We are in the age of the microbiome. Both lay and scientific press proliferate messages about the importance of the microbiome to our health even while they often remain unclear on how to correct microbiota patterns associated with different diseases or suboptimal health states. Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”¹

Certain probiotics have been shown to prevent and treat specific diseases or conditions, inside or outside the gut. But the level and quality of evidence varies greatly. In addition, the health claims allowed by government regulators depend on making discrete distinctions (food vs drug, maintaining health vs treating disease, and emerging evidence vs significant scientific agreement) along dimensions that are increasingly recognized as continuous and complex.² This leads to confusion among doctors and patients about whether to trust claims on product labels and what to make of the absence of such claims.

Find out which probiotic is effective for a patient’s condition. Simply recommending that a patient “take probiotics” is not particularly helpful when the individual wants a product that will aid a specific condition. While probiotics, to date, have not been marketed as drugs in the United States, clinicians can still approach recommending them in an evidence-based manner.

In this article, we review diseases/conditions for which probiotic products have good efficacy data. We discuss probiotic efficacy and safety, offer relevant information on regulatory categories of probiotics, and give direction for proper usage based on the current evidence base. Although this review is meant to be an easy-to-use resource for clinicians, it is not a comprehensive or detailed review of the numerous probiotic products and studies currently available.

Regulatory and commercial variances with probiotics

In the United States, probiotics have been marketed as dietary supplements, medical foods, or conventional foods, all of which require different levels of evidence and types of oversight than drugs. The efficacy of some probiotics in treating or preventing certain diseases and conditions is similar to, if not better than, effects observed with traditional drug interventions (TABLE 1^3-32). However, unlike drugs, which are subject to premarket oversight, the probiotic marketplace contains products with uneven levels of evidence, from well substantiated to greatly limited. Currently, no probiotics are sold in the United States as over-the-counter or prescription drugs, although probiotic drugs will likely enter the US market eventually.

What to consider when recommending a product. When considering probiotics, remember that strain, dosage, and indication are all important. Just as we know that not all antibiotics are equally effective for all infections, so, too, effectiveness among probiotics can—and often does—vary for any given condition. Effectiveness also may vary from patient to patient. Most recommendations made in this review are tied to specific probiotic strains and doses. In some cases, more than one probiotic may be efficacious, likely due to the same or similar underlying mechanism of action. For example, most probiotics produce short-chain fatty acids in the colon, providing a common mechanism supporting digestive health.^33-35

Some probiotics are as effective as, if not better than, drugs traditionally used to treat or prevent certain diseases and conditions.

Contrary to the blanket recommendation preferring higher dosages or a greater number of strains,³⁶ our recommendations are based on levels shown to be effective in clinical trials, which in some contexts can be as low as 100 million colony-forming units (CFU) per day.^37,38 Indeed, a survey we conducted previously of retail dietary supplement products indicated that products with lower CFUs or fewer strains could more readily be linked to evidence of efficacy than multistrain, high-CFU products.³⁹

Continue to: Understanding probiotic product labels is a good start

Understanding probiotic product labels is a good start. Information shown on the label of a probiotic dietary supplement in the United States should include the genus, species, and strains contained in the product, the dose delivered in CFU (the most common measure of the number of live microbes in a probiotic product) through the end of shelf life, and expected benefits. (For help in deciphering these labels, see the label schematic developed by the International Scientific Association for Probiotics and Prebiotics⁴⁰ at https://isappscience.org/infographics/probiotic-labelling/.)

Per guidelines from the Food and Agricultural Organization of the United Nations and the World Health Organization, all probiotic products should have this type of information clearly displayed on the product packaging.⁴¹ However, some probiotic foods display less information; for example, they may not specify the product’s strains or recommended dosage levels. Product Web sites may or may not disclose details missing from the food label. The absence of such information makes it impossible to make evidence-based recommendations about those products.

Probiotics are generally safe, with caveats

The overall safety of typical probiotics (Lactobacillus species, Bifidobacterium species, and Saccharomyces cerevisiae var. boulardii) has been well documented.^42,43 Many probiotic strains have been granted Generally Recognized as Safe status for use in foods in the United States.^44,45 Many traditional probiotic species have been evaluated by the European Food Safety Authority (similar to FDA, except jurisdiction is only over foods, not drugs) and are considered safe for use in food in the European Union.

Be aware that probiotics delivered in dietary supplements and foods are intended for the general population and not for patient populations. Manufacturers therefore are not required to assure safety in vulnerable populations. Nevertheless, probiotics are often stocked in hospital formularies.^46,47 Probiotic usage in vulnerable patient groups has been considered by an expert working group from the standpoint of quality assurance for microbiologic products used to treat and prevent disease, with the experts recommending that health care professionals (including pharmacists and physicians) seek quality information from manufacturers and that manufacturers participate in programs providing third-party (eg, United States Pharmacopeia [USP] or Underwriters Laboratories [UL]) verification of probiotic products to assure products meet applicable purity standards.^48,49

Published case studies have reported that probiotics may be a rare cause of sepsis.⁴³ Recently, Lactobacillus rhamnosus GG was linked to bacteremia in 6 critically ill patients, but all cases resolved without complications.⁵⁰ Further, the death of a premature infant was linked to administration of a probiotic contaminated with an opportunistic pathogenic mold.⁵¹ A randomized controlled trial (RCT) of a multispecies probiotic product in critically ill pancreatitis patients showed higher mortality in the group given the multispecies probiotic.⁵² However, additional examination of the data suggests that the observed higher mortality was due to problems with randomization for disease severity and other concerns, and not to the probiotic.⁵³ Much more frequently, probiotics have been administered orally in at-risk patient groups, including premature infants, cancer patients, and critically ill patients, with no significant increases in adverse events.^54-56

Continue to: Taken together...

Taken together, clinical trials have reported more adverse events in the placebo than probiotic group.⁴² Infection data collected in these trials have been used in subsequent analyses to demonstrate that in some settings, certain probiotics actually reduce the risk of infections. One notable example was a meta-analysis of 37 RCTs that showed that probiotics reduce the incidence of late-onset neonatal sepsis in premature infants.⁵⁷

At the present time, risk of probiotic use is low but still demands awareness, especially in unusual circumstances such as use in particularly vulnerable patients not yet studied or use of a product with limited available safety data. Any recommended product should be manufactured in compliance with applicable regulatory standards and preferably assured through voluntary quality audits.⁴⁹

Evidence of effectiveness is strong for many conditions

Probiotics have been studied for clinical benefit in numerous conditions (FIGURE^{3,8,11,15,19,23,54,58-65}), and systematic reviews of the clinical trials have found the overall results to be sufficiently strong to warrant recommendations, even though some individual trials were of low quality.⁶⁶ Some evidence may require confirmatory studies to clarify which specific product should be recommended.

Admittedly some of the indications are for diseases that most family physicians do not typically manage. For example, the evidence for probiotics for preventing necrotizing enterocolitis in premature infants was reviewed in a Cochrane analysis, which gave an estimated number needed to treat (NNT) of 41 and concluded, “our updated review of available evidence strongly supports a change in practice.”⁵⁴ A recent study of > 4500 infants in India found a probiotic/prebiotic supplement resulted in a 40% reduction in clinical sepsis compared with placebo.⁶⁷ Another common use of probiotics is as adjunctive therapy for mild to moderately active ulcerative colitis, where the current estimated NNT is 4.⁶³ Probiotics may also address gut and non-gut conditions and serve different functions throughout the lifespan.

Probiotic applications most relevant to primary care

We summarize in TABLE 1^3-32 probiotic uses supported by good evidence for indications of general interest in primary care medicine. This table includes endpoints with actionable evidence (including many strength of recommendation taxonomy [SORT] Level 1 studies) that allow us to make strong recommendations. Not all evidence is SORT Grade A, but we agree with the expert groups that deem evidence to be sufficient to warrant recommendations.

Continue to: The granular data...

The granular data we provide can help shape recommendations of a product for a specific indication. Numerous probiotics have been tested on suboptimal gastrointestinal health, including managing functional bowel symptoms ranging from occasional gas, bloating, or constipation through diagnosed irritable bowel syndrome (IBS). Supplements such as Bifidobacterium infantis subsp. longum 35624 (the probiotic in Align), Lactobacillus plantarum 299V (the probiotic in NatureMade Digestive Probiotic Daily Balance), and foods such as Activia yogurt, Yakult cultured milk, or Good Belly juice can be recommended for digestive symptoms.

Base your probiotic dosages on levels shown to be effective in clinical trials, which can be as low as 100 million CFU/d.

For patients experiencing gut symptoms unrelated to diagnosed disease, it may be reasonable for them to try a well-documented strain for 3 to 4 weeks. Currently it is difficult to predict success a priori; this may change as we learn more about how an individual’s microbiome, diet, and genetics affect response to specific probiotics. TABLE 2^68-71 presents sample recommendations from international expert panels for select contexts.

The popular press today commonly recommends consuming more fermented foods. Although we agree in general with this recommendation, physicians should be clear that fermented foods may be a source of live cultures, but not all fermented foods retain live microbes. Further, many fermented foods lack evidence documenting health effects, and therefore are not a source of probiotics. If the patient’s goal is to support regular diet with live microbes, any number of probiotic products or fermented foods that retain viable cultures may suffice. However, when patients request probiotics for specific needs, recommendations should be based on available evidence for specific studied products. (See also, “Questions patients frequently ask about probiotics.”)

Continue to: What to look for in the future

 

 

What to look for in the future

Basic research, human trials, and market development in the field of probiotics are progressing rapidly. Probiotics at this time are primarily from the genera Lactobacillus, Bifidobacterium, and Saccharomyces. But the potential of probiotics has spurred research into previously untapped microbial members of the healthy human microbiota. Microbes such as Akkermansia, Faecalibacterium, and Rosburia may comprise “next-generation probiotics” that will likely be developed as drugs.⁷²

Since the risks of using traditional probiotics are low, trial and error may be warranted at times.

Active areas of research holding some promise involve microbiome-driven components of intractable problems such as metabolic syndrome (obesity,⁷³ diabetes, and lipid dysregulation) and brain dysfunction⁷⁴ (depression, anxiety, cognition, autism). A guide to the clinical use of probiotic products available in the United States, updated yearly, may be a useful reference (but the reader may want to examine the referenced studies as their level of evidence is different than the SORT method).⁷⁵ Science-based videos, infographics, and other resources are available from the International Scientific Association for Probiotics and Prebiotics, (mentioned earlier; www.isappscience.org/).

It appears that probiotics will continue to be widely used and hopefully in a more evidence-based manner. As we learn more about individual microbiome variations, recommendations will likely be more patient specific. Probiotics that have robust evidence represent the strongest recommendations. Even so, since the risks of using traditional probiotics (such as Lactobacillus, Bifidobacterium and Saccharomyces strains) are low, trial and error may be warranted at times.

CORRESPONDENCE
Daniel J. Merenstein, MD, 4000 Reservoir Road NW, Building D 240, Washington, DC 20007; [email protected].

ACKNOWLEDGMENT
We thank Alexandra Mannerings, PhD, for preparing the FIGURE.

We are in the age of the microbiome. Both lay and scientific press proliferate messages about the importance of the microbiome to our health even while they often remain unclear on how to correct microbiota patterns associated with different diseases or suboptimal health states. Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”¹

Certain probiotics have been shown to prevent and treat specific diseases or conditions, inside or outside the gut. But the level and quality of evidence varies greatly. In addition, the health claims allowed by government regulators depend on making discrete distinctions (food vs drug, maintaining health vs treating disease, and emerging evidence vs significant scientific agreement) along dimensions that are increasingly recognized as continuous and complex.² This leads to confusion among doctors and patients about whether to trust claims on product labels and what to make of the absence of such claims.

Find out which probiotic is effective for a patient’s condition. Simply recommending that a patient “take probiotics” is not particularly helpful when the individual wants a product that will aid a specific condition. While probiotics, to date, have not been marketed as drugs in the United States, clinicians can still approach recommending them in an evidence-based manner.

In this article, we review diseases/conditions for which probiotic products have good efficacy data. We discuss probiotic efficacy and safety, offer relevant information on regulatory categories of probiotics, and give direction for proper usage based on the current evidence base. Although this review is meant to be an easy-to-use resource for clinicians, it is not a comprehensive or detailed review of the numerous probiotic products and studies currently available.

Regulatory and commercial variances with probiotics

In the United States, probiotics have been marketed as dietary supplements, medical foods, or conventional foods, all of which require different levels of evidence and types of oversight than drugs. The efficacy of some probiotics in treating or preventing certain diseases and conditions is similar to, if not better than, effects observed with traditional drug interventions (TABLE 1^3-32). However, unlike drugs, which are subject to premarket oversight, the probiotic marketplace contains products with uneven levels of evidence, from well substantiated to greatly limited. Currently, no probiotics are sold in the United States as over-the-counter or prescription drugs, although probiotic drugs will likely enter the US market eventually.

What to consider when recommending a product. When considering probiotics, remember that strain, dosage, and indication are all important. Just as we know that not all antibiotics are equally effective for all infections, so, too, effectiveness among probiotics can—and often does—vary for any given condition. Effectiveness also may vary from patient to patient. Most recommendations made in this review are tied to specific probiotic strains and doses. In some cases, more than one probiotic may be efficacious, likely due to the same or similar underlying mechanism of action. For example, most probiotics produce short-chain fatty acids in the colon, providing a common mechanism supporting digestive health.^33-35

Some probiotics are as effective as, if not better than, drugs traditionally used to treat or prevent certain diseases and conditions.

Contrary to the blanket recommendation preferring higher dosages or a greater number of strains,³⁶ our recommendations are based on levels shown to be effective in clinical trials, which in some contexts can be as low as 100 million colony-forming units (CFU) per day.^37,38 Indeed, a survey we conducted previously of retail dietary supplement products indicated that products with lower CFUs or fewer strains could more readily be linked to evidence of efficacy than multistrain, high-CFU products.³⁹

Continue to: Understanding probiotic product labels is a good start

Understanding probiotic product labels is a good start. Information shown on the label of a probiotic dietary supplement in the United States should include the genus, species, and strains contained in the product, the dose delivered in CFU (the most common measure of the number of live microbes in a probiotic product) through the end of shelf life, and expected benefits. (For help in deciphering these labels, see the label schematic developed by the International Scientific Association for Probiotics and Prebiotics⁴⁰ at https://isappscience.org/infographics/probiotic-labelling/.)

Per guidelines from the Food and Agricultural Organization of the United Nations and the World Health Organization, all probiotic products should have this type of information clearly displayed on the product packaging.⁴¹ However, some probiotic foods display less information; for example, they may not specify the product’s strains or recommended dosage levels. Product Web sites may or may not disclose details missing from the food label. The absence of such information makes it impossible to make evidence-based recommendations about those products.

Probiotics are generally safe, with caveats

The overall safety of typical probiotics (Lactobacillus species, Bifidobacterium species, and Saccharomyces cerevisiae var. boulardii) has been well documented.^42,43 Many probiotic strains have been granted Generally Recognized as Safe status for use in foods in the United States.^44,45 Many traditional probiotic species have been evaluated by the European Food Safety Authority (similar to FDA, except jurisdiction is only over foods, not drugs) and are considered safe for use in food in the European Union.

Be aware that probiotics delivered in dietary supplements and foods are intended for the general population and not for patient populations. Manufacturers therefore are not required to assure safety in vulnerable populations. Nevertheless, probiotics are often stocked in hospital formularies.^46,47 Probiotic usage in vulnerable patient groups has been considered by an expert working group from the standpoint of quality assurance for microbiologic products used to treat and prevent disease, with the experts recommending that health care professionals (including pharmacists and physicians) seek quality information from manufacturers and that manufacturers participate in programs providing third-party (eg, United States Pharmacopeia [USP] or Underwriters Laboratories [UL]) verification of probiotic products to assure products meet applicable purity standards.^48,49

Published case studies have reported that probiotics may be a rare cause of sepsis.⁴³ Recently, Lactobacillus rhamnosus GG was linked to bacteremia in 6 critically ill patients, but all cases resolved without complications.⁵⁰ Further, the death of a premature infant was linked to administration of a probiotic contaminated with an opportunistic pathogenic mold.⁵¹ A randomized controlled trial (RCT) of a multispecies probiotic product in critically ill pancreatitis patients showed higher mortality in the group given the multispecies probiotic.⁵² However, additional examination of the data suggests that the observed higher mortality was due to problems with randomization for disease severity and other concerns, and not to the probiotic.⁵³ Much more frequently, probiotics have been administered orally in at-risk patient groups, including premature infants, cancer patients, and critically ill patients, with no significant increases in adverse events.^54-56

Continue to: Taken together...

Taken together, clinical trials have reported more adverse events in the placebo than probiotic group.⁴² Infection data collected in these trials have been used in subsequent analyses to demonstrate that in some settings, certain probiotics actually reduce the risk of infections. One notable example was a meta-analysis of 37 RCTs that showed that probiotics reduce the incidence of late-onset neonatal sepsis in premature infants.⁵⁷

At the present time, risk of probiotic use is low but still demands awareness, especially in unusual circumstances such as use in particularly vulnerable patients not yet studied or use of a product with limited available safety data. Any recommended product should be manufactured in compliance with applicable regulatory standards and preferably assured through voluntary quality audits.⁴⁹

Evidence of effectiveness is strong for many conditions

Probiotics have been studied for clinical benefit in numerous conditions (FIGURE^{3,8,11,15,19,23,54,58-65}), and systematic reviews of the clinical trials have found the overall results to be sufficiently strong to warrant recommendations, even though some individual trials were of low quality.⁶⁶ Some evidence may require confirmatory studies to clarify which specific product should be recommended.

Admittedly some of the indications are for diseases that most family physicians do not typically manage. For example, the evidence for probiotics for preventing necrotizing enterocolitis in premature infants was reviewed in a Cochrane analysis, which gave an estimated number needed to treat (NNT) of 41 and concluded, “our updated review of available evidence strongly supports a change in practice.”⁵⁴ A recent study of > 4500 infants in India found a probiotic/prebiotic supplement resulted in a 40% reduction in clinical sepsis compared with placebo.⁶⁷ Another common use of probiotics is as adjunctive therapy for mild to moderately active ulcerative colitis, where the current estimated NNT is 4.⁶³ Probiotics may also address gut and non-gut conditions and serve different functions throughout the lifespan.

Probiotic applications most relevant to primary care

We summarize in TABLE 1^3-32 probiotic uses supported by good evidence for indications of general interest in primary care medicine. This table includes endpoints with actionable evidence (including many strength of recommendation taxonomy [SORT] Level 1 studies) that allow us to make strong recommendations. Not all evidence is SORT Grade A, but we agree with the expert groups that deem evidence to be sufficient to warrant recommendations.

Continue to: The granular data...

The granular data we provide can help shape recommendations of a product for a specific indication. Numerous probiotics have been tested on suboptimal gastrointestinal health, including managing functional bowel symptoms ranging from occasional gas, bloating, or constipation through diagnosed irritable bowel syndrome (IBS). Supplements such as Bifidobacterium infantis subsp. longum 35624 (the probiotic in Align), Lactobacillus plantarum 299V (the probiotic in NatureMade Digestive Probiotic Daily Balance), and foods such as Activia yogurt, Yakult cultured milk, or Good Belly juice can be recommended for digestive symptoms.

Base your probiotic dosages on levels shown to be effective in clinical trials, which can be as low as 100 million CFU/d.

For patients experiencing gut symptoms unrelated to diagnosed disease, it may be reasonable for them to try a well-documented strain for 3 to 4 weeks. Currently it is difficult to predict success a priori; this may change as we learn more about how an individual’s microbiome, diet, and genetics affect response to specific probiotics. TABLE 2^68-71 presents sample recommendations from international expert panels for select contexts.

The popular press today commonly recommends consuming more fermented foods. Although we agree in general with this recommendation, physicians should be clear that fermented foods may be a source of live cultures, but not all fermented foods retain live microbes. Further, many fermented foods lack evidence documenting health effects, and therefore are not a source of probiotics. If the patient’s goal is to support regular diet with live microbes, any number of probiotic products or fermented foods that retain viable cultures may suffice. However, when patients request probiotics for specific needs, recommendations should be based on available evidence for specific studied products. (See also, “Questions patients frequently ask about probiotics.”)

Continue to: What to look for in the future

 

 

What to look for in the future

Basic research, human trials, and market development in the field of probiotics are progressing rapidly. Probiotics at this time are primarily from the genera Lactobacillus, Bifidobacterium, and Saccharomyces. But the potential of probiotics has spurred research into previously untapped microbial members of the healthy human microbiota. Microbes such as Akkermansia, Faecalibacterium, and Rosburia may comprise “next-generation probiotics” that will likely be developed as drugs.⁷²

Since the risks of using traditional probiotics are low, trial and error may be warranted at times.

Active areas of research holding some promise involve microbiome-driven components of intractable problems such as metabolic syndrome (obesity,⁷³ diabetes, and lipid dysregulation) and brain dysfunction⁷⁴ (depression, anxiety, cognition, autism). A guide to the clinical use of probiotic products available in the United States, updated yearly, may be a useful reference (but the reader may want to examine the referenced studies as their level of evidence is different than the SORT method).⁷⁵ Science-based videos, infographics, and other resources are available from the International Scientific Association for Probiotics and Prebiotics, (mentioned earlier; www.isappscience.org/).

It appears that probiotics will continue to be widely used and hopefully in a more evidence-based manner. As we learn more about individual microbiome variations, recommendations will likely be more patient specific. Probiotics that have robust evidence represent the strongest recommendations. Even so, since the risks of using traditional probiotics (such as Lactobacillus, Bifidobacterium and Saccharomyces strains) are low, trial and error may be warranted at times.

CORRESPONDENCE
Daniel J. Merenstein, MD, 4000 Reservoir Road NW, Building D 240, Washington, DC 20007; [email protected].

ACKNOWLEDGMENT
We thank Alexandra Mannerings, PhD, for preparing the FIGURE.

We are in the age of the microbiome. Both lay and scientific press proliferate messages about the importance of the microbiome to our health even while they often remain unclear on how to correct microbiota patterns associated with different diseases or suboptimal health states. Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”¹

Certain probiotics have been shown to prevent and treat specific diseases or conditions, inside or outside the gut. But the level and quality of evidence varies greatly. In addition, the health claims allowed by government regulators depend on making discrete distinctions (food vs drug, maintaining health vs treating disease, and emerging evidence vs significant scientific agreement) along dimensions that are increasingly recognized as continuous and complex.² This leads to confusion among doctors and patients about whether to trust claims on product labels and what to make of the absence of such claims.

Find out which probiotic is effective for a patient’s condition. Simply recommending that a patient “take probiotics” is not particularly helpful when the individual wants a product that will aid a specific condition. While probiotics, to date, have not been marketed as drugs in the United States, clinicians can still approach recommending them in an evidence-based manner.

In this article, we review diseases/conditions for which probiotic products have good efficacy data. We discuss probiotic efficacy and safety, offer relevant information on regulatory categories of probiotics, and give direction for proper usage based on the current evidence base. Although this review is meant to be an easy-to-use resource for clinicians, it is not a comprehensive or detailed review of the numerous probiotic products and studies currently available.

Regulatory and commercial variances with probiotics

In the United States, probiotics have been marketed as dietary supplements, medical foods, or conventional foods, all of which require different levels of evidence and types of oversight than drugs. The efficacy of some probiotics in treating or preventing certain diseases and conditions is similar to, if not better than, effects observed with traditional drug interventions (TABLE 1^3-32). However, unlike drugs, which are subject to premarket oversight, the probiotic marketplace contains products with uneven levels of evidence, from well substantiated to greatly limited. Currently, no probiotics are sold in the United States as over-the-counter or prescription drugs, although probiotic drugs will likely enter the US market eventually.

What to consider when recommending a product. When considering probiotics, remember that strain, dosage, and indication are all important. Just as we know that not all antibiotics are equally effective for all infections, so, too, effectiveness among probiotics can—and often does—vary for any given condition. Effectiveness also may vary from patient to patient. Most recommendations made in this review are tied to specific probiotic strains and doses. In some cases, more than one probiotic may be efficacious, likely due to the same or similar underlying mechanism of action. For example, most probiotics produce short-chain fatty acids in the colon, providing a common mechanism supporting digestive health.^33-35

Some probiotics are as effective as, if not better than, drugs traditionally used to treat or prevent certain diseases and conditions.

Contrary to the blanket recommendation preferring higher dosages or a greater number of strains,³⁶ our recommendations are based on levels shown to be effective in clinical trials, which in some contexts can be as low as 100 million colony-forming units (CFU) per day.^37,38 Indeed, a survey we conducted previously of retail dietary supplement products indicated that products with lower CFUs or fewer strains could more readily be linked to evidence of efficacy than multistrain, high-CFU products.³⁹

Continue to: Understanding probiotic product labels is a good start

Understanding probiotic product labels is a good start. Information shown on the label of a probiotic dietary supplement in the United States should include the genus, species, and strains contained in the product, the dose delivered in CFU (the most common measure of the number of live microbes in a probiotic product) through the end of shelf life, and expected benefits. (For help in deciphering these labels, see the label schematic developed by the International Scientific Association for Probiotics and Prebiotics⁴⁰ at https://isappscience.org/infographics/probiotic-labelling/.)

Per guidelines from the Food and Agricultural Organization of the United Nations and the World Health Organization, all probiotic products should have this type of information clearly displayed on the product packaging.⁴¹ However, some probiotic foods display less information; for example, they may not specify the product’s strains or recommended dosage levels. Product Web sites may or may not disclose details missing from the food label. The absence of such information makes it impossible to make evidence-based recommendations about those products.

Probiotics are generally safe, with caveats

The overall safety of typical probiotics (Lactobacillus species, Bifidobacterium species, and Saccharomyces cerevisiae var. boulardii) has been well documented.^42,43 Many probiotic strains have been granted Generally Recognized as Safe status for use in foods in the United States.^44,45 Many traditional probiotic species have been evaluated by the European Food Safety Authority (similar to FDA, except jurisdiction is only over foods, not drugs) and are considered safe for use in food in the European Union.

Be aware that probiotics delivered in dietary supplements and foods are intended for the general population and not for patient populations. Manufacturers therefore are not required to assure safety in vulnerable populations. Nevertheless, probiotics are often stocked in hospital formularies.^46,47 Probiotic usage in vulnerable patient groups has been considered by an expert working group from the standpoint of quality assurance for microbiologic products used to treat and prevent disease, with the experts recommending that health care professionals (including pharmacists and physicians) seek quality information from manufacturers and that manufacturers participate in programs providing third-party (eg, United States Pharmacopeia [USP] or Underwriters Laboratories [UL]) verification of probiotic products to assure products meet applicable purity standards.^48,49

Published case studies have reported that probiotics may be a rare cause of sepsis.⁴³ Recently, Lactobacillus rhamnosus GG was linked to bacteremia in 6 critically ill patients, but all cases resolved without complications.⁵⁰ Further, the death of a premature infant was linked to administration of a probiotic contaminated with an opportunistic pathogenic mold.⁵¹ A randomized controlled trial (RCT) of a multispecies probiotic product in critically ill pancreatitis patients showed higher mortality in the group given the multispecies probiotic.⁵² However, additional examination of the data suggests that the observed higher mortality was due to problems with randomization for disease severity and other concerns, and not to the probiotic.⁵³ Much more frequently, probiotics have been administered orally in at-risk patient groups, including premature infants, cancer patients, and critically ill patients, with no significant increases in adverse events.^54-56

Continue to: Taken together...

Taken together, clinical trials have reported more adverse events in the placebo than probiotic group.⁴² Infection data collected in these trials have been used in subsequent analyses to demonstrate that in some settings, certain probiotics actually reduce the risk of infections. One notable example was a meta-analysis of 37 RCTs that showed that probiotics reduce the incidence of late-onset neonatal sepsis in premature infants.⁵⁷

At the present time, risk of probiotic use is low but still demands awareness, especially in unusual circumstances such as use in particularly vulnerable patients not yet studied or use of a product with limited available safety data. Any recommended product should be manufactured in compliance with applicable regulatory standards and preferably assured through voluntary quality audits.⁴⁹

Evidence of effectiveness is strong for many conditions

Probiotics have been studied for clinical benefit in numerous conditions (FIGURE^{3,8,11,15,19,23,54,58-65}), and systematic reviews of the clinical trials have found the overall results to be sufficiently strong to warrant recommendations, even though some individual trials were of low quality.⁶⁶ Some evidence may require confirmatory studies to clarify which specific product should be recommended.

Admittedly some of the indications are for diseases that most family physicians do not typically manage. For example, the evidence for probiotics for preventing necrotizing enterocolitis in premature infants was reviewed in a Cochrane analysis, which gave an estimated number needed to treat (NNT) of 41 and concluded, “our updated review of available evidence strongly supports a change in practice.”⁵⁴ A recent study of > 4500 infants in India found a probiotic/prebiotic supplement resulted in a 40% reduction in clinical sepsis compared with placebo.⁶⁷ Another common use of probiotics is as adjunctive therapy for mild to moderately active ulcerative colitis, where the current estimated NNT is 4.⁶³ Probiotics may also address gut and non-gut conditions and serve different functions throughout the lifespan.

Probiotic applications most relevant to primary care

We summarize in TABLE 1^3-32 probiotic uses supported by good evidence for indications of general interest in primary care medicine. This table includes endpoints with actionable evidence (including many strength of recommendation taxonomy [SORT] Level 1 studies) that allow us to make strong recommendations. Not all evidence is SORT Grade A, but we agree with the expert groups that deem evidence to be sufficient to warrant recommendations.

Continue to: The granular data...

The granular data we provide can help shape recommendations of a product for a specific indication. Numerous probiotics have been tested on suboptimal gastrointestinal health, including managing functional bowel symptoms ranging from occasional gas, bloating, or constipation through diagnosed irritable bowel syndrome (IBS). Supplements such as Bifidobacterium infantis subsp. longum 35624 (the probiotic in Align), Lactobacillus plantarum 299V (the probiotic in NatureMade Digestive Probiotic Daily Balance), and foods such as Activia yogurt, Yakult cultured milk, or Good Belly juice can be recommended for digestive symptoms.

Base your probiotic dosages on levels shown to be effective in clinical trials, which can be as low as 100 million CFU/d.

For patients experiencing gut symptoms unrelated to diagnosed disease, it may be reasonable for them to try a well-documented strain for 3 to 4 weeks. Currently it is difficult to predict success a priori; this may change as we learn more about how an individual’s microbiome, diet, and genetics affect response to specific probiotics. TABLE 2^68-71 presents sample recommendations from international expert panels for select contexts.

The popular press today commonly recommends consuming more fermented foods. Although we agree in general with this recommendation, physicians should be clear that fermented foods may be a source of live cultures, but not all fermented foods retain live microbes. Further, many fermented foods lack evidence documenting health effects, and therefore are not a source of probiotics. If the patient’s goal is to support regular diet with live microbes, any number of probiotic products or fermented foods that retain viable cultures may suffice. However, when patients request probiotics for specific needs, recommendations should be based on available evidence for specific studied products. (See also, “Questions patients frequently ask about probiotics.”)

Continue to: What to look for in the future

 

 

What to look for in the future

Basic research, human trials, and market development in the field of probiotics are progressing rapidly. Probiotics at this time are primarily from the genera Lactobacillus, Bifidobacterium, and Saccharomyces. But the potential of probiotics has spurred research into previously untapped microbial members of the healthy human microbiota. Microbes such as Akkermansia, Faecalibacterium, and Rosburia may comprise “next-generation probiotics” that will likely be developed as drugs.⁷²

Since the risks of using traditional probiotics are low, trial and error may be warranted at times.

Active areas of research holding some promise involve microbiome-driven components of intractable problems such as metabolic syndrome (obesity,⁷³ diabetes, and lipid dysregulation) and brain dysfunction⁷⁴ (depression, anxiety, cognition, autism). A guide to the clinical use of probiotic products available in the United States, updated yearly, may be a useful reference (but the reader may want to examine the referenced studies as their level of evidence is different than the SORT method).⁷⁵ Science-based videos, infographics, and other resources are available from the International Scientific Association for Probiotics and Prebiotics, (mentioned earlier; www.isappscience.org/).

It appears that probiotics will continue to be widely used and hopefully in a more evidence-based manner. As we learn more about individual microbiome variations, recommendations will likely be more patient specific. Probiotics that have robust evidence represent the strongest recommendations. Even so, since the risks of using traditional probiotics (such as Lactobacillus, Bifidobacterium and Saccharomyces strains) are low, trial and error may be warranted at times.

CORRESPONDENCE
Daniel J. Merenstein, MD, 4000 Reservoir Road NW, Building D 240, Washington, DC 20007; [email protected].

ACKNOWLEDGMENT
We thank Alexandra Mannerings, PhD, for preparing the FIGURE.

Black patients in the Washington, D.C., area face an increased risk of mortality from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), compared with nonblack patients, results from a single-center study showed.

Adam Swigost, MD, presented data on behalf of the study’s principal investigator, Helena B. Pasieka, MD, and associates at MedStar Health Georgetown University in Washington in a video presentation during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

According to the 2009-2012 Nationwide Inpatient Survey, there were 12,195 cases of SJS, 2,373 cases of SJS/TEN overlap, and 2,675 cases of TEN. In 2016, researchers led by Derek Y. Hsu, MD, of Northwestern University, Chicago, found that SJS/TEN was associated with nonwhite race, particularly Asians (odds ratio, 3.27) and blacks (OR, 2.01) (J Invest Dermatol. 2016;136[7]:1387-97).

“This led Dr. Pasieka and our team to ask the question: Are there differences in SJS/TEN outcomes in self-reported blacks in the U.S.?” said Dr. Swigost, a resident in the department of dermatology at MedStar Health Georgetown University.

To find out, he and his colleagues retrospectively analyzed records from 74 patients with SJS/TEN who were treated at Washington Hospital Center in Washington, D.C., from 2009 to 2019. They drew data from clinical diagnoses with histopathologic evaluation, when available, and performed a multivariate analysis adjusted for age, HIV status, black race, and offending drug category.

Of the 75 patients, 43 were female, 45 were black, 16 were white, 6 were Asian, 5 were Indian, 1 was Native American, and 1 was South Asian. Multivariate analysis revealed that black race was the only significant variable associated with an elevated risk of mortality from SJS/TEN (OR, 4.81; P = .04).

Of the 45 black patients in the study, 33 were HIV negative and 12 were HIV positive. “While this variable was not statistically significant, it did seem to have an elevated risk for mortality in HIV-positive patients [4 of 12; 33%], compared with 8 of 33 HIV-negative patients [25%],” Dr. Swigost said.

Next, the researchers investigated the culprit medications in the black patients. As a reference, they compared their data with a 2015 study that set out to document the clinical profile, etiologies, and outcomes of SJS and TEN in hospitals in four sub-Saharan African countries (Int J Dermatol. 2013 May;52[5]:575-9). In the 2015 study, sulfonamides were the most-used drugs (38%) followed by the antiretroviral drug nevirapine (20%) and tuberculosis drugs (6%). In the study by Dr. Swigost and colleagues, the most frequently implicated drugs were sulfonamides (24%), followed by other antibiotics (24%), and anticonvulsants (17%).

“Our patients at MedStar Washington Hospital Center are going to have different comorbidities and medical problems that dictate different medications being used in different proportions,” Dr. Swigost explained.

Delayed detection is one possible reason for the increased mortality observed in black patients. “Dermatology education on a national level is biased most commonly toward white skin,” he said. “Often, diseases can be missed in skin of color. It’s possible that the diagnoses are being delayed and so treatment is being delayed.”

Socioeconomics and access to health care could also play a role in the poor outcome we observed. “Those are variables we want to further analyze in this data,” Dr. Swigost said. “Other things to consider are genetic variations between African and American black patient populations, because in the U.S. our black population is likely more heterogeneous than African patient populations are. It’s possible that there are HLA [human leukocyte antigen] differences that are contributing. Lastly, further characterization and stratification of SJS/TEN risk factors are required.”

Dr. Swigost and Dr. Pasieka reported having no disclosures.

[email protected]

Black patients in the Washington, D.C., area face an increased risk of mortality from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), compared with nonblack patients, results from a single-center study showed.

Adam Swigost, MD, presented data on behalf of the study’s principal investigator, Helena B. Pasieka, MD, and associates at MedStar Health Georgetown University in Washington in a video presentation during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

According to the 2009-2012 Nationwide Inpatient Survey, there were 12,195 cases of SJS, 2,373 cases of SJS/TEN overlap, and 2,675 cases of TEN. In 2016, researchers led by Derek Y. Hsu, MD, of Northwestern University, Chicago, found that SJS/TEN was associated with nonwhite race, particularly Asians (odds ratio, 3.27) and blacks (OR, 2.01) (J Invest Dermatol. 2016;136[7]:1387-97).

“This led Dr. Pasieka and our team to ask the question: Are there differences in SJS/TEN outcomes in self-reported blacks in the U.S.?” said Dr. Swigost, a resident in the department of dermatology at MedStar Health Georgetown University.

To find out, he and his colleagues retrospectively analyzed records from 74 patients with SJS/TEN who were treated at Washington Hospital Center in Washington, D.C., from 2009 to 2019. They drew data from clinical diagnoses with histopathologic evaluation, when available, and performed a multivariate analysis adjusted for age, HIV status, black race, and offending drug category.

Of the 75 patients, 43 were female, 45 were black, 16 were white, 6 were Asian, 5 were Indian, 1 was Native American, and 1 was South Asian. Multivariate analysis revealed that black race was the only significant variable associated with an elevated risk of mortality from SJS/TEN (OR, 4.81; P = .04).

Of the 45 black patients in the study, 33 were HIV negative and 12 were HIV positive. “While this variable was not statistically significant, it did seem to have an elevated risk for mortality in HIV-positive patients [4 of 12; 33%], compared with 8 of 33 HIV-negative patients [25%],” Dr. Swigost said.

Next, the researchers investigated the culprit medications in the black patients. As a reference, they compared their data with a 2015 study that set out to document the clinical profile, etiologies, and outcomes of SJS and TEN in hospitals in four sub-Saharan African countries (Int J Dermatol. 2013 May;52[5]:575-9). In the 2015 study, sulfonamides were the most-used drugs (38%) followed by the antiretroviral drug nevirapine (20%) and tuberculosis drugs (6%). In the study by Dr. Swigost and colleagues, the most frequently implicated drugs were sulfonamides (24%), followed by other antibiotics (24%), and anticonvulsants (17%).

“Our patients at MedStar Washington Hospital Center are going to have different comorbidities and medical problems that dictate different medications being used in different proportions,” Dr. Swigost explained.

Delayed detection is one possible reason for the increased mortality observed in black patients. “Dermatology education on a national level is biased most commonly toward white skin,” he said. “Often, diseases can be missed in skin of color. It’s possible that the diagnoses are being delayed and so treatment is being delayed.”

Socioeconomics and access to health care could also play a role in the poor outcome we observed. “Those are variables we want to further analyze in this data,” Dr. Swigost said. “Other things to consider are genetic variations between African and American black patient populations, because in the U.S. our black population is likely more heterogeneous than African patient populations are. It’s possible that there are HLA [human leukocyte antigen] differences that are contributing. Lastly, further characterization and stratification of SJS/TEN risk factors are required.”

Dr. Swigost and Dr. Pasieka reported having no disclosures.

[email protected]

Black patients in the Washington, D.C., area face an increased risk of mortality from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), compared with nonblack patients, results from a single-center study showed.

Adam Swigost, MD, presented data on behalf of the study’s principal investigator, Helena B. Pasieka, MD, and associates at MedStar Health Georgetown University in Washington in a video presentation during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.

According to the 2009-2012 Nationwide Inpatient Survey, there were 12,195 cases of SJS, 2,373 cases of SJS/TEN overlap, and 2,675 cases of TEN. In 2016, researchers led by Derek Y. Hsu, MD, of Northwestern University, Chicago, found that SJS/TEN was associated with nonwhite race, particularly Asians (odds ratio, 3.27) and blacks (OR, 2.01) (J Invest Dermatol. 2016;136[7]:1387-97).

“This led Dr. Pasieka and our team to ask the question: Are there differences in SJS/TEN outcomes in self-reported blacks in the U.S.?” said Dr. Swigost, a resident in the department of dermatology at MedStar Health Georgetown University.

To find out, he and his colleagues retrospectively analyzed records from 74 patients with SJS/TEN who were treated at Washington Hospital Center in Washington, D.C., from 2009 to 2019. They drew data from clinical diagnoses with histopathologic evaluation, when available, and performed a multivariate analysis adjusted for age, HIV status, black race, and offending drug category.

Of the 75 patients, 43 were female, 45 were black, 16 were white, 6 were Asian, 5 were Indian, 1 was Native American, and 1 was South Asian. Multivariate analysis revealed that black race was the only significant variable associated with an elevated risk of mortality from SJS/TEN (OR, 4.81; P = .04).

Of the 45 black patients in the study, 33 were HIV negative and 12 were HIV positive. “While this variable was not statistically significant, it did seem to have an elevated risk for mortality in HIV-positive patients [4 of 12; 33%], compared with 8 of 33 HIV-negative patients [25%],” Dr. Swigost said.

Next, the researchers investigated the culprit medications in the black patients. As a reference, they compared their data with a 2015 study that set out to document the clinical profile, etiologies, and outcomes of SJS and TEN in hospitals in four sub-Saharan African countries (Int J Dermatol. 2013 May;52[5]:575-9). In the 2015 study, sulfonamides were the most-used drugs (38%) followed by the antiretroviral drug nevirapine (20%) and tuberculosis drugs (6%). In the study by Dr. Swigost and colleagues, the most frequently implicated drugs were sulfonamides (24%), followed by other antibiotics (24%), and anticonvulsants (17%).

“Our patients at MedStar Washington Hospital Center are going to have different comorbidities and medical problems that dictate different medications being used in different proportions,” Dr. Swigost explained.

Delayed detection is one possible reason for the increased mortality observed in black patients. “Dermatology education on a national level is biased most commonly toward white skin,” he said. “Often, diseases can be missed in skin of color. It’s possible that the diagnoses are being delayed and so treatment is being delayed.”

Socioeconomics and access to health care could also play a role in the poor outcome we observed. “Those are variables we want to further analyze in this data,” Dr. Swigost said. “Other things to consider are genetic variations between African and American black patient populations, because in the U.S. our black population is likely more heterogeneous than African patient populations are. It’s possible that there are HLA [human leukocyte antigen] differences that are contributing. Lastly, further characterization and stratification of SJS/TEN risk factors are required.”

Dr. Swigost and Dr. Pasieka reported having no disclosures.

[email protected]

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

[email protected]

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

[email protected]

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

[email protected]

THE CASE

Emily L* is a 20-year-old woman who, on the advice of her college counselor, has made an office appointment to discuss her difficulty in keeping up with college classes. She achieved good grades in high school but is now struggling to deal with the quantity of reading in her courses. She was often able to complete assignments the night before the due date in high school, but this strategy is no longer working. She is having some doubt about her abilities, and is feeling overwhelmed, but is able to enjoy activities with friends. Her college counselor suggested she see her doctor for an assessment of her attention problems.

Ms. L’s family physician interviewed her and, aided by parental input, was able to identify a pattern of disorganized and impulsive behavior that was present even in grade school. Mood disorders and substance abuse were ruled out from the interview and lab testing, and cognitive ability was confirmed through a review of school testing.

● HOW WOULD YOU PROCEED WITH THIS PATIENT?

* The patient’s name has been changed to protect her identity.

Attention-deficit/hyperactivity disorder (ADHD) is classified as a neurodevelopmental disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), its hallmarks being inattentive, hyperactive, or impulsive behaviors that affect functioning or development.¹ ­Historically, it was thought that ADHD was a disorder of children and adolescents, and that patients “grew out” of their behaviors once adulthood was reached. It is now estimated that 50% of children with ADHD will carry the diagnosis into adulthood,² resulting in a prevalence of 5.9% to 7.1% for children³ and 3.4% for adults.⁴ There are 3 presentations of ADHD, known as ADHD-I (inattentive), ADHD-HI (hyperactive-impulsive), and ADHD-C (combined). The inattentive type accounts for 47% of adult cases, and adult ADHD disproportionately affects males compared with females.²

ADHD is a powerful risk factor for future substance use.

An overall pattern of underachievement and variable performance is common throughout life in patients with ADHD. Adults are much more likely to report subtle impairments in higher executive functions such as organization, time management, and modulating emotions. Consequences include poor performance at work, attendance issues, difficulty with social interactions, and an increased likelihood of unemployment.⁵ Among those employed, there is a large disparity in income compared with counterparts without ADHD.⁶ Increased risk of substance use, injury, and traffic accidents also has been reported.¹

Disorders that can mimic or coexist with ADHD

The differential diagnosis for ADHD is wide, and comorbidity with other disorders is common.

Continue to: Bipolar disorder

Bipolar disorder shares with ADHD the core symptoms of hyperactivity, impulsive behavior, and difficulty completing tasks. Mania and ADHD can look very similar if symptoms are observed at a single point in time. Bipolar illness is, by definition, episodic and fluctuating, while ADHD is much more constant. In addition, bipolar illness exhibits significant variation in mood, while ADHD may or may not be associated with impaired mood regulation. Up to 20% of patients with bipolar illness also have ADHD.⁷

Anxiety and depressive disorders can also share symptoms with ADHD-I. These include distractibility, poor concentration, and, in the case of anxiety, rapid changes in train of thought. Sleep disturbance, past trauma, and current acute stressors may manifest as clinical anxiety or depression, or may interfere with concentration and attention independently. As with bipolar illness, clinicians must look carefully at the time course of symptoms, including the age of onset. Classically, mood disorders develop in adolescence or early adulthood, while ADHD always has manifestations in childhood. Inattention and distractibility will track with mood if they are caused by an affective illness, but will remain in ADHD even when the patient is euthymic. On the other hand, patients with ADHD frequently become frustrated or overwhelmed as a result of their difficulties with task completion and social function, a presentation which can mimic anxiety or depression.⁸

Substance use disorder and ADHD interact in multiple ways and can present one of the more challenging diagnostic tasks when assessing a patient with impaired attention or concentration. ADHD is a powerful risk factor for future substance use,⁹ while substance use can impair attention, induce impulsivity, and alter concentration. Further, the treatment of choice for ADHD (stimulant medication) has the potential for misuse. The presence of continuous symptoms across settings is crucial in determining the proper diagnosis of ADHD.

Other conditions. Patients with a learning disability can be inattentive due to their cognitive limitations, or it may be comorbid with ADHD. If an intellectual deficit is suspected, referral for cognitive testing can help clarify the diagnosis. Autism also may cause significant alterations in attention with both hyper-focus and distractibility being common, as they are in ADHD. Intermittent explosive disorder shares the core symptom of impulsivity, but includes aggression, which is not always seen in ADHD. Personality disorders (eg, borderline, narcissistic) may also be difficult to distinguish from ADHD. The key to differentiation is the identification of behavior patterns outside the realms of concentration and attention.⁷

KEY DIAGNOSTIC CRITERIA

The diagnostic criteria for ADHD defined in DSM-5 are found in TABLE 1.¹ Individuals ≥ 17 years old must meet 5 of 9 characteristics of inattention or 5 of 9 characteristics of hyperactivity/impulsivity (criterion A).¹ Some symptoms must have been present prior to age 12 (criterion B). This cutoff is an increase from age 7 advised in DSM-IV.¹⁰ Symptoms must occur across at least 2 settings (criterion C) and significantly interfere with social, academic, or occupational functioning (criterion D). Exclusions include symptoms that occur exclusively in the context of a psychotic disorder or symptoms that are better explained in the context of other mental disorders (criterion E).¹

Continue to: In the primary care setting

In the primary care setting, an assessment for ADHD should, at minimum, involve a review of the patient’s academic and work history, assessment of psychiatric comorbidities and substance use history, and administration of appropriate rating scales. When evaluating adults, these tools include the Adult ADHD Self-Report Scale (ASRS)^11,12 screening tool and the Diagnostic Interview for ADHD in adults (DIVA-5).^13,14 If possible, obtain scale assessments not only from the patient but from family members or other observers who can provide information about the patient in childhood/adolescence and present day.

In an integrated care setting, consider involving a behavioral health consultant for a more comprehensive evaluation of educational, employment, driving, and relationship histories. Historical record review may include report cards from elementary school through high school, standardized test scores, psycho-educational and individual education plan reports, and medical records. Having a snapshot of the patient as a younger child, adolescent, and young adult can help to identify overall patterns of academic underachievement and reveal gaps between potential and overall achievement and performance. Pursue a more thorough evaluation in cases where other comorbid psychiatric disorders are present or when the patient is unfamiliar to you.

TWO GROUPS OF TREATMENT OPTIONS

The treatment of ADHD in adults (and children) can be broadly divided into pharmacologic and nonpharmacologic modalities.

Stimulants are first-line pharmacologic treatment for ADHD in patients with low risk for misuse. Stimulants improve cognitive function, decrease impulsivity, and increase alertness.¹⁵ However, these effects are not exclusive to those with ADHD, and response does not aid in diagnosis. No stimulant is preferred over another, although individuals may respond better to 1 specific agent than to others. Be aware that stimulants may be diverted; patients at increased risk include those with comorbid substance use or mood disorders. Misuse may be especially common on college campuses, where nonprescribed stimulants may be used as study aids or recreationally.

Up to 20% of patients with bipolar illness also have ADHD.

Stimulants come in a variety of formulations that differ primarily in their time profile or mode of delivery. Some preparations (eg, Ritalin LA and Adderall XR) contain a mixture of immediate-release and extended-release mechanisms and therefore have bimodal peaks. Others (eg, Concerta) use an osmotic system to approximate a steadier flow of drug delivery. However, as these drugs have entered the generic market, time response between products is much less predictable. Individual differences in metabolism may also alter duration of action.

Continue to: Lisdexamfetamine (Vyvanse)...

Lisdexamfetamine (Vyvanse) is a pro-drug that requires first-pass metabolism for conversion to an active drug. This may reduce risk of overdose or misuse. Adverse effects of stimulants include decreased appetite, irritability, tics, and cardiac toxicity.¹⁶ Proper titration of dose over successive visits is essential as providers often must balance efficacy, appetite, and sleep.

Nonstimulant therapies are options for patients who cannot tolerate stimulants or are at high risk for misuse. Atomoxetine, a norepinephrine reuptake inhibitor, has qualities that may resemble antidepressants in its 2- to 4-week time lapse before taking effect. Alpha-2 agonists clonidine and guanfacine are approved by the US Food and Drug Administration in their extended release forms for adjunct therapy with stimulants. Pharmacologic therapies are listed in TABLE 2.¹⁶

Nonpharmacologic modalities for adult ADHD include psychoeducation, cognitive behavioral therapy, and work environment modification. While coordination with schools is recognized as an essential aspect of the care of ADHD in children, team care in the treatment of adults with ADHD is often forgotten. Referral for occupational or educational support, written materials on study habits and organizational skills, and the use of memory tools can be very helpful. Modifications in physical environment and time constraints in both work and school settings can enhance productivity in adults with ADHD. Attention to sleep scheduling and sleep hygiene can also improve attention and concentration throughout the day.

CASE

The clinical impression of ADHD-I was confirmed by Ms. L’s score on the ASRS. She was prescribed a long-acting formulation of methylphenidate, starting at a dose of 27 mg/d in the morning and eventually titrated to 54 mg/d. She received psychoeducation in ADHD and learned strategies to reduce distractions in her school and home study environments.

Misuse may be especially common on college campuses, where nonprescribed stimulants may be used recreationally, or as study aids.

She engaged with the education specialists at her school, who helped her discuss testing and assignment modifications with her professors. She began to develop a time-management strategy to complete her assignments; these included reduced evening caffeine intake and improved sleep hygiene. Over time, Ms. L was able to maintain attention for the more extended homework tasks assigned in college. She was also able to enjoy a similar level of success that she had achieved in high school.

CORRESPONDENCE
Jay Brieler, MD, Family and Community Medicine, Saint Louis University School of Medicine, 6420 Clayton Road, Room 2234, St. Louis MO 63117; [email protected].

THE CASE

Emily L* is a 20-year-old woman who, on the advice of her college counselor, has made an office appointment to discuss her difficulty in keeping up with college classes. She achieved good grades in high school but is now struggling to deal with the quantity of reading in her courses. She was often able to complete assignments the night before the due date in high school, but this strategy is no longer working. She is having some doubt about her abilities, and is feeling overwhelmed, but is able to enjoy activities with friends. Her college counselor suggested she see her doctor for an assessment of her attention problems.

Ms. L’s family physician interviewed her and, aided by parental input, was able to identify a pattern of disorganized and impulsive behavior that was present even in grade school. Mood disorders and substance abuse were ruled out from the interview and lab testing, and cognitive ability was confirmed through a review of school testing.

● HOW WOULD YOU PROCEED WITH THIS PATIENT?

* The patient’s name has been changed to protect her identity.

Attention-deficit/hyperactivity disorder (ADHD) is classified as a neurodevelopmental disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), its hallmarks being inattentive, hyperactive, or impulsive behaviors that affect functioning or development.¹ ­Historically, it was thought that ADHD was a disorder of children and adolescents, and that patients “grew out” of their behaviors once adulthood was reached. It is now estimated that 50% of children with ADHD will carry the diagnosis into adulthood,² resulting in a prevalence of 5.9% to 7.1% for children³ and 3.4% for adults.⁴ There are 3 presentations of ADHD, known as ADHD-I (inattentive), ADHD-HI (hyperactive-impulsive), and ADHD-C (combined). The inattentive type accounts for 47% of adult cases, and adult ADHD disproportionately affects males compared with females.²

ADHD is a powerful risk factor for future substance use.

An overall pattern of underachievement and variable performance is common throughout life in patients with ADHD. Adults are much more likely to report subtle impairments in higher executive functions such as organization, time management, and modulating emotions. Consequences include poor performance at work, attendance issues, difficulty with social interactions, and an increased likelihood of unemployment.⁵ Among those employed, there is a large disparity in income compared with counterparts without ADHD.⁶ Increased risk of substance use, injury, and traffic accidents also has been reported.¹

Disorders that can mimic or coexist with ADHD

The differential diagnosis for ADHD is wide, and comorbidity with other disorders is common.

Continue to: Bipolar disorder

Bipolar disorder shares with ADHD the core symptoms of hyperactivity, impulsive behavior, and difficulty completing tasks. Mania and ADHD can look very similar if symptoms are observed at a single point in time. Bipolar illness is, by definition, episodic and fluctuating, while ADHD is much more constant. In addition, bipolar illness exhibits significant variation in mood, while ADHD may or may not be associated with impaired mood regulation. Up to 20% of patients with bipolar illness also have ADHD.⁷

Anxiety and depressive disorders can also share symptoms with ADHD-I. These include distractibility, poor concentration, and, in the case of anxiety, rapid changes in train of thought. Sleep disturbance, past trauma, and current acute stressors may manifest as clinical anxiety or depression, or may interfere with concentration and attention independently. As with bipolar illness, clinicians must look carefully at the time course of symptoms, including the age of onset. Classically, mood disorders develop in adolescence or early adulthood, while ADHD always has manifestations in childhood. Inattention and distractibility will track with mood if they are caused by an affective illness, but will remain in ADHD even when the patient is euthymic. On the other hand, patients with ADHD frequently become frustrated or overwhelmed as a result of their difficulties with task completion and social function, a presentation which can mimic anxiety or depression.⁸

Substance use disorder and ADHD interact in multiple ways and can present one of the more challenging diagnostic tasks when assessing a patient with impaired attention or concentration. ADHD is a powerful risk factor for future substance use,⁹ while substance use can impair attention, induce impulsivity, and alter concentration. Further, the treatment of choice for ADHD (stimulant medication) has the potential for misuse. The presence of continuous symptoms across settings is crucial in determining the proper diagnosis of ADHD.

Other conditions. Patients with a learning disability can be inattentive due to their cognitive limitations, or it may be comorbid with ADHD. If an intellectual deficit is suspected, referral for cognitive testing can help clarify the diagnosis. Autism also may cause significant alterations in attention with both hyper-focus and distractibility being common, as they are in ADHD. Intermittent explosive disorder shares the core symptom of impulsivity, but includes aggression, which is not always seen in ADHD. Personality disorders (eg, borderline, narcissistic) may also be difficult to distinguish from ADHD. The key to differentiation is the identification of behavior patterns outside the realms of concentration and attention.⁷

KEY DIAGNOSTIC CRITERIA

The diagnostic criteria for ADHD defined in DSM-5 are found in TABLE 1.¹ Individuals ≥ 17 years old must meet 5 of 9 characteristics of inattention or 5 of 9 characteristics of hyperactivity/impulsivity (criterion A).¹ Some symptoms must have been present prior to age 12 (criterion B). This cutoff is an increase from age 7 advised in DSM-IV.¹⁰ Symptoms must occur across at least 2 settings (criterion C) and significantly interfere with social, academic, or occupational functioning (criterion D). Exclusions include symptoms that occur exclusively in the context of a psychotic disorder or symptoms that are better explained in the context of other mental disorders (criterion E).¹

Continue to: In the primary care setting

In the primary care setting, an assessment for ADHD should, at minimum, involve a review of the patient’s academic and work history, assessment of psychiatric comorbidities and substance use history, and administration of appropriate rating scales. When evaluating adults, these tools include the Adult ADHD Self-Report Scale (ASRS)^11,12 screening tool and the Diagnostic Interview for ADHD in adults (DIVA-5).^13,14 If possible, obtain scale assessments not only from the patient but from family members or other observers who can provide information about the patient in childhood/adolescence and present day.

In an integrated care setting, consider involving a behavioral health consultant for a more comprehensive evaluation of educational, employment, driving, and relationship histories. Historical record review may include report cards from elementary school through high school, standardized test scores, psycho-educational and individual education plan reports, and medical records. Having a snapshot of the patient as a younger child, adolescent, and young adult can help to identify overall patterns of academic underachievement and reveal gaps between potential and overall achievement and performance. Pursue a more thorough evaluation in cases where other comorbid psychiatric disorders are present or when the patient is unfamiliar to you.

TWO GROUPS OF TREATMENT OPTIONS

The treatment of ADHD in adults (and children) can be broadly divided into pharmacologic and nonpharmacologic modalities.

Stimulants are first-line pharmacologic treatment for ADHD in patients with low risk for misuse. Stimulants improve cognitive function, decrease impulsivity, and increase alertness.¹⁵ However, these effects are not exclusive to those with ADHD, and response does not aid in diagnosis. No stimulant is preferred over another, although individuals may respond better to 1 specific agent than to others. Be aware that stimulants may be diverted; patients at increased risk include those with comorbid substance use or mood disorders. Misuse may be especially common on college campuses, where nonprescribed stimulants may be used as study aids or recreationally.

Up to 20% of patients with bipolar illness also have ADHD.

Stimulants come in a variety of formulations that differ primarily in their time profile or mode of delivery. Some preparations (eg, Ritalin LA and Adderall XR) contain a mixture of immediate-release and extended-release mechanisms and therefore have bimodal peaks. Others (eg, Concerta) use an osmotic system to approximate a steadier flow of drug delivery. However, as these drugs have entered the generic market, time response between products is much less predictable. Individual differences in metabolism may also alter duration of action.

Continue to: Lisdexamfetamine (Vyvanse)...

Lisdexamfetamine (Vyvanse) is a pro-drug that requires first-pass metabolism for conversion to an active drug. This may reduce risk of overdose or misuse. Adverse effects of stimulants include decreased appetite, irritability, tics, and cardiac toxicity.¹⁶ Proper titration of dose over successive visits is essential as providers often must balance efficacy, appetite, and sleep.

Nonstimulant therapies are options for patients who cannot tolerate stimulants or are at high risk for misuse. Atomoxetine, a norepinephrine reuptake inhibitor, has qualities that may resemble antidepressants in its 2- to 4-week time lapse before taking effect. Alpha-2 agonists clonidine and guanfacine are approved by the US Food and Drug Administration in their extended release forms for adjunct therapy with stimulants. Pharmacologic therapies are listed in TABLE 2.¹⁶

Nonpharmacologic modalities for adult ADHD include psychoeducation, cognitive behavioral therapy, and work environment modification. While coordination with schools is recognized as an essential aspect of the care of ADHD in children, team care in the treatment of adults with ADHD is often forgotten. Referral for occupational or educational support, written materials on study habits and organizational skills, and the use of memory tools can be very helpful. Modifications in physical environment and time constraints in both work and school settings can enhance productivity in adults with ADHD. Attention to sleep scheduling and sleep hygiene can also improve attention and concentration throughout the day.

CASE

The clinical impression of ADHD-I was confirmed by Ms. L’s score on the ASRS. She was prescribed a long-acting formulation of methylphenidate, starting at a dose of 27 mg/d in the morning and eventually titrated to 54 mg/d. She received psychoeducation in ADHD and learned strategies to reduce distractions in her school and home study environments.

Misuse may be especially common on college campuses, where nonprescribed stimulants may be used recreationally, or as study aids.

She engaged with the education specialists at her school, who helped her discuss testing and assignment modifications with her professors. She began to develop a time-management strategy to complete her assignments; these included reduced evening caffeine intake and improved sleep hygiene. Over time, Ms. L was able to maintain attention for the more extended homework tasks assigned in college. She was also able to enjoy a similar level of success that she had achieved in high school.

CORRESPONDENCE
Jay Brieler, MD, Family and Community Medicine, Saint Louis University School of Medicine, 6420 Clayton Road, Room 2234, St. Louis MO 63117; [email protected].

THE CASE

Emily L* is a 20-year-old woman who, on the advice of her college counselor, has made an office appointment to discuss her difficulty in keeping up with college classes. She achieved good grades in high school but is now struggling to deal with the quantity of reading in her courses. She was often able to complete assignments the night before the due date in high school, but this strategy is no longer working. She is having some doubt about her abilities, and is feeling overwhelmed, but is able to enjoy activities with friends. Her college counselor suggested she see her doctor for an assessment of her attention problems.

Ms. L’s family physician interviewed her and, aided by parental input, was able to identify a pattern of disorganized and impulsive behavior that was present even in grade school. Mood disorders and substance abuse were ruled out from the interview and lab testing, and cognitive ability was confirmed through a review of school testing.

● HOW WOULD YOU PROCEED WITH THIS PATIENT?

* The patient’s name has been changed to protect her identity.

Attention-deficit/hyperactivity disorder (ADHD) is classified as a neurodevelopmental disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), its hallmarks being inattentive, hyperactive, or impulsive behaviors that affect functioning or development.¹ ­Historically, it was thought that ADHD was a disorder of children and adolescents, and that patients “grew out” of their behaviors once adulthood was reached. It is now estimated that 50% of children with ADHD will carry the diagnosis into adulthood,² resulting in a prevalence of 5.9% to 7.1% for children³ and 3.4% for adults.⁴ There are 3 presentations of ADHD, known as ADHD-I (inattentive), ADHD-HI (hyperactive-impulsive), and ADHD-C (combined). The inattentive type accounts for 47% of adult cases, and adult ADHD disproportionately affects males compared with females.²

ADHD is a powerful risk factor for future substance use.

An overall pattern of underachievement and variable performance is common throughout life in patients with ADHD. Adults are much more likely to report subtle impairments in higher executive functions such as organization, time management, and modulating emotions. Consequences include poor performance at work, attendance issues, difficulty with social interactions, and an increased likelihood of unemployment.⁵ Among those employed, there is a large disparity in income compared with counterparts without ADHD.⁶ Increased risk of substance use, injury, and traffic accidents also has been reported.¹

Disorders that can mimic or coexist with ADHD

The differential diagnosis for ADHD is wide, and comorbidity with other disorders is common.

Continue to: Bipolar disorder

Bipolar disorder shares with ADHD the core symptoms of hyperactivity, impulsive behavior, and difficulty completing tasks. Mania and ADHD can look very similar if symptoms are observed at a single point in time. Bipolar illness is, by definition, episodic and fluctuating, while ADHD is much more constant. In addition, bipolar illness exhibits significant variation in mood, while ADHD may or may not be associated with impaired mood regulation. Up to 20% of patients with bipolar illness also have ADHD.⁷

Anxiety and depressive disorders can also share symptoms with ADHD-I. These include distractibility, poor concentration, and, in the case of anxiety, rapid changes in train of thought. Sleep disturbance, past trauma, and current acute stressors may manifest as clinical anxiety or depression, or may interfere with concentration and attention independently. As with bipolar illness, clinicians must look carefully at the time course of symptoms, including the age of onset. Classically, mood disorders develop in adolescence or early adulthood, while ADHD always has manifestations in childhood. Inattention and distractibility will track with mood if they are caused by an affective illness, but will remain in ADHD even when the patient is euthymic. On the other hand, patients with ADHD frequently become frustrated or overwhelmed as a result of their difficulties with task completion and social function, a presentation which can mimic anxiety or depression.⁸

Substance use disorder and ADHD interact in multiple ways and can present one of the more challenging diagnostic tasks when assessing a patient with impaired attention or concentration. ADHD is a powerful risk factor for future substance use,⁹ while substance use can impair attention, induce impulsivity, and alter concentration. Further, the treatment of choice for ADHD (stimulant medication) has the potential for misuse. The presence of continuous symptoms across settings is crucial in determining the proper diagnosis of ADHD.

Other conditions. Patients with a learning disability can be inattentive due to their cognitive limitations, or it may be comorbid with ADHD. If an intellectual deficit is suspected, referral for cognitive testing can help clarify the diagnosis. Autism also may cause significant alterations in attention with both hyper-focus and distractibility being common, as they are in ADHD. Intermittent explosive disorder shares the core symptom of impulsivity, but includes aggression, which is not always seen in ADHD. Personality disorders (eg, borderline, narcissistic) may also be difficult to distinguish from ADHD. The key to differentiation is the identification of behavior patterns outside the realms of concentration and attention.⁷

KEY DIAGNOSTIC CRITERIA

The diagnostic criteria for ADHD defined in DSM-5 are found in TABLE 1.¹ Individuals ≥ 17 years old must meet 5 of 9 characteristics of inattention or 5 of 9 characteristics of hyperactivity/impulsivity (criterion A).¹ Some symptoms must have been present prior to age 12 (criterion B). This cutoff is an increase from age 7 advised in DSM-IV.¹⁰ Symptoms must occur across at least 2 settings (criterion C) and significantly interfere with social, academic, or occupational functioning (criterion D). Exclusions include symptoms that occur exclusively in the context of a psychotic disorder or symptoms that are better explained in the context of other mental disorders (criterion E).¹

Continue to: In the primary care setting

In the primary care setting, an assessment for ADHD should, at minimum, involve a review of the patient’s academic and work history, assessment of psychiatric comorbidities and substance use history, and administration of appropriate rating scales. When evaluating adults, these tools include the Adult ADHD Self-Report Scale (ASRS)^11,12 screening tool and the Diagnostic Interview for ADHD in adults (DIVA-5).^13,14 If possible, obtain scale assessments not only from the patient but from family members or other observers who can provide information about the patient in childhood/adolescence and present day.

In an integrated care setting, consider involving a behavioral health consultant for a more comprehensive evaluation of educational, employment, driving, and relationship histories. Historical record review may include report cards from elementary school through high school, standardized test scores, psycho-educational and individual education plan reports, and medical records. Having a snapshot of the patient as a younger child, adolescent, and young adult can help to identify overall patterns of academic underachievement and reveal gaps between potential and overall achievement and performance. Pursue a more thorough evaluation in cases where other comorbid psychiatric disorders are present or when the patient is unfamiliar to you.

TWO GROUPS OF TREATMENT OPTIONS

The treatment of ADHD in adults (and children) can be broadly divided into pharmacologic and nonpharmacologic modalities.

Stimulants are first-line pharmacologic treatment for ADHD in patients with low risk for misuse. Stimulants improve cognitive function, decrease impulsivity, and increase alertness.¹⁵ However, these effects are not exclusive to those with ADHD, and response does not aid in diagnosis. No stimulant is preferred over another, although individuals may respond better to 1 specific agent than to others. Be aware that stimulants may be diverted; patients at increased risk include those with comorbid substance use or mood disorders. Misuse may be especially common on college campuses, where nonprescribed stimulants may be used as study aids or recreationally.

Up to 20% of patients with bipolar illness also have ADHD.

Stimulants come in a variety of formulations that differ primarily in their time profile or mode of delivery. Some preparations (eg, Ritalin LA and Adderall XR) contain a mixture of immediate-release and extended-release mechanisms and therefore have bimodal peaks. Others (eg, Concerta) use an osmotic system to approximate a steadier flow of drug delivery. However, as these drugs have entered the generic market, time response between products is much less predictable. Individual differences in metabolism may also alter duration of action.

Continue to: Lisdexamfetamine (Vyvanse)...

Lisdexamfetamine (Vyvanse) is a pro-drug that requires first-pass metabolism for conversion to an active drug. This may reduce risk of overdose or misuse. Adverse effects of stimulants include decreased appetite, irritability, tics, and cardiac toxicity.¹⁶ Proper titration of dose over successive visits is essential as providers often must balance efficacy, appetite, and sleep.

Nonstimulant therapies are options for patients who cannot tolerate stimulants or are at high risk for misuse. Atomoxetine, a norepinephrine reuptake inhibitor, has qualities that may resemble antidepressants in its 2- to 4-week time lapse before taking effect. Alpha-2 agonists clonidine and guanfacine are approved by the US Food and Drug Administration in their extended release forms for adjunct therapy with stimulants. Pharmacologic therapies are listed in TABLE 2.¹⁶

Nonpharmacologic modalities for adult ADHD include psychoeducation, cognitive behavioral therapy, and work environment modification. While coordination with schools is recognized as an essential aspect of the care of ADHD in children, team care in the treatment of adults with ADHD is often forgotten. Referral for occupational or educational support, written materials on study habits and organizational skills, and the use of memory tools can be very helpful. Modifications in physical environment and time constraints in both work and school settings can enhance productivity in adults with ADHD. Attention to sleep scheduling and sleep hygiene can also improve attention and concentration throughout the day.

CASE

The clinical impression of ADHD-I was confirmed by Ms. L’s score on the ASRS. She was prescribed a long-acting formulation of methylphenidate, starting at a dose of 27 mg/d in the morning and eventually titrated to 54 mg/d. She received psychoeducation in ADHD and learned strategies to reduce distractions in her school and home study environments.

Misuse may be especially common on college campuses, where nonprescribed stimulants may be used recreationally, or as study aids.

She engaged with the education specialists at her school, who helped her discuss testing and assignment modifications with her professors. She began to develop a time-management strategy to complete her assignments; these included reduced evening caffeine intake and improved sleep hygiene. Over time, Ms. L was able to maintain attention for the more extended homework tasks assigned in college. She was also able to enjoy a similar level of success that she had achieved in high school.

CORRESPONDENCE
Jay Brieler, MD, Family and Community Medicine, Saint Louis University School of Medicine, 6420 Clayton Road, Room 2234, St. Louis MO 63117; [email protected].

For the first time since detailed measurement began in 2000, there was no significant difference in autism prevalence between black and white 8-year-olds in 2016, according to data from the Centers for Disease Control and Prevention.

MDedge News

The latest analysis from the CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network puts the prevalence of autism spectrum disorder (ASD) at 18.3 per 1,000 children aged 8 years among black children and 18.5 per 1,000 in white children, Matthew J. Maenner, PhD, and associates said in MMWR Surveillance Summaries. Overall prevalence was 18.5 per 1,000 children, or 1 in 54 children, aged 8 years.

“This diminishing disparity in ASD prevalence might signify progress toward earlier and more equitable identification of ASD,” they wrote, while also noting that “black children with ASD were more likely than white children to have an intellectual disability” and were less likely to undergo evaluation by age 36 months.

Among non-Hispanic white children, 45.3% had received a comprehensive evaluation for ASD before the age of 36 months, compared with 39.8% of non-Hispanic black children and 42.9% of Hispanic children, said Dr. Maenner of the CDC’s National Center on Birth Defects and Developmental Disabilities.

The overall rate of early evaluation was 44% for the cohort of 3,981 children who were born in 2008 and included in the 2016 analysis of the 11 ADDM Network sites, they reported.

There was, however, considerable variation in the timing of that initial evaluation for ASD among the sites, which largely consisted of one to seven counties in most states, except for Arkansas (all 75 counties), Tennessee (11 counties), and Wisconsin (10 counties), Dr. Maenner and associates noted.

The two ADDM Network sites at the extremes of that variation were North Carolina and Arkansas. In North Carolina, almost twice as many children (62.3%) had an evaluation by 36 months than in Arkansas (32.6%), although Arkansas closed the gap a bit by evaluating 21.8% of children aged 37-48 months, compared with 11.3% in North Carolina, the investigators said.

“ASD continues to be a public health concern; the latest data from the ADDM Network underscore the ongoing need for timely and accessible developmental assessments, educational supports, and services for persons with ASD and their families,” they concluded.

[email protected]

SOURCE: Maenner MJ et al. MMWR Surveill Summ. 2020 Mar 27;69(SS-4):1-12.

For the first time since detailed measurement began in 2000, there was no significant difference in autism prevalence between black and white 8-year-olds in 2016, according to data from the Centers for Disease Control and Prevention.

MDedge News

The latest analysis from the CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network puts the prevalence of autism spectrum disorder (ASD) at 18.3 per 1,000 children aged 8 years among black children and 18.5 per 1,000 in white children, Matthew J. Maenner, PhD, and associates said in MMWR Surveillance Summaries. Overall prevalence was 18.5 per 1,000 children, or 1 in 54 children, aged 8 years.

“This diminishing disparity in ASD prevalence might signify progress toward earlier and more equitable identification of ASD,” they wrote, while also noting that “black children with ASD were more likely than white children to have an intellectual disability” and were less likely to undergo evaluation by age 36 months.

Among non-Hispanic white children, 45.3% had received a comprehensive evaluation for ASD before the age of 36 months, compared with 39.8% of non-Hispanic black children and 42.9% of Hispanic children, said Dr. Maenner of the CDC’s National Center on Birth Defects and Developmental Disabilities.

The overall rate of early evaluation was 44% for the cohort of 3,981 children who were born in 2008 and included in the 2016 analysis of the 11 ADDM Network sites, they reported.

There was, however, considerable variation in the timing of that initial evaluation for ASD among the sites, which largely consisted of one to seven counties in most states, except for Arkansas (all 75 counties), Tennessee (11 counties), and Wisconsin (10 counties), Dr. Maenner and associates noted.

The two ADDM Network sites at the extremes of that variation were North Carolina and Arkansas. In North Carolina, almost twice as many children (62.3%) had an evaluation by 36 months than in Arkansas (32.6%), although Arkansas closed the gap a bit by evaluating 21.8% of children aged 37-48 months, compared with 11.3% in North Carolina, the investigators said.

“ASD continues to be a public health concern; the latest data from the ADDM Network underscore the ongoing need for timely and accessible developmental assessments, educational supports, and services for persons with ASD and their families,” they concluded.

[email protected]

SOURCE: Maenner MJ et al. MMWR Surveill Summ. 2020 Mar 27;69(SS-4):1-12.

For the first time since detailed measurement began in 2000, there was no significant difference in autism prevalence between black and white 8-year-olds in 2016, according to data from the Centers for Disease Control and Prevention.

MDedge News

The latest analysis from the CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network puts the prevalence of autism spectrum disorder (ASD) at 18.3 per 1,000 children aged 8 years among black children and 18.5 per 1,000 in white children, Matthew J. Maenner, PhD, and associates said in MMWR Surveillance Summaries. Overall prevalence was 18.5 per 1,000 children, or 1 in 54 children, aged 8 years.

“This diminishing disparity in ASD prevalence might signify progress toward earlier and more equitable identification of ASD,” they wrote, while also noting that “black children with ASD were more likely than white children to have an intellectual disability” and were less likely to undergo evaluation by age 36 months.

Among non-Hispanic white children, 45.3% had received a comprehensive evaluation for ASD before the age of 36 months, compared with 39.8% of non-Hispanic black children and 42.9% of Hispanic children, said Dr. Maenner of the CDC’s National Center on Birth Defects and Developmental Disabilities.

The overall rate of early evaluation was 44% for the cohort of 3,981 children who were born in 2008 and included in the 2016 analysis of the 11 ADDM Network sites, they reported.

There was, however, considerable variation in the timing of that initial evaluation for ASD among the sites, which largely consisted of one to seven counties in most states, except for Arkansas (all 75 counties), Tennessee (11 counties), and Wisconsin (10 counties), Dr. Maenner and associates noted.

The two ADDM Network sites at the extremes of that variation were North Carolina and Arkansas. In North Carolina, almost twice as many children (62.3%) had an evaluation by 36 months than in Arkansas (32.6%), although Arkansas closed the gap a bit by evaluating 21.8% of children aged 37-48 months, compared with 11.3% in North Carolina, the investigators said.

“ASD continues to be a public health concern; the latest data from the ADDM Network underscore the ongoing need for timely and accessible developmental assessments, educational supports, and services for persons with ASD and their families,” they concluded.

[email protected]

SOURCE: Maenner MJ et al. MMWR Surveill Summ. 2020 Mar 27;69(SS-4):1-12.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition that affects approximately 1% to 4% of the worldwide population and is 3 times more common in females than in males.¹ The condition is characterized by painful inflamed nodules in apocrine gland–bearing regions that can progress to abscesses, sinus tracts, and/or scarring. Hidradenitis suppurativa is associated with intense pain, work disability, and poor quality of life.¹

Recent evidence has suggested that HS is an autoimmune disease resulting from dysregulation of the γ-secretase/Notch pathway, leading to stimulation of the toll-like receptor–mediated innate immunity that contributes to occlusion and inflammation of the hair follicle. Additionally, elevated levels of proinflammatory cytokines such as tumor necrosis factor α and IL-17 are seen in HS lesions.² The autoimmune nature of HS may account for its increased association with other autoimmune disorders such as thyroid disease and potentially with other unexplored conditions such as fibromyalgia.³

Fibromyalgia is a chronic pain condition that primarily affects females and is commonly associated with other autoimmune conditions.⁴ The primary objective of this retrospective study was to determine the prevalence of fibromyalgia in HS patients and assess if there is an association between HS disease severity and development of fibromyalgia.

We conducted a retrospective chart review of patients at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) who were 18 years and older and had a diagnosis of both HS and fibromyalgia from January 2008 to November 2018. The primary end point was the prevalence of fibromyalgia in the HS population. The secondary end point was the association of HS disease severity with the development of fibromyalgia. Hidradenitis disease severity was defined according to the number of body areas affected by HS: mild disease involved 1 body area, moderate disease involved 2 body areas, and severe disease involved 3 or more body areas. Patient age, sex, and race also were recorded.

A total of 1356 patients were seen during this time period for HS. The prevalence of fibromyalgia in the HS population was 3.2% (n=44). Ninety-five percent (42/44) of patients with HS and fibromyalgia were women; 22 (50%) patients had severe disease, 12 (27%) had moderate disease, 7 (16%) had mild disease, and 3 (7%) had an unknown number of affected body areas. Fifty-seven percent (25/44) of patients were diagnosed with HS prior to the diagnosis of fibromyalgia (Table).

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition that affects approximately 1% to 4% of the worldwide population and is 3 times more common in females than in males.¹ The condition is characterized by painful inflamed nodules in apocrine gland–bearing regions that can progress to abscesses, sinus tracts, and/or scarring. Hidradenitis suppurativa is associated with intense pain, work disability, and poor quality of life.¹

Recent evidence has suggested that HS is an autoimmune disease resulting from dysregulation of the γ-secretase/Notch pathway, leading to stimulation of the toll-like receptor–mediated innate immunity that contributes to occlusion and inflammation of the hair follicle. Additionally, elevated levels of proinflammatory cytokines such as tumor necrosis factor α and IL-17 are seen in HS lesions.² The autoimmune nature of HS may account for its increased association with other autoimmune disorders such as thyroid disease and potentially with other unexplored conditions such as fibromyalgia.³

Fibromyalgia is a chronic pain condition that primarily affects females and is commonly associated with other autoimmune conditions.⁴ The primary objective of this retrospective study was to determine the prevalence of fibromyalgia in HS patients and assess if there is an association between HS disease severity and development of fibromyalgia.

We conducted a retrospective chart review of patients at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) who were 18 years and older and had a diagnosis of both HS and fibromyalgia from January 2008 to November 2018. The primary end point was the prevalence of fibromyalgia in the HS population. The secondary end point was the association of HS disease severity with the development of fibromyalgia. Hidradenitis disease severity was defined according to the number of body areas affected by HS: mild disease involved 1 body area, moderate disease involved 2 body areas, and severe disease involved 3 or more body areas. Patient age, sex, and race also were recorded.

A total of 1356 patients were seen during this time period for HS. The prevalence of fibromyalgia in the HS population was 3.2% (n=44). Ninety-five percent (42/44) of patients with HS and fibromyalgia were women; 22 (50%) patients had severe disease, 12 (27%) had moderate disease, 7 (16%) had mild disease, and 3 (7%) had an unknown number of affected body areas. Fifty-seven percent (25/44) of patients were diagnosed with HS prior to the diagnosis of fibromyalgia (Table).

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition that affects approximately 1% to 4% of the worldwide population and is 3 times more common in females than in males.¹ The condition is characterized by painful inflamed nodules in apocrine gland–bearing regions that can progress to abscesses, sinus tracts, and/or scarring. Hidradenitis suppurativa is associated with intense pain, work disability, and poor quality of life.¹

Recent evidence has suggested that HS is an autoimmune disease resulting from dysregulation of the γ-secretase/Notch pathway, leading to stimulation of the toll-like receptor–mediated innate immunity that contributes to occlusion and inflammation of the hair follicle. Additionally, elevated levels of proinflammatory cytokines such as tumor necrosis factor α and IL-17 are seen in HS lesions.² The autoimmune nature of HS may account for its increased association with other autoimmune disorders such as thyroid disease and potentially with other unexplored conditions such as fibromyalgia.³

Fibromyalgia is a chronic pain condition that primarily affects females and is commonly associated with other autoimmune conditions.⁴ The primary objective of this retrospective study was to determine the prevalence of fibromyalgia in HS patients and assess if there is an association between HS disease severity and development of fibromyalgia.

We conducted a retrospective chart review of patients at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) who were 18 years and older and had a diagnosis of both HS and fibromyalgia from January 2008 to November 2018. The primary end point was the prevalence of fibromyalgia in the HS population. The secondary end point was the association of HS disease severity with the development of fibromyalgia. Hidradenitis disease severity was defined according to the number of body areas affected by HS: mild disease involved 1 body area, moderate disease involved 2 body areas, and severe disease involved 3 or more body areas. Patient age, sex, and race also were recorded.

A total of 1356 patients were seen during this time period for HS. The prevalence of fibromyalgia in the HS population was 3.2% (n=44). Ninety-five percent (42/44) of patients with HS and fibromyalgia were women; 22 (50%) patients had severe disease, 12 (27%) had moderate disease, 7 (16%) had mild disease, and 3 (7%) had an unknown number of affected body areas. Fifty-seven percent (25/44) of patients were diagnosed with HS prior to the diagnosis of fibromyalgia (Table).

Strict adherence to pathology guidelines for interpreting immumohistochemical (IHC) staining in endometrial cancer samples may miss the opportunity to identify patients with Lynch syndrome, investigators cautioned.

Current College of American Pathologists recommendations say that any partial, indeterminate, or “heterogeneous” IHC staining for DNA mismatch repair proteins (MMRP) should be considered as intact expression staining.

However, a retrospective review of patients with endometrial cancer showed that 3 of 13 patients with Lynch syndrome had a small proportion of staining and would have been considered at low risk for Lynch syndrome if the reporting rules were followed to the letter, according to Courtney J. Riedinger, MD, and colleagues from the University of Tennessee Medical Center in Knoxville.

“IHC staining for mismatch repair proteins is a way to screen for who should get genetic testing [for Lynch syndrome],” Dr. Riedinger said in an interview. “The pathology guidelines say that any expression is intact staining, but we found some tumor specimens that have about only 20% staining, and we found that 3 of 27 patients with a range of 20%-60% expression had Lynch syndrome.”

The findings suggest that genetic testing for Lynch syndrome should be considered in patients with heterogeneous staining for MMRP, Dr. Riedinger and colleagues wrote in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled due to the COVID-19 pandemic.A recent systematic review estimated the prevalence of Lynch syndrome in women with endometrial cancer to be 3%. The authors of the review recommended universal screening for Lynch syndrome in women with endometrial cancer (Genet Med. 2019 Oct;21[10]:2167-2180).

As Dr. Riedinger and colleagues noted, screening for Lynch syndrome can be performed clinically with microsatellite instability testing or IHC staining for MMRP.

To determine the frequency of Lynch syndrome in women with endometrial cancer whose samples exhibited heterogeneous staining for MMRP, the investigators conducted a retrospective review.

They identified 455 women who underwent hysterectomy for endometrial cancer during 2012-2017. Of this group, samples from 315 patients had no MMRP loss, 92 had complete loss, and 48 had heterogeneous MMRP staining. Of the latter group, 21 samples were reported as intact, and 27 were reported as heterogeneous.

A total of 13 patients were identified as having Lynch syndrome, including 3 of the 27 patients with reported heterogeneous staining and 10 with reported complete loss of MMRP.

The investigators found the frequency of Lynch syndrome among patients with reported heterogeneous staining was not significantly different than that for patients with complete MMRP loss. In addition, there were no significant differences between samples with heterogeneous or complete loss of staining by type of MMRP.

“Our data suggest genetic testing for Lynch syndrome in patients with heterogeneous IHC staining for MMRP should be considered. Current reporting guidelines regarding MMRP expression in endometrial cancer patients need to be reevaluated,” Dr. Riedinger and colleagues concluded.

Dr. Riedinger reported no conflicts of interest. The study was internally funded.

SOURCE: Riedinger CJ et al. SGO 2020, Abstract 104.

Strict adherence to pathology guidelines for interpreting immumohistochemical (IHC) staining in endometrial cancer samples may miss the opportunity to identify patients with Lynch syndrome, investigators cautioned.

Current College of American Pathologists recommendations say that any partial, indeterminate, or “heterogeneous” IHC staining for DNA mismatch repair proteins (MMRP) should be considered as intact expression staining.

However, a retrospective review of patients with endometrial cancer showed that 3 of 13 patients with Lynch syndrome had a small proportion of staining and would have been considered at low risk for Lynch syndrome if the reporting rules were followed to the letter, according to Courtney J. Riedinger, MD, and colleagues from the University of Tennessee Medical Center in Knoxville.

“IHC staining for mismatch repair proteins is a way to screen for who should get genetic testing [for Lynch syndrome],” Dr. Riedinger said in an interview. “The pathology guidelines say that any expression is intact staining, but we found some tumor specimens that have about only 20% staining, and we found that 3 of 27 patients with a range of 20%-60% expression had Lynch syndrome.”

The findings suggest that genetic testing for Lynch syndrome should be considered in patients with heterogeneous staining for MMRP, Dr. Riedinger and colleagues wrote in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled due to the COVID-19 pandemic.A recent systematic review estimated the prevalence of Lynch syndrome in women with endometrial cancer to be 3%. The authors of the review recommended universal screening for Lynch syndrome in women with endometrial cancer (Genet Med. 2019 Oct;21[10]:2167-2180).

As Dr. Riedinger and colleagues noted, screening for Lynch syndrome can be performed clinically with microsatellite instability testing or IHC staining for MMRP.

To determine the frequency of Lynch syndrome in women with endometrial cancer whose samples exhibited heterogeneous staining for MMRP, the investigators conducted a retrospective review.

They identified 455 women who underwent hysterectomy for endometrial cancer during 2012-2017. Of this group, samples from 315 patients had no MMRP loss, 92 had complete loss, and 48 had heterogeneous MMRP staining. Of the latter group, 21 samples were reported as intact, and 27 were reported as heterogeneous.

A total of 13 patients were identified as having Lynch syndrome, including 3 of the 27 patients with reported heterogeneous staining and 10 with reported complete loss of MMRP.

The investigators found the frequency of Lynch syndrome among patients with reported heterogeneous staining was not significantly different than that for patients with complete MMRP loss. In addition, there were no significant differences between samples with heterogeneous or complete loss of staining by type of MMRP.

“Our data suggest genetic testing for Lynch syndrome in patients with heterogeneous IHC staining for MMRP should be considered. Current reporting guidelines regarding MMRP expression in endometrial cancer patients need to be reevaluated,” Dr. Riedinger and colleagues concluded.

Dr. Riedinger reported no conflicts of interest. The study was internally funded.

SOURCE: Riedinger CJ et al. SGO 2020, Abstract 104.

Strict adherence to pathology guidelines for interpreting immumohistochemical (IHC) staining in endometrial cancer samples may miss the opportunity to identify patients with Lynch syndrome, investigators cautioned.

Current College of American Pathologists recommendations say that any partial, indeterminate, or “heterogeneous” IHC staining for DNA mismatch repair proteins (MMRP) should be considered as intact expression staining.

However, a retrospective review of patients with endometrial cancer showed that 3 of 13 patients with Lynch syndrome had a small proportion of staining and would have been considered at low risk for Lynch syndrome if the reporting rules were followed to the letter, according to Courtney J. Riedinger, MD, and colleagues from the University of Tennessee Medical Center in Knoxville.

“IHC staining for mismatch repair proteins is a way to screen for who should get genetic testing [for Lynch syndrome],” Dr. Riedinger said in an interview. “The pathology guidelines say that any expression is intact staining, but we found some tumor specimens that have about only 20% staining, and we found that 3 of 27 patients with a range of 20%-60% expression had Lynch syndrome.”

The findings suggest that genetic testing for Lynch syndrome should be considered in patients with heterogeneous staining for MMRP, Dr. Riedinger and colleagues wrote in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled due to the COVID-19 pandemic.A recent systematic review estimated the prevalence of Lynch syndrome in women with endometrial cancer to be 3%. The authors of the review recommended universal screening for Lynch syndrome in women with endometrial cancer (Genet Med. 2019 Oct;21[10]:2167-2180).

As Dr. Riedinger and colleagues noted, screening for Lynch syndrome can be performed clinically with microsatellite instability testing or IHC staining for MMRP.

To determine the frequency of Lynch syndrome in women with endometrial cancer whose samples exhibited heterogeneous staining for MMRP, the investigators conducted a retrospective review.

They identified 455 women who underwent hysterectomy for endometrial cancer during 2012-2017. Of this group, samples from 315 patients had no MMRP loss, 92 had complete loss, and 48 had heterogeneous MMRP staining. Of the latter group, 21 samples were reported as intact, and 27 were reported as heterogeneous.

A total of 13 patients were identified as having Lynch syndrome, including 3 of the 27 patients with reported heterogeneous staining and 10 with reported complete loss of MMRP.

The investigators found the frequency of Lynch syndrome among patients with reported heterogeneous staining was not significantly different than that for patients with complete MMRP loss. In addition, there were no significant differences between samples with heterogeneous or complete loss of staining by type of MMRP.

“Our data suggest genetic testing for Lynch syndrome in patients with heterogeneous IHC staining for MMRP should be considered. Current reporting guidelines regarding MMRP expression in endometrial cancer patients need to be reevaluated,” Dr. Riedinger and colleagues concluded.

Dr. Riedinger reported no conflicts of interest. The study was internally funded.

SOURCE: Riedinger CJ et al. SGO 2020, Abstract 104.

In New York state, just over 86% of reported COVID-19 deaths involved at least one comorbidity, according to the state’s department of health.

As of midnight on April 6, there had been 5,489 fatalities caused by COVID-19 in the state, of which 86.2% (4,732) had at least one underlying condition, the New York State Department of Health reported April 7 on its COVID-19 tracker.

The leading comorbidity, seen in 55.4% of all deaths, was hypertension. In comparison, a recent estimate from the U.S. Department of Health & Human Services put the prevalence of high blood pressure at about 45% in the overall adult population.

In New York, the rest of the 10 most common comorbidities in COVID-19 fatalities were diabetes (37.3%), hyperlipidemia (18.5%), coronary artery disease (12.4%), renal disease (11.0%), dementia (9.1%), chronic obstructive pulmonary disease (8.3%), cancer (8.1%), atrial fibrillation (7.1%), and heart failure (7.1%), the NYSDOH said.

Other data on the tracker site show that 63% of all deaths involved a patient who was aged 70 years or older and that 61% of COVID-19 patients who have died in New York were male and 38.8% were female (sex unknown for 0.2%). Among all individuals who have tested positive, 54.8% were male and 44.6% were female (sex unknown for 0.6%).

As of the end of day on April 6, a total of 340,058 persons had been tested in the state and 40.8% (138,863) were positive for the SARS-CoV-2 virus. By county, the highest positive rates are in New York City: Queens at 57.4%, Brooklyn at 52.4%, and the Bronx at 52.3%, according to the NYSDOH.

[email protected]

In New York state, just over 86% of reported COVID-19 deaths involved at least one comorbidity, according to the state’s department of health.

As of midnight on April 6, there had been 5,489 fatalities caused by COVID-19 in the state, of which 86.2% (4,732) had at least one underlying condition, the New York State Department of Health reported April 7 on its COVID-19 tracker.

The leading comorbidity, seen in 55.4% of all deaths, was hypertension. In comparison, a recent estimate from the U.S. Department of Health & Human Services put the prevalence of high blood pressure at about 45% in the overall adult population.

In New York, the rest of the 10 most common comorbidities in COVID-19 fatalities were diabetes (37.3%), hyperlipidemia (18.5%), coronary artery disease (12.4%), renal disease (11.0%), dementia (9.1%), chronic obstructive pulmonary disease (8.3%), cancer (8.1%), atrial fibrillation (7.1%), and heart failure (7.1%), the NYSDOH said.

Other data on the tracker site show that 63% of all deaths involved a patient who was aged 70 years or older and that 61% of COVID-19 patients who have died in New York were male and 38.8% were female (sex unknown for 0.2%). Among all individuals who have tested positive, 54.8% were male and 44.6% were female (sex unknown for 0.6%).

As of the end of day on April 6, a total of 340,058 persons had been tested in the state and 40.8% (138,863) were positive for the SARS-CoV-2 virus. By county, the highest positive rates are in New York City: Queens at 57.4%, Brooklyn at 52.4%, and the Bronx at 52.3%, according to the NYSDOH.

[email protected]

In New York state, just over 86% of reported COVID-19 deaths involved at least one comorbidity, according to the state’s department of health.

As of midnight on April 6, there had been 5,489 fatalities caused by COVID-19 in the state, of which 86.2% (4,732) had at least one underlying condition, the New York State Department of Health reported April 7 on its COVID-19 tracker.

The leading comorbidity, seen in 55.4% of all deaths, was hypertension. In comparison, a recent estimate from the U.S. Department of Health & Human Services put the prevalence of high blood pressure at about 45% in the overall adult population.

In New York, the rest of the 10 most common comorbidities in COVID-19 fatalities were diabetes (37.3%), hyperlipidemia (18.5%), coronary artery disease (12.4%), renal disease (11.0%), dementia (9.1%), chronic obstructive pulmonary disease (8.3%), cancer (8.1%), atrial fibrillation (7.1%), and heart failure (7.1%), the NYSDOH said.

Other data on the tracker site show that 63% of all deaths involved a patient who was aged 70 years or older and that 61% of COVID-19 patients who have died in New York were male and 38.8% were female (sex unknown for 0.2%). Among all individuals who have tested positive, 54.8% were male and 44.6% were female (sex unknown for 0.6%).

As of the end of day on April 6, a total of 340,058 persons had been tested in the state and 40.8% (138,863) were positive for the SARS-CoV-2 virus. By county, the highest positive rates are in New York City: Queens at 57.4%, Brooklyn at 52.4%, and the Bronx at 52.3%, according to the NYSDOH.

[email protected]

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

STOWE, VT. – Menstrual migraine is more disabling than migraine that has no association with menstruation, said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.

What is menstrual migraine?

Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.

Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.

For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
 

Gathering information during the visit

A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.

Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
 

Available treatments

NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.

Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.

Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.

For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.

In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
 

Oral contraceptives and the risk of stroke

Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.

“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”

No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.

“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
 

Choosing preventive and rescue medications

Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.

Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.

Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.

[email protected]

STOWE, VT. – Menstrual migraine is more disabling than migraine that has no association with menstruation, said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.

What is menstrual migraine?

Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.

Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.

For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
 

Gathering information during the visit

A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.

Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
 

Available treatments

NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.

Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.

Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.

For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.

In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
 

Oral contraceptives and the risk of stroke

Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.

“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”

No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.

“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
 

Choosing preventive and rescue medications

Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.

Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.

Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.

[email protected]

STOWE, VT. – Menstrual migraine is more disabling than migraine that has no association with menstruation, said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.

What is menstrual migraine?

Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.

Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.

For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
 

Gathering information during the visit

A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.

Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
 

Available treatments

NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.

Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.

Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.

For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.

In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
 

Oral contraceptives and the risk of stroke

Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.

“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”

No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.

“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
 

Choosing preventive and rescue medications

Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.

Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.

Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.

[email protected]