synchronous tonic-clonic activity typically seen in epileptic seizures [1,24,25]. Back arching and pelvic thrusting movements can also be seen in PNES. Despite these differences, it may still be challenging to distinguish the semi-purposeful behaviors of PNES from the automatisms of certain focal epileptic seizures. The often bizarre-appearing, hypermotor activity that can be seen in frontal lobe seizures is often especially difficult to differentiate from PNES [1,23].

Another important consideration is that consciousness is preserved in PNES, while consciousness and responsiveness are frequently impaired in epileptic seizures. Patients with PNES are often apparently unresponsive during events, although there is no true impairment of awareness. Other characteristics that are more commonly seen in PNES are crying and eye closure [26]. Self-injury and incontinence may be reported, but they are less often clearly witnessed or documented [27,28]. Additionally, although patients may at times appear to be asleep at seizure onset, EEG recordings document the patient to actually be asleep in less than 1% of cases [29]. While epileptic seizures often respond well to antiepileptic medications, PNES characteristically do not [1,3,6,8].

In certain situations, provocation maneuvers may be utilized in order to reproduce PNES in patients undergoing EEG monitoring. In comparison to epileptic seizures, suggestion and emotional stimuli are more likely to trigger psychogenic events [1]. Methods utilized to provoke PNES may include saline injections, placement of a tuning fork on the head or body, or even hypnosis, when a suggestion is concurrently provided that such maneuvers can trigger the patient’s seizures [1,30,31]. When evaluating seizures that are provoked in such a manner, it is important to consider whether or not the event captured is in fact a typical event for the patient, or whether the provocation has uncovered a different, atypical event. Given that PNES and epileptic seizures can co-exist within the same patient, care should be taken to avoid making a diagnosis based on capturing an atypical event, or capturing only a subset of a patient’s seizure types. This could result in failure to make an accurate and thorough diagnosis [23]. There is debate regarding the ethics of provoking seizures by way of suggestion. Some members of the epilepsy community feel that provoking seizures through suggestion is inherently deceitful, and therefore can damage the physician-patient relationship. Others assert that such provocative testing can be undertaken in an honest manner, and can ultimately help achieve an accurate diagnosis for the patient [32].

As previously mentioned, there is a proportion of patients who have co-existing epileptic seizures and PNES, and obtaining an accurate diagnosis can be especially challenging in this group. Studies have reported that around 10% to 40% of patients with PNES also have epilepsy [1,22,23,33]. Care must be taken to distinguish between differences in seizure types and if necessary, video EEG monitoring may be needed to capture both seizure types for an accurate diagnosis. This testing can then be useful in education with families and caregivers who may be shown the videos with consent from the patient in order to guide future care.

Evaluation And Diagnosis

As in much of neurology, a thorough history, along with detailed clinical observation remains essential in the diagnosis of patients with PNES and for distinguishing these events from epilepsy. Video EEG monitoring of seizures is a key adjunct to the history and clinical observation in diagnosing this condition [1,2]. Long-term video EEG monitoring is considered the “gold standard” in the characterization and differential diagnosis of seizures. Additional potentially helpful diagnostic techniques include video EEG-monitored seizure provocation, serum prolactin levels, single photon emission computed tomography, and neuropsychological testing.

Video EEG Monitoring

EEG monitoring for characterization of clinical events can be conducted on an ambulatory or outpatient basis or in dedicated inpatient epilepsy monitoring units. Ambulatory monitoring can be useful in the case of patients who report seizures that are more frequent in their home environment or in patients with frequent events. If events are infrequent, then inpatient monitoring may be more efficacious [1]. With longer-term inpatient monitoring, antiepileptic medications can be withdrawn in a supervised setting, in order to lower the seizure threshold as well as to safely discontinue medications that may not be necessary. Such medication titrations are typically not safe in an unsupervised outpatient setting. Some ambulatory EEG monitoring systems do allow for simultaneous video and EEG recording. However, an advantage to inpatient monitoring, which is not afforded in the outpatient setting, is the ability for nursing staff or physicians to perform clinical testing during events to assess for patient responsiveness and other features. Additionally, with inpatient monitoring, EEG technicians can routinely assess for any technical problems with the electrodes or recording system.

Another benefit of video EEG monitoring is that the state (waking, drowsy, or asleep) of the patient at the onset of an event can be established. While epileptic seizures can arise from any state, PNES most often occur from wakefulness. Patients with PNES may appear to be asleep at the onset of events, and they may report seizures from sleep. Video EEG monitoring can help to establish the waking or sleep state of the patient that may aid in diagnosis [29].

Prolactin Levels

Serum prolactin levels may be helpful in the diagnosis of PNES [35,36]. Following generalized tonic-clonic or complex partial epileptic seizures, the serum prolactin can rise from two to threefold to five to tenfold [37]. The maximal rise in serum prolactin occurs in the initial 20 to 60 minutes after the seizure [35–37]. A similar rise in serum prolactin would not be expected in PNES. Although prolactin levels may have some utility in diagnosis, they are not currently routinely ordered as part of a standard admission to most inpatient epilepsy monitoring units. This may be due in part to the fact that false-positive and false-negative results can occur with these levels [37–39]. For example, there may not be a rise in the prolactin level after a simple partial seizure or more subtle complex partial seizure.

Neuropsychological Testing

Neuropsychological testing is also a key component in the evaluation and diagnosis of PNES. Ideally, a mental health provider with a background in psychological assessment and neuropsychological intervention for patients with psychogenic disorders would perform the evaluation [40,41].

The goal of the evaluation should not solely focused on whether the patient suffers from nonepileptic or epileptic seizures. An epileptologist upon review of clinical, electrographic, and neuropsychological data better makes this determination. Moreover, neuropsychological testing cannot in itself either diagnose or exclude the possibility that a seizure disorder is nonepileptic because of the considerable overlap between epileptic and nonepileptic test results [40,41]. Neuropsychological evaluations aid this assessment by (1) determining the potential or likelihood of significant contributing psychopathology or cognitive difficulties, (2) defining the nature of the associated psychological or psychosocial issues, and (3) assessing how a patient might benefit from various psychologically based interventions [1]. The testing may identify psychological problems that can guide treatment after diagnosis.

Delays in Diagnosis

Correct and prompt diagnosis is essential for patients with PNES as is appropriate referral to a knowledgeable trained mental health professional. On average, patients with PNES are diagnosed 7.2 years after manifestation (SD 9.3 years), with mean delay of 5 to 7 years. Younger age, interictal epileptiform potentials in the EEG, and anticonvulsant treatment are associated with longer delays [42,43]. Delays are also thought to occur because of problems with “ownership” of these patients. Although typically neurologists are involved in the diagnosis of PNES, often using video EEG monitoring done in an inpatient setting, the next step is often a referral to a psychiatrist or mental health care provider. There are sometimes delays in the initial referral to the neurologist, delays in referral to specialists for video EEG testing, and also to the physicians, psychologists or social workers who may provide treatment. Another disconnect can occur if patients are “lost to follow-up” if they receive a referral for mental health care and either do not follow up on this on their own, or if the reason for this care is not fully explained. In addition, many mental health professionals are not trained in the evaluation and treatment of psychogenic symptoms and may even feel uncomfortable in dealing with these patients [13,44].

Many studies have been suggestive that delays in diagnosis may result in poorer outcomes [45,46], while other studies have suggested that patients who have an acute diagnosis of PNES upon presentation may do particularly well [8,47–49]. Some of the most recent large outcome studies suggest that there may be no worsening of outcome associated with delays in diagnosis and that outcome was predicted by other factors [50–52].

Management

Management of patients with PNES is similar to that for patients with other types of so-called abnormal illness behavior, although there remains a relative paucity of evidence for specific treatment strategies for PNES [1]. The first consideration should be the manner in which the diagnosis of PNES is presented to the patient and family. It is important to be honest with the patient and demonstrate a positive approach to the diagnosis [53]. The physician should emphasize as favorable or good news the fact that the patient does not have epilepsy, and should also stress that the disorder, although serious and "real," does not require treatment with antiepileptic medications and that once stress or emotional issues are resolved, the patient has the potential to gain better control of these events [1,54,55]. Nevertheless, not all patients readily accept the diagnosis or this type of approach. Some patients may seek other opinions, and this should not be discouraged. An adversarial relationship with the patient should be avoided. The patient should be encouraged to return if desired, and records should be made available to other health care providers to avoid duplication of services.

After the diagnosis of PNES is presented, supportive measures should be initiated. PNES patients may benefit from education and support that can be provided by the neurologist or primary care physician [1]. If the neuropsychological assessment suggests a clinical profile that requires a professional mental health intervention, then an appropriate referral should be made. Regular follow-up visits for the patient with the neurologist are useful even if a mental health professional is involved [49,56]. This allows the patient to get medical attention without demonstrating illness behavior. Patient education and support are stressed at these visits. Because family issues are often important contributing factors, physicians should consider involving family members in visits with consent of the patient [1].

A variety of treatment strategies are employed for the management of PNES including cognitive behavioral therapy (CBT), group and family therapy, antidepressant medication, and other forms of rehabilitation [5,57,58]. A 2007 Cochrane review that identified 608 references for non-medication PNES treatments found that only 3 studies met criteria for a randomized controlled trial. One of the more recently favored treatment options for PNES that has been applied to the treatment of various somatoform disorders and other psychiatric disorders in the past is CBT [57,59,60]. This form of psychotherapy can be administered by trained personnel in a time-limited fashion using defined protocols. The basis of this treatment is that the patient learns to increase awareness of their dysfunctional thoughts and learns new ways to respond to them [57,58]. To date, several groups have reported results of nonrandomized trials as well as case reports and case series which have established the utility of this treatment. There have been reports of significant reductions in seizure frequency and this treatment strategy appears very promising [61–65]. Preliminary randomized controlled trials have also been piloted and are also suggestive that this may be a validated treatment approach [66].

Prognosis

The outcomes of patients with PNES vary. Long-term follow-up studies show that about half of all patients with PNES function reasonably well following their diagnosis. However, only approximately one-third of patients will completely stop having seizures or related problems, and approximately 50% percent have poor functional outcomes [1,2,50]. When the diagnosis of PNES is based on reliable criteria such a video EEG monitoring, misdiagnosis is unlikely. Instead, the usual cause for a poor outcome is related to a patient’s chronic psychological and social problems[1,8,22,50].

It is noteworthy that children with PNES appear to have a much better prognosis than adults [9,10]. In fact, the etiology in children may be related more to transient stress and coping disorders, while adults are more likely to have PNES within the context of more chronic psychological maladjustment, such as personality disorders [10]. Another factor that accounts for the better outcomes in children is that they are usually properly diagnosed earlier in the course of their disorder [9,10].

Patients with milder psychopathology respond better to supportive educational or behavioral therapeutic approaches. In contrast, patients with more severe psychopathology and factitious disorders more often have associated chronic personality problems and correspondingly, a poorer prognosis [1,50]. Also it appears that patients who continue to be followed by the diagnosing neurologist or center do better than patients who are not seen after diagnosis [49,67]. As knowledge about the nature of PNES and their associated psychopathology is gained, better treatment strategies can be developed that will improve the care and prognosis of these difficult and challenging patients.

A large study of 164 patients who were followed for 10 years were considered to have “poor outcome” in general but favorable factors included higher education, younger age of onset and diagnosis, and less “dramatic” attacks, defined as lack of “positive motor features, no ictal incontinence or tongue biting.” These findings were consistent with prior studies [52,68].

In addition, the patients who tended to have less seizures and do better long term, had less somatoform and dissociative symptoms on psychometric testing [51]. These findings are often explained by the theory that patients who do not do well have poor coping strategies to deal with stress and anxiety and that in a sense, these patients have emotional dysregulation.

Special Issues

Coexisting Epileptic and Psychogenic Nonepileptic Seizures

A complicating factor in diagnosis is that both PNES and epileptic seizures may occur in a single patient. Indeed, approximately 10% to 40% of patients identified to have PNES also have been reported to have epileptic seizures [1,23,33,56]. There are several possible explanations for this. Some patients with epilepsy may learn that seizures result in attention and fill certain psychological needs. Alternatively, they may have concomitant neurologic problems, personality disorders, cognitive deficits, or impaired coping mechanisms that predispose them to psychogenic symptoms [69–71]. Fortunately, in such patients with combined seizure disorders, the epileptic seizures are usually well controlled or of only historical relevance at the time a patient develops PNES [1,22,23,33,72–74].

In other patients, both epileptic and PNES may start simultaneously, making management even more complex. In such patients, we have found it particularly helpful to focus on the semiology of seizure manifestations as recorded by video EEG monitoring to distinguish PNES from the epileptic seizures. We then direct our treatment of the patient according to the semiology manifesting at that time. We also have found it useful to show the videos of seizures to family members or caregivers with patient consent to help them understand how to respond best to a patient’s symptoms when epileptic and PNES co-exist.

Misdiagnosis of Psychogenic Nonepileptic Seizures

Sometimes events that are initially diagnosed as nonepileptic actually prove to be epileptic. Such events can be called “pseudo-pseudo” or “epileptic-nonepileptic” seizures [1]. Frontal lobe seizures in particular may not be associated with significant EEG changes ictally and therefore misdiagnosed as PNES [23,75,76]. Clinical presentation and proper diagnosis of these types of events warrant emphasis.

Notable manifestations of frontal lobe seizures that may easily be confused with hysterical behavior include shouting, laughing, cursing, clapping, snapping, genital manipulation, pelvic thrusting, pedaling, running, kicking, and thrashing [23,75–77]. Not all of these behaviors are specific for frontal lobe seizures. For example, bicycling leg movements have also been reported in seizures originating from the temporal lobe [78].

Summary

PNES represent a common yet challenging problem within neurology. This is due to the difficulty in diagnosis as well as lack of effective and widely available treatment options. Overall outcomes of patients with PNES vary, and may relate to an individual patient’s chronic psychological and social problems. However, an accurate and timely diagnosis remains critical and can help provide direction for implementing appropriate treatment.

Corresponding author: Jennifer Hopp, MD, Department of Neurology, University of Maryland Medical Center, Room S12C09, 22 South Greene Street, Baltimore, MD 21201, [email protected].

Financial disclosures: None.

From the Department of Neurology, University of Maryland School of Medicine, Baltimore, MD.

Abstracts

• Objective: To provide a review of psychogenic nonepileptic seizures, including a discussion of the diagnosis, treatment, and clinical significance of the disorder.
• Methods: Review of the relevant literature.
• Results: Psychogenic nonepileptic seizures are a common and potentially disabling neurologic disorder. They are most prevalent in young adults, and more commonly seen in women versus men. Certain psychosocial variables may impact the development of the condition. The diagnosis is made through a detailed history and observation of clinical events in conjunction with video EEG monitoring. Neuropsychological testing is an important component in the evaluation. Treatment includes establishment of an accurate diagnosis, management of any underlying psychiatric diagnoses, and regular follow-up with a neurologist or trained care provider.
• Conclusion: Psychogenic nonepileptic seizures represent a complex interaction between neurologic and psychological factors. Obtaining an accurate diagnosis through the use of video EEG monitoring and clinical observation is an important initial step in treatment and improved quality of life in this patient population.

Psychogenic nonepileptic seizures (PNES) are commonly encountered in outpatient specialty epilepsy clinics as well as inpatient epilepsy monitoring units. They comprise approximately 20% of all refractory seizure disorders referred to specialty epilepsy centers [1–4]. PNES are thought to be psychological in origin as opposed to arising from abnormal electrical discharges as in epileptic seizures. PNES may be more frequent and disabling than epileptic seizures, and patients with PNES may report worse outcomes [5,6]. Increased utilization of long-term video EEG monitoring along with greater recognition of psychogenic neurologic disorders has allowed for improved diagnosis of PNES. However, many diagnostic and therapeutic challenges remain. There are often delays in obtaining an accurate diagnosis, and optimal management remains challenging, often leading to inappropriate, ineffective, and costly treatment, sometimes for many years [6–8].

Epidemiology

PNES are seen across the spectrum of age-groups, from children [9,10] to elderly persons, but they most often occur in young adults between the ages of 15 to 35 years [1,8]. Caution should be used when considering this diagnosis in infants or young children, in whom it is more common to see physiologic events that may mimic epileptic seizures, including gastroesophageal reflux, shuddering, night terrors, or breath holding spells [1,9,10].

PNES are prevalent within epilepsy practices. Patients with PNES comprise approximately 5% to 20% patients thought to have intractable epilepsy seen in outpatient centers, and within epilepsy monitoring units they account for 10% to 40% of patients [1,2,6,8]. A population-based study approximates the incidence of PNES at 1.4 per 100,000 people and 3.4 per 100,000 people between the ages of 15 to 24 years [4].

There is a female preponderance in PNES, which is similar to other conversion and somatoform disorders. Overall, women comprise approximately 70% to 80% of patients with the PNES diagnosis [1,2,6]. There are psychosocial variables that are seen in some patients with this disorder. An important factor that has been described is past history of sexual or physical abuse. In one series, there was a history of sexual abuse in almost 25% of patients with PNES, and history of either sexual abuse, physical abuse, or both in 32% of patients [11]. A history of sexual and/or physical abuse is not exclusive to these patients, and can certainly be seen in patients with epilepsy as well. For example, in a control population of epilepsy patients, there was a reported rate of past sexual or physical abuse approaching 9% [12].

A prior history of head trauma, often of a relatively mild degree, has been described as a potential inciting factor for some cases of PNES [6,13]. In the literature, studies report that as many as 20% of PNES patients attributed their seizures to head trauma, often rather mild head trauma [6,14].

Historcial Context

Historically, what today are called PNES originate with the concept of hysteria, a medical diagnosis in women that can be traced to antiquity [15,16]. By the late 1800s, one of the founders of neurology, Jean Charcot, established hysterical seizures as an important clinical entity with his detailed, elegant descriptions of patients. Charcot formulated clinical methods for distinguishing hysteria and particularly hysterical seizures from epilepsy. He presumed that hysteria and epilepsy were closely related, and he termed seizures due to hysteria as “hysteroepilepsy” or “epileptiform” hysteria. Charcot proposed that hysterical seizures were organic disorders of the brain, like other forms of seizures and epilepsy, and emphasized their relation to disturbance of the female reproductive system [17,18]. Charcot utilized techniques such as manipulation of “hysterogenic zones” and ovarian compression as well as suggestion to both treat and provoke hysteria and hysterical seizures, which he described and documented [17,18]. One of Charcot’s most celebrated students, Sigmund Freud, observed Charcot’s demonstrations but drew different conclusions. He theorized that hysteria and hysterical seizures were not organic disorders of the brain as Charcot proposed, but were rather emotional disorders of the unconscious mind due to repressed energies or drives. Based largely the theories of Freud and Charcot, individuals with hysteria were distinguished from those with epilepsy, with hysterical seizures related to psychological dysfunction while epileptic seizures were associated with physical or organic brain disorders [15,16].

With the introduction of EEG recording in the 1930s, it became possible to characterize epilepsy as an electrical disorder of the brain with associated EEG changes and more effectively distinguish it from hysterical seizures, which did not have such abnormalities. In addition, in the first half of the 20th century, the nature of hysteria as seen and diagnosed by physicians seemed to change. The dramatic, theatrical convulsions described by Charcot and his contemporaries appeared less commonly, while disorders such as chronic pain seemed to increase [1,19].

However, by the 1960s, several reports confirmed that hysterical seizures were actually still prevalent. Newer terms like “pseudoseizures” were used to describe these disorders because the term “hysteria” was thought to be somewhat derogatory, anti-feminist, and antiquated [20,21]. In the 1970s and thereafter, with the increasing availability of video EEG monitoring and growth of inpatient epilepsy monitoring units, it was discovered that these hysterical, pseudo-, or what were also by then termed psychogenic seizures, were actually still common [1,22].

More recently, it has been recognized that the pendulum in some cases may have swung too far in regard to the diagnosis of this disorder. Some rare patients with seizures initially diagnosed as PNES may actually have forms of epileptic seizures such as frontal lobe epilepsy or related physiological disorders rather than psychogenic causes for their episodes [1,23]. These types of epileptic seizures can be very difficult to diagnose properly unless one appreciates how they present and manifest and remains vigilant for them during evaluation [1,23].

Terminology

There is an ongoing debate regarding the appropriate terminology for psychogenic events, and there is no uniform standardized definition or classification at this time. The term that is currently preferred within the epilepsy community for seizures of psychological origin that are thought to be associated with conversion, somatization, or dissociative disorders is “psychogenic nonepileptic seizures” (PNES). This terminology is felt to be non-disparaging and more neutral as compared with other terms such as pseudoseizures, which were previously favored. Nonepileptic seizures or nonepileptic events are broader terms meant to incorporate both physiologic and psychological causes for disorders that are mistaken for epilepsy. PNES are widely defined as paroxysmal events that appear similar to epileptic seizures but are not due to abnormal electrical discharges in the brain and as noted, are typically thought to be related or caused by conversion, somatization, or dissociative disorders.

Physiologic nonepileptic events are another category of physical disorders that may be mistaken for epilepsy. The underlying causes differ between age-groups, and can include conditions such as cardiac arrhythmias, migraine variants, syncope, or metabolic abnormalities. Physiologic nonepileptic seizures account for only a small proportion of all patients with nonepileptic seizures or events [1]. In general, any patient with a psychological disorder that causes symptoms that are mistaken for epilepsy can be said to have PNES.

Clinical Characteristics And Presentation

The duration of PNES is often significantly longer than that seen in epileptic seizures, which usually last less than 3 minutes, excluding the postictal period. PNES may also exhibit waxing and waning convulsive activity, although this finding can certainly be seen in epileptic seizures as well. PNES may be shown to have distractibility with external stimuli. Additionally, the movements in PNES may appear asymmetric, asynchronous, or purposeful, although this is not diagnostic for this disorder. This may contrast with the well-defined, synchronous tonic-clonic activity typically seen in epileptic seizures [1,24,25]. Back arching and pelvic thrusting movements can also be seen in PNES. Despite these differences, it may still be challenging to distinguish the semi-purposeful behaviors of PNES from the automatisms of certain focal epileptic seizures. The often bizarre-appearing, hypermotor activity that can be seen in frontal lobe seizures is often especially difficult to differentiate from PNES [1,23].

Another important consideration is that consciousness is preserved in PNES, while consciousness and responsiveness are frequently impaired in epileptic seizures. Patients with PNES are often apparently unresponsive during events, although there is no true impairment of awareness. Other characteristics that are more commonly seen in PNES are crying and eye closure [26]. Self-injury and incontinence may be reported, but they are less often clearly witnessed or documented [27,28]. Additionally, although patients may at times appear to be asleep at seizure onset, EEG recordings document the patient to actually be asleep in less than 1% of cases [29]. While epileptic seizures often respond well to antiepileptic medications, PNES characteristically do not [1,3,6,8].

In certain situations, provocation maneuvers may be utilized in order to reproduce PNES in patients undergoing EEG monitoring. In comparison to epileptic seizures, suggestion and emotional stimuli are more likely to trigger psychogenic events [1]. Methods utilized to provoke PNES may include saline injections, placement of a tuning fork on the head or body, or even hypnosis, when a suggestion is concurrently provided that such maneuvers can trigger the patient’s seizures [1,30,31]. When evaluating seizures that are provoked in such a manner, it is important to consider whether or not the event captured is in fact a typical event for the patient, or whether the provocation has uncovered a different, atypical event. Given that PNES and epileptic seizures can co-exist within the same patient, care should be taken to avoid making a diagnosis based on capturing an atypical event, or capturing only a subset of a patient’s seizure types. This could result in failure to make an accurate and thorough diagnosis [23]. There is debate regarding the ethics of provoking seizures by way of suggestion. Some members of the epilepsy community feel that provoking seizures through suggestion is inherently deceitful, and therefore can damage the physician-patient relationship. Others assert that such provocative testing can be undertaken in an honest manner, and can ultimately help achieve an accurate diagnosis for the patient [32].

As previously mentioned, there is a proportion of patients who have co-existing epileptic seizures and PNES, and obtaining an accurate diagnosis can be especially challenging in this group. Studies have reported that around 10% to 40% of patients with PNES also have epilepsy [1,22,23,33]. Care must be taken to distinguish between differences in seizure types and if necessary, video EEG monitoring may be needed to capture both seizure types for an accurate diagnosis. This testing can then be useful in education with families and caregivers who may be shown the videos with consent from the patient in order to guide future care.

Evaluation And Diagnosis

As in much of neurology, a thorough history, along with detailed clinical observation remains essential in the diagnosis of patients with PNES and for distinguishing these events from epilepsy. Video EEG monitoring of seizures is a key adjunct to the history and clinical observation in diagnosing this condition [1,2]. Long-term video EEG monitoring is considered the “gold standard” in the characterization and differential diagnosis of seizures. Additional potentially helpful diagnostic techniques include video EEG-monitored seizure provocation, serum prolactin levels, single photon emission computed tomography, and neuropsychological testing.

Video EEG Monitoring

EEG monitoring for characterization of clinical events can be conducted on an ambulatory or outpatient basis or in dedicated inpatient epilepsy monitoring units. Ambulatory monitoring can be useful in the case of patients who report seizures that are more frequent in their home environment or in patients with frequent events. If events are infrequent, then inpatient monitoring may be more efficacious [1]. With longer-term inpatient monitoring, antiepileptic medications can be withdrawn in a supervised setting, in order to lower the seizure threshold as well as to safely discontinue medications that may not be necessary. Such medication titrations are typically not safe in an unsupervised outpatient setting. Some ambulatory EEG monitoring systems do allow for simultaneous video and EEG recording. However, an advantage to inpatient monitoring, which is not afforded in the outpatient setting, is the ability for nursing staff or physicians to perform clinical testing during events to assess for patient responsiveness and other features. Additionally, with inpatient monitoring, EEG technicians can routinely assess for any technical problems with the electrodes or recording system.

Another benefit of video EEG monitoring is that the state (waking, drowsy, or asleep) of the patient at the onset of an event can be established. While epileptic seizures can arise from any state, PNES most often occur from wakefulness. Patients with PNES may appear to be asleep at the onset of events, and they may report seizures from sleep. Video EEG monitoring can help to establish the waking or sleep state of the patient that may aid in diagnosis [29].

Prolactin Levels

Serum prolactin levels may be helpful in the diagnosis of PNES [35,36]. Following generalized tonic-clonic or complex partial epileptic seizures, the serum prolactin can rise from two to threefold to five to tenfold [37]. The maximal rise in serum prolactin occurs in the initial 20 to 60 minutes after the seizure [35–37]. A similar rise in serum prolactin would not be expected in PNES. Although prolactin levels may have some utility in diagnosis, they are not currently routinely ordered as part of a standard admission to most inpatient epilepsy monitoring units. This may be due in part to the fact that false-positive and false-negative results can occur with these levels [37–39]. For example, there may not be a rise in the prolactin level after a simple partial seizure or more subtle complex partial seizure.

Neuropsychological Testing

Neuropsychological testing is also a key component in the evaluation and diagnosis of PNES. Ideally, a mental health provider with a background in psychological assessment and neuropsychological intervention for patients with psychogenic disorders would perform the evaluation [40,41].

The goal of the evaluation should not solely focused on whether the patient suffers from nonepileptic or epileptic seizures. An epileptologist upon review of clinical, electrographic, and neuropsychological data better makes this determination. Moreover, neuropsychological testing cannot in itself either diagnose or exclude the possibility that a seizure disorder is nonepileptic because of the considerable overlap between epileptic and nonepileptic test results [40,41]. Neuropsychological evaluations aid this assessment by (1) determining the potential or likelihood of significant contributing psychopathology or cognitive difficulties, (2) defining the nature of the associated psychological or psychosocial issues, and (3) assessing how a patient might benefit from various psychologically based interventions [1]. The testing may identify psychological problems that can guide treatment after diagnosis.

Delays in Diagnosis

Correct and prompt diagnosis is essential for patients with PNES as is appropriate referral to a knowledgeable trained mental health professional. On average, patients with PNES are diagnosed 7.2 years after manifestation (SD 9.3 years), with mean delay of 5 to 7 years. Younger age, interictal epileptiform potentials in the EEG, and anticonvulsant treatment are associated with longer delays [42,43]. Delays are also thought to occur because of problems with “ownership” of these patients. Although typically neurologists are involved in the diagnosis of PNES, often using video EEG monitoring done in an inpatient setting, the next step is often a referral to a psychiatrist or mental health care provider. There are sometimes delays in the initial referral to the neurologist, delays in referral to specialists for video EEG testing, and also to the physicians, psychologists or social workers who may provide treatment. Another disconnect can occur if patients are “lost to follow-up” if they receive a referral for mental health care and either do not follow up on this on their own, or if the reason for this care is not fully explained. In addition, many mental health professionals are not trained in the evaluation and treatment of psychogenic symptoms and may even feel uncomfortable in dealing with these patients [13,44].

Many studies have been suggestive that delays in diagnosis may result in poorer outcomes [45,46], while other studies have suggested that patients who have an acute diagnosis of PNES upon presentation may do particularly well [8,47–49]. Some of the most recent large outcome studies suggest that there may be no worsening of outcome associated with delays in diagnosis and that outcome was predicted by other factors [50–52].

Management

Management of patients with PNES is similar to that for patients with other types of so-called abnormal illness behavior, although there remains a relative paucity of evidence for specific treatment strategies for PNES [1]. The first consideration should be the manner in which the diagnosis of PNES is presented to the patient and family. It is important to be honest with the patient and demonstrate a positive approach to the diagnosis [53]. The physician should emphasize as favorable or good news the fact that the patient does not have epilepsy, and should also stress that the disorder, although serious and "real," does not require treatment with antiepileptic medications and that once stress or emotional issues are resolved, the patient has the potential to gain better control of these events [1,54,55]. Nevertheless, not all patients readily accept the diagnosis or this type of approach. Some patients may seek other opinions, and this should not be discouraged. An adversarial relationship with the patient should be avoided. The patient should be encouraged to return if desired, and records should be made available to other health care providers to avoid duplication of services.

After the diagnosis of PNES is presented, supportive measures should be initiated. PNES patients may benefit from education and support that can be provided by the neurologist or primary care physician [1]. If the neuropsychological assessment suggests a clinical profile that requires a professional mental health intervention, then an appropriate referral should be made. Regular follow-up visits for the patient with the neurologist are useful even if a mental health professional is involved [49,56]. This allows the patient to get medical attention without demonstrating illness behavior. Patient education and support are stressed at these visits. Because family issues are often important contributing factors, physicians should consider involving family members in visits with consent of the patient [1].

A variety of treatment strategies are employed for the management of PNES including cognitive behavioral therapy (CBT), group and family therapy, antidepressant medication, and other forms of rehabilitation [5,57,58]. A 2007 Cochrane review that identified 608 references for non-medication PNES treatments found that only 3 studies met criteria for a randomized controlled trial. One of the more recently favored treatment options for PNES that has been applied to the treatment of various somatoform disorders and other psychiatric disorders in the past is CBT [57,59,60]. This form of psychotherapy can be administered by trained personnel in a time-limited fashion using defined protocols. The basis of this treatment is that the patient learns to increase awareness of their dysfunctional thoughts and learns new ways to respond to them [57,58]. To date, several groups have reported results of nonrandomized trials as well as case reports and case series which have established the utility of this treatment. There have been reports of significant reductions in seizure frequency and this treatment strategy appears very promising [61–65]. Preliminary randomized controlled trials have also been piloted and are also suggestive that this may be a validated treatment approach [66].

Prognosis

The outcomes of patients with PNES vary. Long-term follow-up studies show that about half of all patients with PNES function reasonably well following their diagnosis. However, only approximately one-third of patients will completely stop having seizures or related problems, and approximately 50% percent have poor functional outcomes [1,2,50]. When the diagnosis of PNES is based on reliable criteria such a video EEG monitoring, misdiagnosis is unlikely. Instead, the usual cause for a poor outcome is related to a patient’s chronic psychological and social problems[1,8,22,50].

It is noteworthy that children with PNES appear to have a much better prognosis than adults [9,10]. In fact, the etiology in children may be related more to transient stress and coping disorders, while adults are more likely to have PNES within the context of more chronic psychological maladjustment, such as personality disorders [10]. Another factor that accounts for the better outcomes in children is that they are usually properly diagnosed earlier in the course of their disorder [9,10].

Patients with milder psychopathology respond better to supportive educational or behavioral therapeutic approaches. In contrast, patients with more severe psychopathology and factitious disorders more often have associated chronic personality problems and correspondingly, a poorer prognosis [1,50]. Also it appears that patients who continue to be followed by the diagnosing neurologist or center do better than patients who are not seen after diagnosis [49,67]. As knowledge about the nature of PNES and their associated psychopathology is gained, better treatment strategies can be developed that will improve the care and prognosis of these difficult and challenging patients.

A large study of 164 patients who were followed for 10 years were considered to have “poor outcome” in general but favorable factors included higher education, younger age of onset and diagnosis, and less “dramatic” attacks, defined as lack of “positive motor features, no ictal incontinence or tongue biting.” These findings were consistent with prior studies [52,68].

In addition, the patients who tended to have less seizures and do better long term, had less somatoform and dissociative symptoms on psychometric testing [51]. These findings are often explained by the theory that patients who do not do well have poor coping strategies to deal with stress and anxiety and that in a sense, these patients have emotional dysregulation.

Special Issues

Coexisting Epileptic and Psychogenic Nonepileptic Seizures

A complicating factor in diagnosis is that both PNES and epileptic seizures may occur in a single patient. Indeed, approximately 10% to 40% of patients identified to have PNES also have been reported to have epileptic seizures [1,23,33,56]. There are several possible explanations for this. Some patients with epilepsy may learn that seizures result in attention and fill certain psychological needs. Alternatively, they may have concomitant neurologic problems, personality disorders, cognitive deficits, or impaired coping mechanisms that predispose them to psychogenic symptoms [69–71]. Fortunately, in such patients with combined seizure disorders, the epileptic seizures are usually well controlled or of only historical relevance at the time a patient develops PNES [1,22,23,33,72–74].

In other patients, both epileptic and PNES may start simultaneously, making management even more complex. In such patients, we have found it particularly helpful to focus on the semiology of seizure manifestations as recorded by video EEG monitoring to distinguish PNES from the epileptic seizures. We then direct our treatment of the patient according to the semiology manifesting at that time. We also have found it useful to show the videos of seizures to family members or caregivers with patient consent to help them understand how to respond best to a patient’s symptoms when epileptic and PNES co-exist.

Misdiagnosis of Psychogenic Nonepileptic Seizures

Sometimes events that are initially diagnosed as nonepileptic actually prove to be epileptic. Such events can be called “pseudo-pseudo” or “epileptic-nonepileptic” seizures [1]. Frontal lobe seizures in particular may not be associated with significant EEG changes ictally and therefore misdiagnosed as PNES [23,75,76]. Clinical presentation and proper diagnosis of these types of events warrant emphasis.

Notable manifestations of frontal lobe seizures that may easily be confused with hysterical behavior include shouting, laughing, cursing, clapping, snapping, genital manipulation, pelvic thrusting, pedaling, running, kicking, and thrashing [23,75–77]. Not all of these behaviors are specific for frontal lobe seizures. For example, bicycling leg movements have also been reported in seizures originating from the temporal lobe [78].

Summary

PNES represent a common yet challenging problem within neurology. This is due to the difficulty in diagnosis as well as lack of effective and widely available treatment options. Overall outcomes of patients with PNES vary, and may relate to an individual patient’s chronic psychological and social problems. However, an accurate and timely diagnosis remains critical and can help provide direction for implementing appropriate treatment.

Corresponding author: Jennifer Hopp, MD, Department of Neurology, University of Maryland Medical Center, Room S12C09, 22 South Greene Street, Baltimore, MD 21201, [email protected].

Financial disclosures: None.

From the Department of Neurology, University of Maryland School of Medicine, Baltimore, MD.

Abstracts

• Objective: To provide a review of psychogenic nonepileptic seizures, including a discussion of the diagnosis, treatment, and clinical significance of the disorder.
• Methods: Review of the relevant literature.
• Results: Psychogenic nonepileptic seizures are a common and potentially disabling neurologic disorder. They are most prevalent in young adults, and more commonly seen in women versus men. Certain psychosocial variables may impact the development of the condition. The diagnosis is made through a detailed history and observation of clinical events in conjunction with video EEG monitoring. Neuropsychological testing is an important component in the evaluation. Treatment includes establishment of an accurate diagnosis, management of any underlying psychiatric diagnoses, and regular follow-up with a neurologist or trained care provider.
• Conclusion: Psychogenic nonepileptic seizures represent a complex interaction between neurologic and psychological factors. Obtaining an accurate diagnosis through the use of video EEG monitoring and clinical observation is an important initial step in treatment and improved quality of life in this patient population.

Psychogenic nonepileptic seizures (PNES) are commonly encountered in outpatient specialty epilepsy clinics as well as inpatient epilepsy monitoring units. They comprise approximately 20% of all refractory seizure disorders referred to specialty epilepsy centers [1–4]. PNES are thought to be psychological in origin as opposed to arising from abnormal electrical discharges as in epileptic seizures. PNES may be more frequent and disabling than epileptic seizures, and patients with PNES may report worse outcomes [5,6]. Increased utilization of long-term video EEG monitoring along with greater recognition of psychogenic neurologic disorders has allowed for improved diagnosis of PNES. However, many diagnostic and therapeutic challenges remain. There are often delays in obtaining an accurate diagnosis, and optimal management remains challenging, often leading to inappropriate, ineffective, and costly treatment, sometimes for many years [6–8].

Epidemiology

PNES are seen across the spectrum of age-groups, from children [9,10] to elderly persons, but they most often occur in young adults between the ages of 15 to 35 years [1,8]. Caution should be used when considering this diagnosis in infants or young children, in whom it is more common to see physiologic events that may mimic epileptic seizures, including gastroesophageal reflux, shuddering, night terrors, or breath holding spells [1,9,10].

PNES are prevalent within epilepsy practices. Patients with PNES comprise approximately 5% to 20% patients thought to have intractable epilepsy seen in outpatient centers, and within epilepsy monitoring units they account for 10% to 40% of patients [1,2,6,8]. A population-based study approximates the incidence of PNES at 1.4 per 100,000 people and 3.4 per 100,000 people between the ages of 15 to 24 years [4].

There is a female preponderance in PNES, which is similar to other conversion and somatoform disorders. Overall, women comprise approximately 70% to 80% of patients with the PNES diagnosis [1,2,6]. There are psychosocial variables that are seen in some patients with this disorder. An important factor that has been described is past history of sexual or physical abuse. In one series, there was a history of sexual abuse in almost 25% of patients with PNES, and history of either sexual abuse, physical abuse, or both in 32% of patients [11]. A history of sexual and/or physical abuse is not exclusive to these patients, and can certainly be seen in patients with epilepsy as well. For example, in a control population of epilepsy patients, there was a reported rate of past sexual or physical abuse approaching 9% [12].

A prior history of head trauma, often of a relatively mild degree, has been described as a potential inciting factor for some cases of PNES [6,13]. In the literature, studies report that as many as 20% of PNES patients attributed their seizures to head trauma, often rather mild head trauma [6,14].

Historcial Context

Historically, what today are called PNES originate with the concept of hysteria, a medical diagnosis in women that can be traced to antiquity [15,16]. By the late 1800s, one of the founders of neurology, Jean Charcot, established hysterical seizures as an important clinical entity with his detailed, elegant descriptions of patients. Charcot formulated clinical methods for distinguishing hysteria and particularly hysterical seizures from epilepsy. He presumed that hysteria and epilepsy were closely related, and he termed seizures due to hysteria as “hysteroepilepsy” or “epileptiform” hysteria. Charcot proposed that hysterical seizures were organic disorders of the brain, like other forms of seizures and epilepsy, and emphasized their relation to disturbance of the female reproductive system [17,18]. Charcot utilized techniques such as manipulation of “hysterogenic zones” and ovarian compression as well as suggestion to both treat and provoke hysteria and hysterical seizures, which he described and documented [17,18]. One of Charcot’s most celebrated students, Sigmund Freud, observed Charcot’s demonstrations but drew different conclusions. He theorized that hysteria and hysterical seizures were not organic disorders of the brain as Charcot proposed, but were rather emotional disorders of the unconscious mind due to repressed energies or drives. Based largely the theories of Freud and Charcot, individuals with hysteria were distinguished from those with epilepsy, with hysterical seizures related to psychological dysfunction while epileptic seizures were associated with physical or organic brain disorders [15,16].

With the introduction of EEG recording in the 1930s, it became possible to characterize epilepsy as an electrical disorder of the brain with associated EEG changes and more effectively distinguish it from hysterical seizures, which did not have such abnormalities. In addition, in the first half of the 20th century, the nature of hysteria as seen and diagnosed by physicians seemed to change. The dramatic, theatrical convulsions described by Charcot and his contemporaries appeared less commonly, while disorders such as chronic pain seemed to increase [1,19].

However, by the 1960s, several reports confirmed that hysterical seizures were actually still prevalent. Newer terms like “pseudoseizures” were used to describe these disorders because the term “hysteria” was thought to be somewhat derogatory, anti-feminist, and antiquated [20,21]. In the 1970s and thereafter, with the increasing availability of video EEG monitoring and growth of inpatient epilepsy monitoring units, it was discovered that these hysterical, pseudo-, or what were also by then termed psychogenic seizures, were actually still common [1,22].

More recently, it has been recognized that the pendulum in some cases may have swung too far in regard to the diagnosis of this disorder. Some rare patients with seizures initially diagnosed as PNES may actually have forms of epileptic seizures such as frontal lobe epilepsy or related physiological disorders rather than psychogenic causes for their episodes [1,23]. These types of epileptic seizures can be very difficult to diagnose properly unless one appreciates how they present and manifest and remains vigilant for them during evaluation [1,23].

Terminology

There is an ongoing debate regarding the appropriate terminology for psychogenic events, and there is no uniform standardized definition or classification at this time. The term that is currently preferred within the epilepsy community for seizures of psychological origin that are thought to be associated with conversion, somatization, or dissociative disorders is “psychogenic nonepileptic seizures” (PNES). This terminology is felt to be non-disparaging and more neutral as compared with other terms such as pseudoseizures, which were previously favored. Nonepileptic seizures or nonepileptic events are broader terms meant to incorporate both physiologic and psychological causes for disorders that are mistaken for epilepsy. PNES are widely defined as paroxysmal events that appear similar to epileptic seizures but are not due to abnormal electrical discharges in the brain and as noted, are typically thought to be related or caused by conversion, somatization, or dissociative disorders.

Physiologic nonepileptic events are another category of physical disorders that may be mistaken for epilepsy. The underlying causes differ between age-groups, and can include conditions such as cardiac arrhythmias, migraine variants, syncope, or metabolic abnormalities. Physiologic nonepileptic seizures account for only a small proportion of all patients with nonepileptic seizures or events [1]. In general, any patient with a psychological disorder that causes symptoms that are mistaken for epilepsy can be said to have PNES.

Clinical Characteristics And Presentation

The duration of PNES is often significantly longer than that seen in epileptic seizures, which usually last less than 3 minutes, excluding the postictal period. PNES may also exhibit waxing and waning convulsive activity, although this finding can certainly be seen in epileptic seizures as well. PNES may be shown to have distractibility with external stimuli. Additionally, the movements in PNES may appear asymmetric, asynchronous, or purposeful, although this is not diagnostic for this disorder. This may contrast with the well-defined, synchronous tonic-clonic activity typically seen in epileptic seizures [1,24,25]. Back arching and pelvic thrusting movements can also be seen in PNES. Despite these differences, it may still be challenging to distinguish the semi-purposeful behaviors of PNES from the automatisms of certain focal epileptic seizures. The often bizarre-appearing, hypermotor activity that can be seen in frontal lobe seizures is often especially difficult to differentiate from PNES [1,23].

Another important consideration is that consciousness is preserved in PNES, while consciousness and responsiveness are frequently impaired in epileptic seizures. Patients with PNES are often apparently unresponsive during events, although there is no true impairment of awareness. Other characteristics that are more commonly seen in PNES are crying and eye closure [26]. Self-injury and incontinence may be reported, but they are less often clearly witnessed or documented [27,28]. Additionally, although patients may at times appear to be asleep at seizure onset, EEG recordings document the patient to actually be asleep in less than 1% of cases [29]. While epileptic seizures often respond well to antiepileptic medications, PNES characteristically do not [1,3,6,8].

In certain situations, provocation maneuvers may be utilized in order to reproduce PNES in patients undergoing EEG monitoring. In comparison to epileptic seizures, suggestion and emotional stimuli are more likely to trigger psychogenic events [1]. Methods utilized to provoke PNES may include saline injections, placement of a tuning fork on the head or body, or even hypnosis, when a suggestion is concurrently provided that such maneuvers can trigger the patient’s seizures [1,30,31]. When evaluating seizures that are provoked in such a manner, it is important to consider whether or not the event captured is in fact a typical event for the patient, or whether the provocation has uncovered a different, atypical event. Given that PNES and epileptic seizures can co-exist within the same patient, care should be taken to avoid making a diagnosis based on capturing an atypical event, or capturing only a subset of a patient’s seizure types. This could result in failure to make an accurate and thorough diagnosis [23]. There is debate regarding the ethics of provoking seizures by way of suggestion. Some members of the epilepsy community feel that provoking seizures through suggestion is inherently deceitful, and therefore can damage the physician-patient relationship. Others assert that such provocative testing can be undertaken in an honest manner, and can ultimately help achieve an accurate diagnosis for the patient [32].

As previously mentioned, there is a proportion of patients who have co-existing epileptic seizures and PNES, and obtaining an accurate diagnosis can be especially challenging in this group. Studies have reported that around 10% to 40% of patients with PNES also have epilepsy [1,22,23,33]. Care must be taken to distinguish between differences in seizure types and if necessary, video EEG monitoring may be needed to capture both seizure types for an accurate diagnosis. This testing can then be useful in education with families and caregivers who may be shown the videos with consent from the patient in order to guide future care.

Evaluation And Diagnosis

As in much of neurology, a thorough history, along with detailed clinical observation remains essential in the diagnosis of patients with PNES and for distinguishing these events from epilepsy. Video EEG monitoring of seizures is a key adjunct to the history and clinical observation in diagnosing this condition [1,2]. Long-term video EEG monitoring is considered the “gold standard” in the characterization and differential diagnosis of seizures. Additional potentially helpful diagnostic techniques include video EEG-monitored seizure provocation, serum prolactin levels, single photon emission computed tomography, and neuropsychological testing.

Video EEG Monitoring

EEG monitoring for characterization of clinical events can be conducted on an ambulatory or outpatient basis or in dedicated inpatient epilepsy monitoring units. Ambulatory monitoring can be useful in the case of patients who report seizures that are more frequent in their home environment or in patients with frequent events. If events are infrequent, then inpatient monitoring may be more efficacious [1]. With longer-term inpatient monitoring, antiepileptic medications can be withdrawn in a supervised setting, in order to lower the seizure threshold as well as to safely discontinue medications that may not be necessary. Such medication titrations are typically not safe in an unsupervised outpatient setting. Some ambulatory EEG monitoring systems do allow for simultaneous video and EEG recording. However, an advantage to inpatient monitoring, which is not afforded in the outpatient setting, is the ability for nursing staff or physicians to perform clinical testing during events to assess for patient responsiveness and other features. Additionally, with inpatient monitoring, EEG technicians can routinely assess for any technical problems with the electrodes or recording system.

Another benefit of video EEG monitoring is that the state (waking, drowsy, or asleep) of the patient at the onset of an event can be established. While epileptic seizures can arise from any state, PNES most often occur from wakefulness. Patients with PNES may appear to be asleep at the onset of events, and they may report seizures from sleep. Video EEG monitoring can help to establish the waking or sleep state of the patient that may aid in diagnosis [29].

Prolactin Levels

Serum prolactin levels may be helpful in the diagnosis of PNES [35,36]. Following generalized tonic-clonic or complex partial epileptic seizures, the serum prolactin can rise from two to threefold to five to tenfold [37]. The maximal rise in serum prolactin occurs in the initial 20 to 60 minutes after the seizure [35–37]. A similar rise in serum prolactin would not be expected in PNES. Although prolactin levels may have some utility in diagnosis, they are not currently routinely ordered as part of a standard admission to most inpatient epilepsy monitoring units. This may be due in part to the fact that false-positive and false-negative results can occur with these levels [37–39]. For example, there may not be a rise in the prolactin level after a simple partial seizure or more subtle complex partial seizure.

Neuropsychological Testing

Neuropsychological testing is also a key component in the evaluation and diagnosis of PNES. Ideally, a mental health provider with a background in psychological assessment and neuropsychological intervention for patients with psychogenic disorders would perform the evaluation [40,41].

The goal of the evaluation should not solely focused on whether the patient suffers from nonepileptic or epileptic seizures. An epileptologist upon review of clinical, electrographic, and neuropsychological data better makes this determination. Moreover, neuropsychological testing cannot in itself either diagnose or exclude the possibility that a seizure disorder is nonepileptic because of the considerable overlap between epileptic and nonepileptic test results [40,41]. Neuropsychological evaluations aid this assessment by (1) determining the potential or likelihood of significant contributing psychopathology or cognitive difficulties, (2) defining the nature of the associated psychological or psychosocial issues, and (3) assessing how a patient might benefit from various psychologically based interventions [1]. The testing may identify psychological problems that can guide treatment after diagnosis.

Delays in Diagnosis

Correct and prompt diagnosis is essential for patients with PNES as is appropriate referral to a knowledgeable trained mental health professional. On average, patients with PNES are diagnosed 7.2 years after manifestation (SD 9.3 years), with mean delay of 5 to 7 years. Younger age, interictal epileptiform potentials in the EEG, and anticonvulsant treatment are associated with longer delays [42,43]. Delays are also thought to occur because of problems with “ownership” of these patients. Although typically neurologists are involved in the diagnosis of PNES, often using video EEG monitoring done in an inpatient setting, the next step is often a referral to a psychiatrist or mental health care provider. There are sometimes delays in the initial referral to the neurologist, delays in referral to specialists for video EEG testing, and also to the physicians, psychologists or social workers who may provide treatment. Another disconnect can occur if patients are “lost to follow-up” if they receive a referral for mental health care and either do not follow up on this on their own, or if the reason for this care is not fully explained. In addition, many mental health professionals are not trained in the evaluation and treatment of psychogenic symptoms and may even feel uncomfortable in dealing with these patients [13,44].

Many studies have been suggestive that delays in diagnosis may result in poorer outcomes [45,46], while other studies have suggested that patients who have an acute diagnosis of PNES upon presentation may do particularly well [8,47–49]. Some of the most recent large outcome studies suggest that there may be no worsening of outcome associated with delays in diagnosis and that outcome was predicted by other factors [50–52].

Management

Management of patients with PNES is similar to that for patients with other types of so-called abnormal illness behavior, although there remains a relative paucity of evidence for specific treatment strategies for PNES [1]. The first consideration should be the manner in which the diagnosis of PNES is presented to the patient and family. It is important to be honest with the patient and demonstrate a positive approach to the diagnosis [53]. The physician should emphasize as favorable or good news the fact that the patient does not have epilepsy, and should also stress that the disorder, although serious and "real," does not require treatment with antiepileptic medications and that once stress or emotional issues are resolved, the patient has the potential to gain better control of these events [1,54,55]. Nevertheless, not all patients readily accept the diagnosis or this type of approach. Some patients may seek other opinions, and this should not be discouraged. An adversarial relationship with the patient should be avoided. The patient should be encouraged to return if desired, and records should be made available to other health care providers to avoid duplication of services.

After the diagnosis of PNES is presented, supportive measures should be initiated. PNES patients may benefit from education and support that can be provided by the neurologist or primary care physician [1]. If the neuropsychological assessment suggests a clinical profile that requires a professional mental health intervention, then an appropriate referral should be made. Regular follow-up visits for the patient with the neurologist are useful even if a mental health professional is involved [49,56]. This allows the patient to get medical attention without demonstrating illness behavior. Patient education and support are stressed at these visits. Because family issues are often important contributing factors, physicians should consider involving family members in visits with consent of the patient [1].

A variety of treatment strategies are employed for the management of PNES including cognitive behavioral therapy (CBT), group and family therapy, antidepressant medication, and other forms of rehabilitation [5,57,58]. A 2007 Cochrane review that identified 608 references for non-medication PNES treatments found that only 3 studies met criteria for a randomized controlled trial. One of the more recently favored treatment options for PNES that has been applied to the treatment of various somatoform disorders and other psychiatric disorders in the past is CBT [57,59,60]. This form of psychotherapy can be administered by trained personnel in a time-limited fashion using defined protocols. The basis of this treatment is that the patient learns to increase awareness of their dysfunctional thoughts and learns new ways to respond to them [57,58]. To date, several groups have reported results of nonrandomized trials as well as case reports and case series which have established the utility of this treatment. There have been reports of significant reductions in seizure frequency and this treatment strategy appears very promising [61–65]. Preliminary randomized controlled trials have also been piloted and are also suggestive that this may be a validated treatment approach [66].

Prognosis

The outcomes of patients with PNES vary. Long-term follow-up studies show that about half of all patients with PNES function reasonably well following their diagnosis. However, only approximately one-third of patients will completely stop having seizures or related problems, and approximately 50% percent have poor functional outcomes [1,2,50]. When the diagnosis of PNES is based on reliable criteria such a video EEG monitoring, misdiagnosis is unlikely. Instead, the usual cause for a poor outcome is related to a patient’s chronic psychological and social problems[1,8,22,50].

It is noteworthy that children with PNES appear to have a much better prognosis than adults [9,10]. In fact, the etiology in children may be related more to transient stress and coping disorders, while adults are more likely to have PNES within the context of more chronic psychological maladjustment, such as personality disorders [10]. Another factor that accounts for the better outcomes in children is that they are usually properly diagnosed earlier in the course of their disorder [9,10].

Patients with milder psychopathology respond better to supportive educational or behavioral therapeutic approaches. In contrast, patients with more severe psychopathology and factitious disorders more often have associated chronic personality problems and correspondingly, a poorer prognosis [1,50]. Also it appears that patients who continue to be followed by the diagnosing neurologist or center do better than patients who are not seen after diagnosis [49,67]. As knowledge about the nature of PNES and their associated psychopathology is gained, better treatment strategies can be developed that will improve the care and prognosis of these difficult and challenging patients.

A large study of 164 patients who were followed for 10 years were considered to have “poor outcome” in general but favorable factors included higher education, younger age of onset and diagnosis, and less “dramatic” attacks, defined as lack of “positive motor features, no ictal incontinence or tongue biting.” These findings were consistent with prior studies [52,68].

In addition, the patients who tended to have less seizures and do better long term, had less somatoform and dissociative symptoms on psychometric testing [51]. These findings are often explained by the theory that patients who do not do well have poor coping strategies to deal with stress and anxiety and that in a sense, these patients have emotional dysregulation.

Special Issues

Coexisting Epileptic and Psychogenic Nonepileptic Seizures

A complicating factor in diagnosis is that both PNES and epileptic seizures may occur in a single patient. Indeed, approximately 10% to 40% of patients identified to have PNES also have been reported to have epileptic seizures [1,23,33,56]. There are several possible explanations for this. Some patients with epilepsy may learn that seizures result in attention and fill certain psychological needs. Alternatively, they may have concomitant neurologic problems, personality disorders, cognitive deficits, or impaired coping mechanisms that predispose them to psychogenic symptoms [69–71]. Fortunately, in such patients with combined seizure disorders, the epileptic seizures are usually well controlled or of only historical relevance at the time a patient develops PNES [1,22,23,33,72–74].

In other patients, both epileptic and PNES may start simultaneously, making management even more complex. In such patients, we have found it particularly helpful to focus on the semiology of seizure manifestations as recorded by video EEG monitoring to distinguish PNES from the epileptic seizures. We then direct our treatment of the patient according to the semiology manifesting at that time. We also have found it useful to show the videos of seizures to family members or caregivers with patient consent to help them understand how to respond best to a patient’s symptoms when epileptic and PNES co-exist.

Misdiagnosis of Psychogenic Nonepileptic Seizures

Sometimes events that are initially diagnosed as nonepileptic actually prove to be epileptic. Such events can be called “pseudo-pseudo” or “epileptic-nonepileptic” seizures [1]. Frontal lobe seizures in particular may not be associated with significant EEG changes ictally and therefore misdiagnosed as PNES [23,75,76]. Clinical presentation and proper diagnosis of these types of events warrant emphasis.

Notable manifestations of frontal lobe seizures that may easily be confused with hysterical behavior include shouting, laughing, cursing, clapping, snapping, genital manipulation, pelvic thrusting, pedaling, running, kicking, and thrashing [23,75–77]. Not all of these behaviors are specific for frontal lobe seizures. For example, bicycling leg movements have also been reported in seizures originating from the temporal lobe [78].

Summary

PNES represent a common yet challenging problem within neurology. This is due to the difficulty in diagnosis as well as lack of effective and widely available treatment options. Overall outcomes of patients with PNES vary, and may relate to an individual patient’s chronic psychological and social problems. However, an accurate and timely diagnosis remains critical and can help provide direction for implementing appropriate treatment.

Corresponding author: Jennifer Hopp, MD, Department of Neurology, University of Maryland Medical Center, Room S12C09, 22 South Greene Street, Baltimore, MD 21201, [email protected].

Financial disclosures: None.

Study Overview

Objective. To determine whether having a body mass index (BMI) in the obese range (30 kg/m²) as an older adult woman is associated with changes in late-age survival and morbidity.

Design. Observational cohort study.

Setting and participants. This study relied upon data collected as part of the Women’s Health Initiative (WHI), an observational study and clinical trial focusing on the health of postmenopausal women aged 50–79 years at enrollment. For the purposes of the WHI, women were recruited from centers across the United States between 1993 and 1998 and could participate in several intervention studies (hormone replacement therapy, low-fat diet, calcium/vitamin D supplementation) or an observational study [1].

For this paper, the authors utilized data from those WHI participants who, based on their age at enrollment, could have reached age 85 years by September of 2012. The authors excluded women who did not provide follow-up health information within 18 months of their 85th birthdays or who reported mobility disabilities at their baseline data collection. This resulted in a total of 36,611 women for analysis.

There were a number of baseline measures collected on the study participants. Via written survey, participants self-reported their race and ethnicity, hormone use status, smoking status, alcohol consumption, physical activity level, depressive symptoms, and a number of demographic characteristics. Study personnel objectively measured height and weight to calculate baseline BMI and also measured waist circumference (WC, in cm).

The primary exposure measure for this study was BMI category at trial entry categorized as follows: underweight (< 18.5 kg/m²), healthy weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²) or obese class I (30–34.9 kg/m²), II (35–39.9 kg/m²) or III (≥ 40 kg/m²), using standard accepted cut-points except for Asian/Pacific Islander participants, where alternative World Health Organization (WHO) cut-points were used. The WHO cut-points are slightly lower to account for usual body habitus and disease risk in that population. BMI changes over study follow-up were not included in the exposure measure for this study. WC (dichotomized around 88 cm) was also used as an exposure measure.

Main outcome measures. Disease-free survival status during the follow-up period. In the year at which participants were supposed to reach their 85th birthdays, they were categorized as to whether they had survived or not. Survival status was ascertained by hospital record review, autopsy reports, death certificates and review of the National Death Index. Those who survived were sub-grouped according to type of survival into 1 of the following categories: (1) no incident disease and no mobility disability (healthy), (2) baseline disease present but no incident disease or mobility disability during follow-up (prevalent disease), (3) incident disease but no mobility disability during follow-up (incident disease), and (4) incident mobility disability with or without incident disease (disabled).

Diseases of interest (prevalent and incident) included coronary and cerebrovascular disease, cancer, diabetes and hip fracture—the conditions the investigators felt most increased risk of death or morbidity and mobility disability in this population of aging women. Baseline disease status was defined using self-report, but incident disease in follow-up was more rigorously defined using self-report plus medical record review, except for incident diabetes, which required only self-report of diagnosis plus report of new oral hypoglycemic or insulin use.

Because the outcome of interest (survival status) had 5 possible categories, multinomial logistic regression was used as the analytic technique, with baseline BMI category and WC categories as predictors. The authors adjusted for baseline characteristics including age, race/ethnicity, study arm (intervention or observational for WHI), educational level, marital status, smoking status, ethanol use, self-reported physical activity and depression symptoms. Because of the possibly interrelated predictors (BMI and WC), the authors built BMI models with and without WC, and when WC was the primary predictor they adjusted for a participant’s BMI in order to try to isolate the impact of central adiposity. Additionally, they performed the analyses stratified by race and ethnicity as well as by smoking status.

Results. The mean (SD) baseline age of participants was 72.4 (3) years, and the vast majority (88.5%) self-identified as non-Hispanic white. At the end of the follow-up period, of the initial 36,611 participants, 9079 (24.8%) had died, 6702 (18.3%) had become disabled, 8512 (23.2%) had developed incident disease without disability, 5366 (14.6%) had prevalent but no incident disease, and 6952 (18.9%) were categorized as healthy. There were a number of potentially confounding baseline characteristics that differed between the survival categories. Importantly, race was associated with survival status—non-Hispanic white women were more likely to be in the “healthy” category at follow-up than their counterparts from other races/ethnicities. Baseline smokers were more likely not to live to 85 years, and those with less than a high school education were also more likely not to live to 85 years.

In models adjusting for baseline covariates, with BMI category as the primary predictor, women with an obese baseline BMI had significantly increased odds of not living to 85 years of age, relative to women in a healthy baseline BMI category, with increasing odds of death among those with higher baseline BMI levels (class I obesity odds ratio [OR] 1.72 [95% CI 1.55–1.92], class II obesity OR 3.28 [95% CI 2.69–4.01], class III obesity OR 3.48 [95% CI 2.52–4.80]). Amongst survivors, baseline obesity was also associated with greater odds of developing incident disease, relative to healthy weight women (class I obesity OR 1.65 [95% CI 1.48–1.84], class II obesity OR 2.44 (95% CI 2.02–2.96), class III obesity OR 1.73 [95% CI 1.21–2.46]). There was a striking relationship between baseline obesity and the odds of incident disability during follow-up (class I obesity OR 3.22 [95% CI 2.87–3.61], class II obesity OR 6.62 [95% CI 5.41–8.09], class III obesity OR 6.65 [95% CI 4.80–9.21]).

Women who were overweight at baseline also displayed statistically significant but more modestly increased odds of incident disease, mobility disability, and death relative to their normal-weight counterparts. Importantly, even in multivariable models, being underweight at baseline was also associated with significantly increased odds of death before age 85 relative to healthy weight individuals (OR 2.09 [95% CI 1.54–2.85]) but not with increased odds of incident disease or disability.

When WC status was adjusted for in the “BMI-outcome” models, the odds of death, disability, and incident disease were attenuated for obese women but remained elevated, particularly for women with class II or III obesity. When WC was examined as a primary predictor in multivariable models (adjusted for BMI category), those women with baseline WC ≥ 88 cm experienced increased odds of incident disease (OR 1.47 [95% CI 1.33–1.62]), mobility disability (OR 1.64 [95% CI 1.49–1.84]) and death (OR 1.83 [95% CI 1.66–2.03]) compared to women with smaller baseline WC.

When participants were stratified by race/ethnicity, the relationships for increasing odds of incident disease/disability with baseline obesity persisted for non-Hispanic white and black/African-American participants. Hispanic/Latina participants who were obese at baseline, however, did not have significantly increased odds of death before 85 years relative to healthy weight counterparts, although there were far fewer of these women represented in the cohort (n = 600). Asian/Pacific Islander (API) participants (n = 781), the majority of whom were in the healthy weight range at baseline (57%), showed a somewhat different pattern. Odds ratios for incident disease and death among obese API women were not significantly elevated relative to healthy weight women (although the “n ”s for these groups was relatively small), however the odds of incident disability was significantly elevated amongst API women who were obese at baseline (OR 4.95 [95% CI 1.51–16.23]).

Conclusion. Compared to older women with a healthy BMI, obese women and those with increased abdominal circumference had a lower chance of surviving to age 85 years. Those who did survive were more likely to develop incident disease and/or disability than their healthy weight counterparts.

Commentary

The prevalence of obesity has risen substantially over the past several decades, and few demographic groups have found themselves spared from the epidemic [2]. Although much focus is placed on obesity incidence and prevalence among children and young adults, adults over age 60, a growing segment of the US population, are heavily impacted by the rising rates of obesity as well, with 42% of women and 37% of men in this group characterized as obese in 2010 [2]. This trend has potentially major implications for policy makers who are tasked with cutting the cost of programs such as Medicare.

Obesity has only recently been recognized as a disease by the American Medical Association, and yet it has long been associated with costly and debilitating chronic conditions such as type 2 diabetes, hypertension, sleep apnea, and degenerative joint disease [3]. Despite this fact, several epidemiologic studies have suggested an “obesity paradox”—older adults who are mildly obese have mortality rates similar to normal weight adults, and those who are overweight appear to have lower mortality [4]. These papers have generated controversy among obesity researchers and epidemiologists who have grappled with the following question: How is it possible that overweight and obesity, while clearly linked to so many chronic conditions that increase mortality and morbidity, might be a good thing? Is there such a thing as a “healthy level of obesity,” or, can you be “fit and fat?” In the midst of these discussions and the media storm that inevitably surrounds them, patients are confronted with confusing mixed messages, possibly making them less likely to attempt to maintain a healthy body weight. Unfortunately, as many prior authors have asserted, most of the epidemiologic studies that assert this protective effect of overweight and obesity have not accounted for potentially important confounders of the “weight category–mortality” relationship, such as smoking status [5]. Among older adults, a substantial fraction of those in the normal weight category are at a so-called healthy BMI for very unhealthy reasons, such as cigarette smoking, cancer, or other chronic conditions (ie, they were heavier but lost weight due to underlying illness). Including these sick (but so-called “healthy weight”) people alongside those who are truly healthy and in a healthy BMI range muddies the picture and does not effectively isolate the impact of weight status on morbidity and mortality.

This cohort study by Rillamas-Sun et al makes an important contribution to the discussion by relying on a very large and comprehensive dataset, with an impressive follow-up period of nearly 2 decades, to more fully isolate the relationship between BMI category and survival for postmenopausal women. By adjusting for important potential confounders such as baseline smoking status, alcohol use, chronic disease status and a number of sociodemographic factors, and by separating out the chronically ill patients from the beginning, the investigators reached conclusions that seem to align better with all that we know about the increased health risks conferred by obesity. They found that postmenopausal women who were obese but without prevalent disease at baseline had increased odds of death before age 85, as well as increased odds of incident chronic disease (such as cardiovascular disease or diabetes) and increased odds of incident disability relative to postmenopausal women starting out in a healthy BMI range. Degree of obesity seemed to matter as well; those with class II and III obesity had significantly increased odds of developing mobility impairment, in particular, relative to normal weight women. This is particularly important when viewed through the lens of caring for an aging population—those who have significant mobility impairment will have a much harder time caring for themselves as they age. Furthermore, they found that overweight women also faced slightly increased odds of these outcomes relative to normal weight women. Abdominal adiposity, in particular, appeared to confer risk of death and disease, as elevated odds of mortality and incident disease or disability persisted in women with waist circumference ≥ 88 cm even after adjusting for BMI. As has been suggested by prior research on this topic, this study also supported the finding that being underweight increases ones odds of death, however, there was no increased incidence of disease or mobility disability for underweight women (relative to healthy starting weight).

The authors of the study made a wise decision in separating women with baseline chronic illness from those who had not yet been diagnosed with diabetes, cardiovascular disease or other chronic condition at baseline. As is pointed out in an editorial accompanying this study [6], this creates a scenario where the exposure (obesity) clearly predates the outcome (chronic illness), helping to avoid contamination of risk estimates by reverse causation (ie, is chronic illness leading to increased obesity, with the downstream increase in mortality actually due to the chronic illness?).

Despite the clear strengths of the study, there are several important limitations that must be acknowledged in interpreting the results. The most obvious is that BMI status was only measured at baseline. There is no way of knowing either what a participant’s weight trajectory had been in their younger years, or what happened to the BMI during the study follow-up period, both of which could certainly impact a participant’s risk of morbidity or mortality. Given a follow-up period of nearly 20 years, it is possible that there was crossover between BMI (exposure) categories after baseline assignment. Furthermore, the study does not address the very important question of how an intervention to promote weight loss in older women might impact morbidity and mortality—it is possible that encouraging weight loss in this population may in fact worsen health outcomes for some patients [6].

The generalizability of the study may be somewhat limited. The study population itself represented a group of women who were likely relatively healthy and motivated, having self-selected to participate in the WHI, thus they could have been healthier than groups studied in previous population-based samples. Furthermore, the study results may not generalize to men, however other similar cohort studies with male participants have reached similar conclusions [7].

Applications for Clinical Practice

To promote longevity and maintenance of independence in our growing population of postmenopausal women, it is important that physicians continue to educate and assist their patients in maintaining a healthy weight as they age. Although the impact of intentional weight loss in obese older women is not addressed by this paper, it does support the idea that obese postmenopausal women are at higher risk of death before age 85 years and disability. Therefore, for these patients, physicians should take particular care to reinforce healthy lifestyle choices such as good nutrition and regular physical activity.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To determine whether having a body mass index (BMI) in the obese range (30 kg/m²) as an older adult woman is associated with changes in late-age survival and morbidity.

Design. Observational cohort study.

Setting and participants. This study relied upon data collected as part of the Women’s Health Initiative (WHI), an observational study and clinical trial focusing on the health of postmenopausal women aged 50–79 years at enrollment. For the purposes of the WHI, women were recruited from centers across the United States between 1993 and 1998 and could participate in several intervention studies (hormone replacement therapy, low-fat diet, calcium/vitamin D supplementation) or an observational study [1].

For this paper, the authors utilized data from those WHI participants who, based on their age at enrollment, could have reached age 85 years by September of 2012. The authors excluded women who did not provide follow-up health information within 18 months of their 85th birthdays or who reported mobility disabilities at their baseline data collection. This resulted in a total of 36,611 women for analysis.

There were a number of baseline measures collected on the study participants. Via written survey, participants self-reported their race and ethnicity, hormone use status, smoking status, alcohol consumption, physical activity level, depressive symptoms, and a number of demographic characteristics. Study personnel objectively measured height and weight to calculate baseline BMI and also measured waist circumference (WC, in cm).

The primary exposure measure for this study was BMI category at trial entry categorized as follows: underweight (< 18.5 kg/m²), healthy weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²) or obese class I (30–34.9 kg/m²), II (35–39.9 kg/m²) or III (≥ 40 kg/m²), using standard accepted cut-points except for Asian/Pacific Islander participants, where alternative World Health Organization (WHO) cut-points were used. The WHO cut-points are slightly lower to account for usual body habitus and disease risk in that population. BMI changes over study follow-up were not included in the exposure measure for this study. WC (dichotomized around 88 cm) was also used as an exposure measure.

Main outcome measures. Disease-free survival status during the follow-up period. In the year at which participants were supposed to reach their 85th birthdays, they were categorized as to whether they had survived or not. Survival status was ascertained by hospital record review, autopsy reports, death certificates and review of the National Death Index. Those who survived were sub-grouped according to type of survival into 1 of the following categories: (1) no incident disease and no mobility disability (healthy), (2) baseline disease present but no incident disease or mobility disability during follow-up (prevalent disease), (3) incident disease but no mobility disability during follow-up (incident disease), and (4) incident mobility disability with or without incident disease (disabled).

Diseases of interest (prevalent and incident) included coronary and cerebrovascular disease, cancer, diabetes and hip fracture—the conditions the investigators felt most increased risk of death or morbidity and mobility disability in this population of aging women. Baseline disease status was defined using self-report, but incident disease in follow-up was more rigorously defined using self-report plus medical record review, except for incident diabetes, which required only self-report of diagnosis plus report of new oral hypoglycemic or insulin use.

Because the outcome of interest (survival status) had 5 possible categories, multinomial logistic regression was used as the analytic technique, with baseline BMI category and WC categories as predictors. The authors adjusted for baseline characteristics including age, race/ethnicity, study arm (intervention or observational for WHI), educational level, marital status, smoking status, ethanol use, self-reported physical activity and depression symptoms. Because of the possibly interrelated predictors (BMI and WC), the authors built BMI models with and without WC, and when WC was the primary predictor they adjusted for a participant’s BMI in order to try to isolate the impact of central adiposity. Additionally, they performed the analyses stratified by race and ethnicity as well as by smoking status.

Results. The mean (SD) baseline age of participants was 72.4 (3) years, and the vast majority (88.5%) self-identified as non-Hispanic white. At the end of the follow-up period, of the initial 36,611 participants, 9079 (24.8%) had died, 6702 (18.3%) had become disabled, 8512 (23.2%) had developed incident disease without disability, 5366 (14.6%) had prevalent but no incident disease, and 6952 (18.9%) were categorized as healthy. There were a number of potentially confounding baseline characteristics that differed between the survival categories. Importantly, race was associated with survival status—non-Hispanic white women were more likely to be in the “healthy” category at follow-up than their counterparts from other races/ethnicities. Baseline smokers were more likely not to live to 85 years, and those with less than a high school education were also more likely not to live to 85 years.

In models adjusting for baseline covariates, with BMI category as the primary predictor, women with an obese baseline BMI had significantly increased odds of not living to 85 years of age, relative to women in a healthy baseline BMI category, with increasing odds of death among those with higher baseline BMI levels (class I obesity odds ratio [OR] 1.72 [95% CI 1.55–1.92], class II obesity OR 3.28 [95% CI 2.69–4.01], class III obesity OR 3.48 [95% CI 2.52–4.80]). Amongst survivors, baseline obesity was also associated with greater odds of developing incident disease, relative to healthy weight women (class I obesity OR 1.65 [95% CI 1.48–1.84], class II obesity OR 2.44 (95% CI 2.02–2.96), class III obesity OR 1.73 [95% CI 1.21–2.46]). There was a striking relationship between baseline obesity and the odds of incident disability during follow-up (class I obesity OR 3.22 [95% CI 2.87–3.61], class II obesity OR 6.62 [95% CI 5.41–8.09], class III obesity OR 6.65 [95% CI 4.80–9.21]).

Women who were overweight at baseline also displayed statistically significant but more modestly increased odds of incident disease, mobility disability, and death relative to their normal-weight counterparts. Importantly, even in multivariable models, being underweight at baseline was also associated with significantly increased odds of death before age 85 relative to healthy weight individuals (OR 2.09 [95% CI 1.54–2.85]) but not with increased odds of incident disease or disability.

When WC status was adjusted for in the “BMI-outcome” models, the odds of death, disability, and incident disease were attenuated for obese women but remained elevated, particularly for women with class II or III obesity. When WC was examined as a primary predictor in multivariable models (adjusted for BMI category), those women with baseline WC ≥ 88 cm experienced increased odds of incident disease (OR 1.47 [95% CI 1.33–1.62]), mobility disability (OR 1.64 [95% CI 1.49–1.84]) and death (OR 1.83 [95% CI 1.66–2.03]) compared to women with smaller baseline WC.

When participants were stratified by race/ethnicity, the relationships for increasing odds of incident disease/disability with baseline obesity persisted for non-Hispanic white and black/African-American participants. Hispanic/Latina participants who were obese at baseline, however, did not have significantly increased odds of death before 85 years relative to healthy weight counterparts, although there were far fewer of these women represented in the cohort (n = 600). Asian/Pacific Islander (API) participants (n = 781), the majority of whom were in the healthy weight range at baseline (57%), showed a somewhat different pattern. Odds ratios for incident disease and death among obese API women were not significantly elevated relative to healthy weight women (although the “n ”s for these groups was relatively small), however the odds of incident disability was significantly elevated amongst API women who were obese at baseline (OR 4.95 [95% CI 1.51–16.23]).

Conclusion. Compared to older women with a healthy BMI, obese women and those with increased abdominal circumference had a lower chance of surviving to age 85 years. Those who did survive were more likely to develop incident disease and/or disability than their healthy weight counterparts.

Commentary

The prevalence of obesity has risen substantially over the past several decades, and few demographic groups have found themselves spared from the epidemic [2]. Although much focus is placed on obesity incidence and prevalence among children and young adults, adults over age 60, a growing segment of the US population, are heavily impacted by the rising rates of obesity as well, with 42% of women and 37% of men in this group characterized as obese in 2010 [2]. This trend has potentially major implications for policy makers who are tasked with cutting the cost of programs such as Medicare.

Obesity has only recently been recognized as a disease by the American Medical Association, and yet it has long been associated with costly and debilitating chronic conditions such as type 2 diabetes, hypertension, sleep apnea, and degenerative joint disease [3]. Despite this fact, several epidemiologic studies have suggested an “obesity paradox”—older adults who are mildly obese have mortality rates similar to normal weight adults, and those who are overweight appear to have lower mortality [4]. These papers have generated controversy among obesity researchers and epidemiologists who have grappled with the following question: How is it possible that overweight and obesity, while clearly linked to so many chronic conditions that increase mortality and morbidity, might be a good thing? Is there such a thing as a “healthy level of obesity,” or, can you be “fit and fat?” In the midst of these discussions and the media storm that inevitably surrounds them, patients are confronted with confusing mixed messages, possibly making them less likely to attempt to maintain a healthy body weight. Unfortunately, as many prior authors have asserted, most of the epidemiologic studies that assert this protective effect of overweight and obesity have not accounted for potentially important confounders of the “weight category–mortality” relationship, such as smoking status [5]. Among older adults, a substantial fraction of those in the normal weight category are at a so-called healthy BMI for very unhealthy reasons, such as cigarette smoking, cancer, or other chronic conditions (ie, they were heavier but lost weight due to underlying illness). Including these sick (but so-called “healthy weight”) people alongside those who are truly healthy and in a healthy BMI range muddies the picture and does not effectively isolate the impact of weight status on morbidity and mortality.

This cohort study by Rillamas-Sun et al makes an important contribution to the discussion by relying on a very large and comprehensive dataset, with an impressive follow-up period of nearly 2 decades, to more fully isolate the relationship between BMI category and survival for postmenopausal women. By adjusting for important potential confounders such as baseline smoking status, alcohol use, chronic disease status and a number of sociodemographic factors, and by separating out the chronically ill patients from the beginning, the investigators reached conclusions that seem to align better with all that we know about the increased health risks conferred by obesity. They found that postmenopausal women who were obese but without prevalent disease at baseline had increased odds of death before age 85, as well as increased odds of incident chronic disease (such as cardiovascular disease or diabetes) and increased odds of incident disability relative to postmenopausal women starting out in a healthy BMI range. Degree of obesity seemed to matter as well; those with class II and III obesity had significantly increased odds of developing mobility impairment, in particular, relative to normal weight women. This is particularly important when viewed through the lens of caring for an aging population—those who have significant mobility impairment will have a much harder time caring for themselves as they age. Furthermore, they found that overweight women also faced slightly increased odds of these outcomes relative to normal weight women. Abdominal adiposity, in particular, appeared to confer risk of death and disease, as elevated odds of mortality and incident disease or disability persisted in women with waist circumference ≥ 88 cm even after adjusting for BMI. As has been suggested by prior research on this topic, this study also supported the finding that being underweight increases ones odds of death, however, there was no increased incidence of disease or mobility disability for underweight women (relative to healthy starting weight).

The authors of the study made a wise decision in separating women with baseline chronic illness from those who had not yet been diagnosed with diabetes, cardiovascular disease or other chronic condition at baseline. As is pointed out in an editorial accompanying this study [6], this creates a scenario where the exposure (obesity) clearly predates the outcome (chronic illness), helping to avoid contamination of risk estimates by reverse causation (ie, is chronic illness leading to increased obesity, with the downstream increase in mortality actually due to the chronic illness?).

Despite the clear strengths of the study, there are several important limitations that must be acknowledged in interpreting the results. The most obvious is that BMI status was only measured at baseline. There is no way of knowing either what a participant’s weight trajectory had been in their younger years, or what happened to the BMI during the study follow-up period, both of which could certainly impact a participant’s risk of morbidity or mortality. Given a follow-up period of nearly 20 years, it is possible that there was crossover between BMI (exposure) categories after baseline assignment. Furthermore, the study does not address the very important question of how an intervention to promote weight loss in older women might impact morbidity and mortality—it is possible that encouraging weight loss in this population may in fact worsen health outcomes for some patients [6].

The generalizability of the study may be somewhat limited. The study population itself represented a group of women who were likely relatively healthy and motivated, having self-selected to participate in the WHI, thus they could have been healthier than groups studied in previous population-based samples. Furthermore, the study results may not generalize to men, however other similar cohort studies with male participants have reached similar conclusions [7].

Applications for Clinical Practice

To promote longevity and maintenance of independence in our growing population of postmenopausal women, it is important that physicians continue to educate and assist their patients in maintaining a healthy weight as they age. Although the impact of intentional weight loss in obese older women is not addressed by this paper, it does support the idea that obese postmenopausal women are at higher risk of death before age 85 years and disability. Therefore, for these patients, physicians should take particular care to reinforce healthy lifestyle choices such as good nutrition and regular physical activity.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To determine whether having a body mass index (BMI) in the obese range (30 kg/m²) as an older adult woman is associated with changes in late-age survival and morbidity.

Design. Observational cohort study.

Setting and participants. This study relied upon data collected as part of the Women’s Health Initiative (WHI), an observational study and clinical trial focusing on the health of postmenopausal women aged 50–79 years at enrollment. For the purposes of the WHI, women were recruited from centers across the United States between 1993 and 1998 and could participate in several intervention studies (hormone replacement therapy, low-fat diet, calcium/vitamin D supplementation) or an observational study [1].

For this paper, the authors utilized data from those WHI participants who, based on their age at enrollment, could have reached age 85 years by September of 2012. The authors excluded women who did not provide follow-up health information within 18 months of their 85th birthdays or who reported mobility disabilities at their baseline data collection. This resulted in a total of 36,611 women for analysis.

There were a number of baseline measures collected on the study participants. Via written survey, participants self-reported their race and ethnicity, hormone use status, smoking status, alcohol consumption, physical activity level, depressive symptoms, and a number of demographic characteristics. Study personnel objectively measured height and weight to calculate baseline BMI and also measured waist circumference (WC, in cm).

The primary exposure measure for this study was BMI category at trial entry categorized as follows: underweight (< 18.5 kg/m²), healthy weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²) or obese class I (30–34.9 kg/m²), II (35–39.9 kg/m²) or III (≥ 40 kg/m²), using standard accepted cut-points except for Asian/Pacific Islander participants, where alternative World Health Organization (WHO) cut-points were used. The WHO cut-points are slightly lower to account for usual body habitus and disease risk in that population. BMI changes over study follow-up were not included in the exposure measure for this study. WC (dichotomized around 88 cm) was also used as an exposure measure.

Main outcome measures. Disease-free survival status during the follow-up period. In the year at which participants were supposed to reach their 85th birthdays, they were categorized as to whether they had survived or not. Survival status was ascertained by hospital record review, autopsy reports, death certificates and review of the National Death Index. Those who survived were sub-grouped according to type of survival into 1 of the following categories: (1) no incident disease and no mobility disability (healthy), (2) baseline disease present but no incident disease or mobility disability during follow-up (prevalent disease), (3) incident disease but no mobility disability during follow-up (incident disease), and (4) incident mobility disability with or without incident disease (disabled).

Diseases of interest (prevalent and incident) included coronary and cerebrovascular disease, cancer, diabetes and hip fracture—the conditions the investigators felt most increased risk of death or morbidity and mobility disability in this population of aging women. Baseline disease status was defined using self-report, but incident disease in follow-up was more rigorously defined using self-report plus medical record review, except for incident diabetes, which required only self-report of diagnosis plus report of new oral hypoglycemic or insulin use.

Because the outcome of interest (survival status) had 5 possible categories, multinomial logistic regression was used as the analytic technique, with baseline BMI category and WC categories as predictors. The authors adjusted for baseline characteristics including age, race/ethnicity, study arm (intervention or observational for WHI), educational level, marital status, smoking status, ethanol use, self-reported physical activity and depression symptoms. Because of the possibly interrelated predictors (BMI and WC), the authors built BMI models with and without WC, and when WC was the primary predictor they adjusted for a participant’s BMI in order to try to isolate the impact of central adiposity. Additionally, they performed the analyses stratified by race and ethnicity as well as by smoking status.

Results. The mean (SD) baseline age of participants was 72.4 (3) years, and the vast majority (88.5%) self-identified as non-Hispanic white. At the end of the follow-up period, of the initial 36,611 participants, 9079 (24.8%) had died, 6702 (18.3%) had become disabled, 8512 (23.2%) had developed incident disease without disability, 5366 (14.6%) had prevalent but no incident disease, and 6952 (18.9%) were categorized as healthy. There were a number of potentially confounding baseline characteristics that differed between the survival categories. Importantly, race was associated with survival status—non-Hispanic white women were more likely to be in the “healthy” category at follow-up than their counterparts from other races/ethnicities. Baseline smokers were more likely not to live to 85 years, and those with less than a high school education were also more likely not to live to 85 years.

In models adjusting for baseline covariates, with BMI category as the primary predictor, women with an obese baseline BMI had significantly increased odds of not living to 85 years of age, relative to women in a healthy baseline BMI category, with increasing odds of death among those with higher baseline BMI levels (class I obesity odds ratio [OR] 1.72 [95% CI 1.55–1.92], class II obesity OR 3.28 [95% CI 2.69–4.01], class III obesity OR 3.48 [95% CI 2.52–4.80]). Amongst survivors, baseline obesity was also associated with greater odds of developing incident disease, relative to healthy weight women (class I obesity OR 1.65 [95% CI 1.48–1.84], class II obesity OR 2.44 (95% CI 2.02–2.96), class III obesity OR 1.73 [95% CI 1.21–2.46]). There was a striking relationship between baseline obesity and the odds of incident disability during follow-up (class I obesity OR 3.22 [95% CI 2.87–3.61], class II obesity OR 6.62 [95% CI 5.41–8.09], class III obesity OR 6.65 [95% CI 4.80–9.21]).

Women who were overweight at baseline also displayed statistically significant but more modestly increased odds of incident disease, mobility disability, and death relative to their normal-weight counterparts. Importantly, even in multivariable models, being underweight at baseline was also associated with significantly increased odds of death before age 85 relative to healthy weight individuals (OR 2.09 [95% CI 1.54–2.85]) but not with increased odds of incident disease or disability.

When WC status was adjusted for in the “BMI-outcome” models, the odds of death, disability, and incident disease were attenuated for obese women but remained elevated, particularly for women with class II or III obesity. When WC was examined as a primary predictor in multivariable models (adjusted for BMI category), those women with baseline WC ≥ 88 cm experienced increased odds of incident disease (OR 1.47 [95% CI 1.33–1.62]), mobility disability (OR 1.64 [95% CI 1.49–1.84]) and death (OR 1.83 [95% CI 1.66–2.03]) compared to women with smaller baseline WC.

When participants were stratified by race/ethnicity, the relationships for increasing odds of incident disease/disability with baseline obesity persisted for non-Hispanic white and black/African-American participants. Hispanic/Latina participants who were obese at baseline, however, did not have significantly increased odds of death before 85 years relative to healthy weight counterparts, although there were far fewer of these women represented in the cohort (n = 600). Asian/Pacific Islander (API) participants (n = 781), the majority of whom were in the healthy weight range at baseline (57%), showed a somewhat different pattern. Odds ratios for incident disease and death among obese API women were not significantly elevated relative to healthy weight women (although the “n ”s for these groups was relatively small), however the odds of incident disability was significantly elevated amongst API women who were obese at baseline (OR 4.95 [95% CI 1.51–16.23]).

Conclusion. Compared to older women with a healthy BMI, obese women and those with increased abdominal circumference had a lower chance of surviving to age 85 years. Those who did survive were more likely to develop incident disease and/or disability than their healthy weight counterparts.

Commentary

The prevalence of obesity has risen substantially over the past several decades, and few demographic groups have found themselves spared from the epidemic [2]. Although much focus is placed on obesity incidence and prevalence among children and young adults, adults over age 60, a growing segment of the US population, are heavily impacted by the rising rates of obesity as well, with 42% of women and 37% of men in this group characterized as obese in 2010 [2]. This trend has potentially major implications for policy makers who are tasked with cutting the cost of programs such as Medicare.

Obesity has only recently been recognized as a disease by the American Medical Association, and yet it has long been associated with costly and debilitating chronic conditions such as type 2 diabetes, hypertension, sleep apnea, and degenerative joint disease [3]. Despite this fact, several epidemiologic studies have suggested an “obesity paradox”—older adults who are mildly obese have mortality rates similar to normal weight adults, and those who are overweight appear to have lower mortality [4]. These papers have generated controversy among obesity researchers and epidemiologists who have grappled with the following question: How is it possible that overweight and obesity, while clearly linked to so many chronic conditions that increase mortality and morbidity, might be a good thing? Is there such a thing as a “healthy level of obesity,” or, can you be “fit and fat?” In the midst of these discussions and the media storm that inevitably surrounds them, patients are confronted with confusing mixed messages, possibly making them less likely to attempt to maintain a healthy body weight. Unfortunately, as many prior authors have asserted, most of the epidemiologic studies that assert this protective effect of overweight and obesity have not accounted for potentially important confounders of the “weight category–mortality” relationship, such as smoking status [5]. Among older adults, a substantial fraction of those in the normal weight category are at a so-called healthy BMI for very unhealthy reasons, such as cigarette smoking, cancer, or other chronic conditions (ie, they were heavier but lost weight due to underlying illness). Including these sick (but so-called “healthy weight”) people alongside those who are truly healthy and in a healthy BMI range muddies the picture and does not effectively isolate the impact of weight status on morbidity and mortality.

This cohort study by Rillamas-Sun et al makes an important contribution to the discussion by relying on a very large and comprehensive dataset, with an impressive follow-up period of nearly 2 decades, to more fully isolate the relationship between BMI category and survival for postmenopausal women. By adjusting for important potential confounders such as baseline smoking status, alcohol use, chronic disease status and a number of sociodemographic factors, and by separating out the chronically ill patients from the beginning, the investigators reached conclusions that seem to align better with all that we know about the increased health risks conferred by obesity. They found that postmenopausal women who were obese but without prevalent disease at baseline had increased odds of death before age 85, as well as increased odds of incident chronic disease (such as cardiovascular disease or diabetes) and increased odds of incident disability relative to postmenopausal women starting out in a healthy BMI range. Degree of obesity seemed to matter as well; those with class II and III obesity had significantly increased odds of developing mobility impairment, in particular, relative to normal weight women. This is particularly important when viewed through the lens of caring for an aging population—those who have significant mobility impairment will have a much harder time caring for themselves as they age. Furthermore, they found that overweight women also faced slightly increased odds of these outcomes relative to normal weight women. Abdominal adiposity, in particular, appeared to confer risk of death and disease, as elevated odds of mortality and incident disease or disability persisted in women with waist circumference ≥ 88 cm even after adjusting for BMI. As has been suggested by prior research on this topic, this study also supported the finding that being underweight increases ones odds of death, however, there was no increased incidence of disease or mobility disability for underweight women (relative to healthy starting weight).

The authors of the study made a wise decision in separating women with baseline chronic illness from those who had not yet been diagnosed with diabetes, cardiovascular disease or other chronic condition at baseline. As is pointed out in an editorial accompanying this study [6], this creates a scenario where the exposure (obesity) clearly predates the outcome (chronic illness), helping to avoid contamination of risk estimates by reverse causation (ie, is chronic illness leading to increased obesity, with the downstream increase in mortality actually due to the chronic illness?).

Despite the clear strengths of the study, there are several important limitations that must be acknowledged in interpreting the results. The most obvious is that BMI status was only measured at baseline. There is no way of knowing either what a participant’s weight trajectory had been in their younger years, or what happened to the BMI during the study follow-up period, both of which could certainly impact a participant’s risk of morbidity or mortality. Given a follow-up period of nearly 20 years, it is possible that there was crossover between BMI (exposure) categories after baseline assignment. Furthermore, the study does not address the very important question of how an intervention to promote weight loss in older women might impact morbidity and mortality—it is possible that encouraging weight loss in this population may in fact worsen health outcomes for some patients [6].

The generalizability of the study may be somewhat limited. The study population itself represented a group of women who were likely relatively healthy and motivated, having self-selected to participate in the WHI, thus they could have been healthier than groups studied in previous population-based samples. Furthermore, the study results may not generalize to men, however other similar cohort studies with male participants have reached similar conclusions [7].

Applications for Clinical Practice

To promote longevity and maintenance of independence in our growing population of postmenopausal women, it is important that physicians continue to educate and assist their patients in maintaining a healthy weight as they age. Although the impact of intentional weight loss in obese older women is not addressed by this paper, it does support the idea that obese postmenopausal women are at higher risk of death before age 85 years and disability. Therefore, for these patients, physicians should take particular care to reinforce healthy lifestyle choices such as good nutrition and regular physical activity.

—Kristina Lewis, MD, MPH