Conference Coverage

Today there are so many evidence-based drug therapies for heart failure with reduced ejection fraction (HFrEF) that physicians treating HF patients almost don’t know what to do them.

It’s an exciting new age that way, but to many vexingly unclear how best to merge the shiny new options with mainstay regimens based on time-honored renin-angiotensin system (RAS) inhibitors and beta-blockers.

To impart some clarity, the authors of a new HF guideline document recently took center stage at the Heart Failure Association of the European Society of Cardiology (ESC-HFA) annual meeting to preview their updated recommendations, with novel twists based on recent major trials, for the new age of HF pharmacotherapeutics.

The guideline committee considered the evidence base that existed “up until the end of March of this year,” Theresa A. McDonagh, MD, King’s College London, said during the presentation. The document “is now finalized, it’s with the publishers, and it will be presented in full with simultaneous publication at the ESC meeting” that starts August 27.

It describes a game plan, already followed by some clinicians in practice without official guidance, for initiating drugs from each of four classes in virtually all patients with HFrEF.
 

New indicated drugs, new perspective for HFrEF

Three of the drug categories are old acquaintances. Among them are the RAS inhibitors, which include angiotensin-receptor/neprilysin inhibitors, beta-blockers, and the mineralocorticoid receptor antagonists. The latter drugs are gaining new respect after having been underplayed in HF prescribing despite longstanding evidence of efficacy.

Completing the quartet of first-line HFrEF drug classes is a recent arrival to the HF arena, the sodium-glucose cotransporter 2 inhibitors.

“We now have new data and a simplified treatment algorithm for heart failure with reduced ejection fraction based on the early administration of the four major classes of drugs,” said Marco Metra, MD, University of Brescia (Italy), previewing the medical-therapy portions of the new guideline at the ESC-HFA sessions, which launched virtually and live in Florence, Italy, on July 29.

The new game plan offers a simple answer to a once-common but complex question: How and in what order are the different drug classes initiated in patients with HFrEF? In the new document, the stated goal is to get them all on board expeditiously and safely, by any means possible.

The guideline writers did not specify a sequence, preferring to leave that decision to physicians, said Dr. Metra, who stated only two guiding principles. The first is to consider the patient’s unique circumstances. The order in which the drugs are introduced might vary, depending on, for example, whether the patient has low or high blood pressure or renal dysfunction.

Second, “it is very important that we try to give all four classes of drugs to the patient in the shortest time possible, because this saves lives,” he said.

That there is no recommendation on sequencing the drugs has led some to the wrong interpretation that all should be started at once, observed coauthor Javed Butler, MD, MPH, University of Mississippi, Jackson, as a panelist during the presentation. Far from it, he said. “The doctor with the patient in front of you can make the best decision. The idea here is to get all the therapies on as soon as possible, as safely as possible.”

“The order in which they are introduced is not really important,” agreed Vijay Chopra, MD, Max Super Specialty Hospital Saket, New Delhi, another coauthor on the panel. “The important thing is that at least some dose of all the four drugs needs to be introduced in the first 4-6 weeks, and then up-titrated.”

Other medical therapy can be more tailored, Dr. Metra noted, such as loop diuretics for patients with congestion, iron for those with iron deficiency, and other drugs depending on whether there is, for example, atrial fibrillation or coronary disease.
 

Adoption of emerging definitions

The document adopts the emerging characterization of HFrEF by a left ventricular ejection fraction (LVEF) up to 40%.

And it will leverage an expanding evidence base for medication in a segment of patients once said to have HF with preserved ejection fraction (HFpEF), who had therefore lacked specific, guideline-directed medical therapies. Now, patients with an LVEF of 41%-49% will be said to have HF with mildly reduced ejection fraction (HFmrEF), a tweak to the recently introduced HF with “mid-range” LVEF that is designed to assert its nature as something to treat. The new document’s HFmrEF recommendations come with various class and level-of-evidence ratings.

That leaves HFpEF to be characterized by an LVEF of 50% in combination with structural or functional abnormalities associated with LV diastolic dysfunction or raised LV filling pressures, including raised natriuretic peptide levels.

The definitions are consistent with those proposed internationally by the ESC-HFA, the Heart Failure Society of America, and other groups in a statement published in March.
 

Expanded HFrEF med landscape

Since the 2016 ESC guideline on HF therapy, Dr. McDonagh said, “there’s been no substantial change in the evidence for many of the classical drugs that we use in heart failure. However, we had a lot of new and exciting evidence to consider,” especially in support of the SGLT2 inhibitors as one of the core medications in HFrEF.

The new data came from two controlled trials in particular. In DAPA-HF, patients with HFrEF who were initially without diabetes and who went on dapagliflozin (Farxiga, AstraZeneca) showed a 27% drop in cardiovascular (CV) death or worsening-HF events over a median of 18 months.

“That was followed up with very concordant results with empagliflozin [Jardiance, Boehringer Ingelheim/Eli Lilly] in HFrEF in the EMPEROR-Reduced trial,” Dr. McDonagh said. In that trial, comparable patients who took empagliflozin showed a 25% drop in a primary endpoint similar to that in DAPA-HF over the median 16-month follow-up.

Other HFrEF recommendations are for selected patients. They include ivabradine, already in the guidelines, for patients in sinus rhythm with an elevated resting heart rate who can’t take beta-blockers for whatever reason. But, Dr. McDonagh noted, “we had some new classes of drugs to consider as well.”

In particular, the oral soluble guanylate-cyclase receptor stimulator vericiguat (Verquvo) emerged about a year ago from the VICTORIA trial as a modest success for patients with HFrEF and a previous HF hospitalization. In the trial with more than 5,000 patients, treatment with vericiguat atop standard drug and device therapy was followed by a significant 10% drop in risk for CV death or HF hospitalization.

Available now or likely to be available in the United States, the European Union, Japan, and other countries, vericiguat is recommended in the new guideline for VICTORIA-like patients who don’t adequately respond to other indicated medications.
 

Little for HFpEF as newly defined

“Almost nothing is new” in the guidelines for HFpEF, Dr. Metra said. The document recommends screening for and treatment of any underlying disorder and comorbidities, plus diuretics for any congestion. “That’s what we have to date.”

But that evidence base might soon change. The new HFpEF recommendations could possibly be up-staged at the ESC sessions by the August 27 scheduled presentation of EMPEROR-Preserved, a randomized test of empagliflozin in HFpEF and – it could be said – HFmrEF. The trial entered patients with chronic HF and an LVEF greater than 40%.

Eli Lilly and Boehringer Ingelheim offered the world a peek at the results, which suggest the SGLT2 inhibitor had a positive impact on the primary endpoint of CV death or HF hospitalization. They announced the cursory top-line outcomes in early July as part of its regulatory obligations, noting that the trial had “met” its primary endpoint.

But many unknowns remain, including the degree of benefit and whether it varied among subgroups, and especially whether outcomes were different for HFmrEF than for HFpEF.
 

Upgrades for familiar agents

Still, HFmrEF gets noteworthy attention in the document. “For the first time, we have recommendations for these patients,” Dr. Metra said. “We already knew that diuretics are indicated for the treatment of congestion. But now, ACE inhibitors, ARBs, beta-blockers, mineralocorticoid antagonists, as well as sacubitril/valsartan, may be considered to improve outcomes in these patients.” Their upgrades in the new guidelines were based on review of trials in the CHARM program and of TOPCAT and PARAGON-HF, among others, he said.

The new document also includes “treatment algorithms based on phenotypes”; that is, comorbidities and less common HF precipitants. For example, “assessment of iron status is now mandated in all patients with heart failure,” Dr. Metra said.

AFFIRM-HF is the key trial in this arena, with its more than 1,100 iron-deficient patients with LVEF less than 50% who had been recently hospitalized for HF. A year of treatment with ferric carboxymaltose (Ferinject/Injectafer, Vifor) led to a 26% drop in risk for HF hospitalization, but without affecting mortality.

For those who are iron deficient, Dr. Metra said, “ferric carboxymaltose intravenously should be considered not only in patients with low ejection fraction and outpatients, but also in patients recently hospitalized for acute heart failure.”

The SGLT2 inhibitors are recommended in HFrEF patients with type 2 diabetes. And treatment with tafamidis (Vyndaqel, Pfizer) in patients with genetic or wild-type transthyretin cardiac amyloidosis gets a class I recommendation based on survival gains seen in the ATTR-ACT trial.

Also recommended is a full CV assessment for patients with cancer who are on cardiotoxic agents or otherwise might be at risk for chemotherapy cardiotoxicity. “Beta-blockers and ACE inhibitors should be considered in those who develop left ventricular systolic dysfunction after anticancer therapy,” Dr. Metra said.

The ongoing pandemic made its mark on the document’s genesis, as it has with most everything else. “For better or worse, we were a ‘COVID guideline,’ ” Dr. McDonagh said. The writing committee consisted of “a large task force of 31 individuals, including two patients,” and there were “only two face-to-face meetings prior to the first wave of COVID hitting Europe.”

The committee voted on each of the recommendations, “and we had to have agreement of more than 75% of the task force to assign a class of recommendation or level of evidence,” she said. “I think we did the best we could in the circumstances. We had the benefit of many discussions over Zoom, and I think at the end of the day we have achieved a consensus.”

With such a large body of participants and the 75% threshold for agreement, “you end up with perhaps a conservative guideline. But that’s not a bad thing for clinical practice, for guidelines to be conservative,” Dr. McDonagh said. “They’re mainly concerned with looking at evidence and safety.”

A version of this article first appeared on Medscape.com.

Today there are so many evidence-based drug therapies for heart failure with reduced ejection fraction (HFrEF) that physicians treating HF patients almost don’t know what to do them.

It’s an exciting new age that way, but to many vexingly unclear how best to merge the shiny new options with mainstay regimens based on time-honored renin-angiotensin system (RAS) inhibitors and beta-blockers.

To impart some clarity, the authors of a new HF guideline document recently took center stage at the Heart Failure Association of the European Society of Cardiology (ESC-HFA) annual meeting to preview their updated recommendations, with novel twists based on recent major trials, for the new age of HF pharmacotherapeutics.

The guideline committee considered the evidence base that existed “up until the end of March of this year,” Theresa A. McDonagh, MD, King’s College London, said during the presentation. The document “is now finalized, it’s with the publishers, and it will be presented in full with simultaneous publication at the ESC meeting” that starts August 27.

It describes a game plan, already followed by some clinicians in practice without official guidance, for initiating drugs from each of four classes in virtually all patients with HFrEF.
 

New indicated drugs, new perspective for HFrEF

Three of the drug categories are old acquaintances. Among them are the RAS inhibitors, which include angiotensin-receptor/neprilysin inhibitors, beta-blockers, and the mineralocorticoid receptor antagonists. The latter drugs are gaining new respect after having been underplayed in HF prescribing despite longstanding evidence of efficacy.

Completing the quartet of first-line HFrEF drug classes is a recent arrival to the HF arena, the sodium-glucose cotransporter 2 inhibitors.

“We now have new data and a simplified treatment algorithm for heart failure with reduced ejection fraction based on the early administration of the four major classes of drugs,” said Marco Metra, MD, University of Brescia (Italy), previewing the medical-therapy portions of the new guideline at the ESC-HFA sessions, which launched virtually and live in Florence, Italy, on July 29.

The new game plan offers a simple answer to a once-common but complex question: How and in what order are the different drug classes initiated in patients with HFrEF? In the new document, the stated goal is to get them all on board expeditiously and safely, by any means possible.

The guideline writers did not specify a sequence, preferring to leave that decision to physicians, said Dr. Metra, who stated only two guiding principles. The first is to consider the patient’s unique circumstances. The order in which the drugs are introduced might vary, depending on, for example, whether the patient has low or high blood pressure or renal dysfunction.

Second, “it is very important that we try to give all four classes of drugs to the patient in the shortest time possible, because this saves lives,” he said.

That there is no recommendation on sequencing the drugs has led some to the wrong interpretation that all should be started at once, observed coauthor Javed Butler, MD, MPH, University of Mississippi, Jackson, as a panelist during the presentation. Far from it, he said. “The doctor with the patient in front of you can make the best decision. The idea here is to get all the therapies on as soon as possible, as safely as possible.”

“The order in which they are introduced is not really important,” agreed Vijay Chopra, MD, Max Super Specialty Hospital Saket, New Delhi, another coauthor on the panel. “The important thing is that at least some dose of all the four drugs needs to be introduced in the first 4-6 weeks, and then up-titrated.”

Other medical therapy can be more tailored, Dr. Metra noted, such as loop diuretics for patients with congestion, iron for those with iron deficiency, and other drugs depending on whether there is, for example, atrial fibrillation or coronary disease.
 

Adoption of emerging definitions

The document adopts the emerging characterization of HFrEF by a left ventricular ejection fraction (LVEF) up to 40%.

And it will leverage an expanding evidence base for medication in a segment of patients once said to have HF with preserved ejection fraction (HFpEF), who had therefore lacked specific, guideline-directed medical therapies. Now, patients with an LVEF of 41%-49% will be said to have HF with mildly reduced ejection fraction (HFmrEF), a tweak to the recently introduced HF with “mid-range” LVEF that is designed to assert its nature as something to treat. The new document’s HFmrEF recommendations come with various class and level-of-evidence ratings.

That leaves HFpEF to be characterized by an LVEF of 50% in combination with structural or functional abnormalities associated with LV diastolic dysfunction or raised LV filling pressures, including raised natriuretic peptide levels.

The definitions are consistent with those proposed internationally by the ESC-HFA, the Heart Failure Society of America, and other groups in a statement published in March.
 

Expanded HFrEF med landscape

Since the 2016 ESC guideline on HF therapy, Dr. McDonagh said, “there’s been no substantial change in the evidence for many of the classical drugs that we use in heart failure. However, we had a lot of new and exciting evidence to consider,” especially in support of the SGLT2 inhibitors as one of the core medications in HFrEF.

The new data came from two controlled trials in particular. In DAPA-HF, patients with HFrEF who were initially without diabetes and who went on dapagliflozin (Farxiga, AstraZeneca) showed a 27% drop in cardiovascular (CV) death or worsening-HF events over a median of 18 months.

“That was followed up with very concordant results with empagliflozin [Jardiance, Boehringer Ingelheim/Eli Lilly] in HFrEF in the EMPEROR-Reduced trial,” Dr. McDonagh said. In that trial, comparable patients who took empagliflozin showed a 25% drop in a primary endpoint similar to that in DAPA-HF over the median 16-month follow-up.

Other HFrEF recommendations are for selected patients. They include ivabradine, already in the guidelines, for patients in sinus rhythm with an elevated resting heart rate who can’t take beta-blockers for whatever reason. But, Dr. McDonagh noted, “we had some new classes of drugs to consider as well.”

In particular, the oral soluble guanylate-cyclase receptor stimulator vericiguat (Verquvo) emerged about a year ago from the VICTORIA trial as a modest success for patients with HFrEF and a previous HF hospitalization. In the trial with more than 5,000 patients, treatment with vericiguat atop standard drug and device therapy was followed by a significant 10% drop in risk for CV death or HF hospitalization.

Available now or likely to be available in the United States, the European Union, Japan, and other countries, vericiguat is recommended in the new guideline for VICTORIA-like patients who don’t adequately respond to other indicated medications.
 

Little for HFpEF as newly defined

“Almost nothing is new” in the guidelines for HFpEF, Dr. Metra said. The document recommends screening for and treatment of any underlying disorder and comorbidities, plus diuretics for any congestion. “That’s what we have to date.”

But that evidence base might soon change. The new HFpEF recommendations could possibly be up-staged at the ESC sessions by the August 27 scheduled presentation of EMPEROR-Preserved, a randomized test of empagliflozin in HFpEF and – it could be said – HFmrEF. The trial entered patients with chronic HF and an LVEF greater than 40%.

Eli Lilly and Boehringer Ingelheim offered the world a peek at the results, which suggest the SGLT2 inhibitor had a positive impact on the primary endpoint of CV death or HF hospitalization. They announced the cursory top-line outcomes in early July as part of its regulatory obligations, noting that the trial had “met” its primary endpoint.

But many unknowns remain, including the degree of benefit and whether it varied among subgroups, and especially whether outcomes were different for HFmrEF than for HFpEF.
 

Upgrades for familiar agents

Still, HFmrEF gets noteworthy attention in the document. “For the first time, we have recommendations for these patients,” Dr. Metra said. “We already knew that diuretics are indicated for the treatment of congestion. But now, ACE inhibitors, ARBs, beta-blockers, mineralocorticoid antagonists, as well as sacubitril/valsartan, may be considered to improve outcomes in these patients.” Their upgrades in the new guidelines were based on review of trials in the CHARM program and of TOPCAT and PARAGON-HF, among others, he said.

The new document also includes “treatment algorithms based on phenotypes”; that is, comorbidities and less common HF precipitants. For example, “assessment of iron status is now mandated in all patients with heart failure,” Dr. Metra said.

AFFIRM-HF is the key trial in this arena, with its more than 1,100 iron-deficient patients with LVEF less than 50% who had been recently hospitalized for HF. A year of treatment with ferric carboxymaltose (Ferinject/Injectafer, Vifor) led to a 26% drop in risk for HF hospitalization, but without affecting mortality.

For those who are iron deficient, Dr. Metra said, “ferric carboxymaltose intravenously should be considered not only in patients with low ejection fraction and outpatients, but also in patients recently hospitalized for acute heart failure.”

The SGLT2 inhibitors are recommended in HFrEF patients with type 2 diabetes. And treatment with tafamidis (Vyndaqel, Pfizer) in patients with genetic or wild-type transthyretin cardiac amyloidosis gets a class I recommendation based on survival gains seen in the ATTR-ACT trial.

Also recommended is a full CV assessment for patients with cancer who are on cardiotoxic agents or otherwise might be at risk for chemotherapy cardiotoxicity. “Beta-blockers and ACE inhibitors should be considered in those who develop left ventricular systolic dysfunction after anticancer therapy,” Dr. Metra said.

The ongoing pandemic made its mark on the document’s genesis, as it has with most everything else. “For better or worse, we were a ‘COVID guideline,’ ” Dr. McDonagh said. The writing committee consisted of “a large task force of 31 individuals, including two patients,” and there were “only two face-to-face meetings prior to the first wave of COVID hitting Europe.”

The committee voted on each of the recommendations, “and we had to have agreement of more than 75% of the task force to assign a class of recommendation or level of evidence,” she said. “I think we did the best we could in the circumstances. We had the benefit of many discussions over Zoom, and I think at the end of the day we have achieved a consensus.”

With such a large body of participants and the 75% threshold for agreement, “you end up with perhaps a conservative guideline. But that’s not a bad thing for clinical practice, for guidelines to be conservative,” Dr. McDonagh said. “They’re mainly concerned with looking at evidence and safety.”

A version of this article first appeared on Medscape.com.

Today there are so many evidence-based drug therapies for heart failure with reduced ejection fraction (HFrEF) that physicians treating HF patients almost don’t know what to do them.

It’s an exciting new age that way, but to many vexingly unclear how best to merge the shiny new options with mainstay regimens based on time-honored renin-angiotensin system (RAS) inhibitors and beta-blockers.

To impart some clarity, the authors of a new HF guideline document recently took center stage at the Heart Failure Association of the European Society of Cardiology (ESC-HFA) annual meeting to preview their updated recommendations, with novel twists based on recent major trials, for the new age of HF pharmacotherapeutics.

The guideline committee considered the evidence base that existed “up until the end of March of this year,” Theresa A. McDonagh, MD, King’s College London, said during the presentation. The document “is now finalized, it’s with the publishers, and it will be presented in full with simultaneous publication at the ESC meeting” that starts August 27.

It describes a game plan, already followed by some clinicians in practice without official guidance, for initiating drugs from each of four classes in virtually all patients with HFrEF.
 

New indicated drugs, new perspective for HFrEF

Three of the drug categories are old acquaintances. Among them are the RAS inhibitors, which include angiotensin-receptor/neprilysin inhibitors, beta-blockers, and the mineralocorticoid receptor antagonists. The latter drugs are gaining new respect after having been underplayed in HF prescribing despite longstanding evidence of efficacy.

Completing the quartet of first-line HFrEF drug classes is a recent arrival to the HF arena, the sodium-glucose cotransporter 2 inhibitors.

“We now have new data and a simplified treatment algorithm for heart failure with reduced ejection fraction based on the early administration of the four major classes of drugs,” said Marco Metra, MD, University of Brescia (Italy), previewing the medical-therapy portions of the new guideline at the ESC-HFA sessions, which launched virtually and live in Florence, Italy, on July 29.

The new game plan offers a simple answer to a once-common but complex question: How and in what order are the different drug classes initiated in patients with HFrEF? In the new document, the stated goal is to get them all on board expeditiously and safely, by any means possible.

The guideline writers did not specify a sequence, preferring to leave that decision to physicians, said Dr. Metra, who stated only two guiding principles. The first is to consider the patient’s unique circumstances. The order in which the drugs are introduced might vary, depending on, for example, whether the patient has low or high blood pressure or renal dysfunction.

Second, “it is very important that we try to give all four classes of drugs to the patient in the shortest time possible, because this saves lives,” he said.

That there is no recommendation on sequencing the drugs has led some to the wrong interpretation that all should be started at once, observed coauthor Javed Butler, MD, MPH, University of Mississippi, Jackson, as a panelist during the presentation. Far from it, he said. “The doctor with the patient in front of you can make the best decision. The idea here is to get all the therapies on as soon as possible, as safely as possible.”

“The order in which they are introduced is not really important,” agreed Vijay Chopra, MD, Max Super Specialty Hospital Saket, New Delhi, another coauthor on the panel. “The important thing is that at least some dose of all the four drugs needs to be introduced in the first 4-6 weeks, and then up-titrated.”

Other medical therapy can be more tailored, Dr. Metra noted, such as loop diuretics for patients with congestion, iron for those with iron deficiency, and other drugs depending on whether there is, for example, atrial fibrillation or coronary disease.
 

Adoption of emerging definitions

The document adopts the emerging characterization of HFrEF by a left ventricular ejection fraction (LVEF) up to 40%.

And it will leverage an expanding evidence base for medication in a segment of patients once said to have HF with preserved ejection fraction (HFpEF), who had therefore lacked specific, guideline-directed medical therapies. Now, patients with an LVEF of 41%-49% will be said to have HF with mildly reduced ejection fraction (HFmrEF), a tweak to the recently introduced HF with “mid-range” LVEF that is designed to assert its nature as something to treat. The new document’s HFmrEF recommendations come with various class and level-of-evidence ratings.

That leaves HFpEF to be characterized by an LVEF of 50% in combination with structural or functional abnormalities associated with LV diastolic dysfunction or raised LV filling pressures, including raised natriuretic peptide levels.

The definitions are consistent with those proposed internationally by the ESC-HFA, the Heart Failure Society of America, and other groups in a statement published in March.
 

Expanded HFrEF med landscape

Since the 2016 ESC guideline on HF therapy, Dr. McDonagh said, “there’s been no substantial change in the evidence for many of the classical drugs that we use in heart failure. However, we had a lot of new and exciting evidence to consider,” especially in support of the SGLT2 inhibitors as one of the core medications in HFrEF.

The new data came from two controlled trials in particular. In DAPA-HF, patients with HFrEF who were initially without diabetes and who went on dapagliflozin (Farxiga, AstraZeneca) showed a 27% drop in cardiovascular (CV) death or worsening-HF events over a median of 18 months.

“That was followed up with very concordant results with empagliflozin [Jardiance, Boehringer Ingelheim/Eli Lilly] in HFrEF in the EMPEROR-Reduced trial,” Dr. McDonagh said. In that trial, comparable patients who took empagliflozin showed a 25% drop in a primary endpoint similar to that in DAPA-HF over the median 16-month follow-up.

Other HFrEF recommendations are for selected patients. They include ivabradine, already in the guidelines, for patients in sinus rhythm with an elevated resting heart rate who can’t take beta-blockers for whatever reason. But, Dr. McDonagh noted, “we had some new classes of drugs to consider as well.”

In particular, the oral soluble guanylate-cyclase receptor stimulator vericiguat (Verquvo) emerged about a year ago from the VICTORIA trial as a modest success for patients with HFrEF and a previous HF hospitalization. In the trial with more than 5,000 patients, treatment with vericiguat atop standard drug and device therapy was followed by a significant 10% drop in risk for CV death or HF hospitalization.

Available now or likely to be available in the United States, the European Union, Japan, and other countries, vericiguat is recommended in the new guideline for VICTORIA-like patients who don’t adequately respond to other indicated medications.
 

Little for HFpEF as newly defined

“Almost nothing is new” in the guidelines for HFpEF, Dr. Metra said. The document recommends screening for and treatment of any underlying disorder and comorbidities, plus diuretics for any congestion. “That’s what we have to date.”

But that evidence base might soon change. The new HFpEF recommendations could possibly be up-staged at the ESC sessions by the August 27 scheduled presentation of EMPEROR-Preserved, a randomized test of empagliflozin in HFpEF and – it could be said – HFmrEF. The trial entered patients with chronic HF and an LVEF greater than 40%.

Eli Lilly and Boehringer Ingelheim offered the world a peek at the results, which suggest the SGLT2 inhibitor had a positive impact on the primary endpoint of CV death or HF hospitalization. They announced the cursory top-line outcomes in early July as part of its regulatory obligations, noting that the trial had “met” its primary endpoint.

But many unknowns remain, including the degree of benefit and whether it varied among subgroups, and especially whether outcomes were different for HFmrEF than for HFpEF.
 

Upgrades for familiar agents

Still, HFmrEF gets noteworthy attention in the document. “For the first time, we have recommendations for these patients,” Dr. Metra said. “We already knew that diuretics are indicated for the treatment of congestion. But now, ACE inhibitors, ARBs, beta-blockers, mineralocorticoid antagonists, as well as sacubitril/valsartan, may be considered to improve outcomes in these patients.” Their upgrades in the new guidelines were based on review of trials in the CHARM program and of TOPCAT and PARAGON-HF, among others, he said.

The new document also includes “treatment algorithms based on phenotypes”; that is, comorbidities and less common HF precipitants. For example, “assessment of iron status is now mandated in all patients with heart failure,” Dr. Metra said.

AFFIRM-HF is the key trial in this arena, with its more than 1,100 iron-deficient patients with LVEF less than 50% who had been recently hospitalized for HF. A year of treatment with ferric carboxymaltose (Ferinject/Injectafer, Vifor) led to a 26% drop in risk for HF hospitalization, but without affecting mortality.

For those who are iron deficient, Dr. Metra said, “ferric carboxymaltose intravenously should be considered not only in patients with low ejection fraction and outpatients, but also in patients recently hospitalized for acute heart failure.”

The SGLT2 inhibitors are recommended in HFrEF patients with type 2 diabetes. And treatment with tafamidis (Vyndaqel, Pfizer) in patients with genetic or wild-type transthyretin cardiac amyloidosis gets a class I recommendation based on survival gains seen in the ATTR-ACT trial.

Also recommended is a full CV assessment for patients with cancer who are on cardiotoxic agents or otherwise might be at risk for chemotherapy cardiotoxicity. “Beta-blockers and ACE inhibitors should be considered in those who develop left ventricular systolic dysfunction after anticancer therapy,” Dr. Metra said.

The ongoing pandemic made its mark on the document’s genesis, as it has with most everything else. “For better or worse, we were a ‘COVID guideline,’ ” Dr. McDonagh said. The writing committee consisted of “a large task force of 31 individuals, including two patients,” and there were “only two face-to-face meetings prior to the first wave of COVID hitting Europe.”

The committee voted on each of the recommendations, “and we had to have agreement of more than 75% of the task force to assign a class of recommendation or level of evidence,” she said. “I think we did the best we could in the circumstances. We had the benefit of many discussions over Zoom, and I think at the end of the day we have achieved a consensus.”

With such a large body of participants and the 75% threshold for agreement, “you end up with perhaps a conservative guideline. But that’s not a bad thing for clinical practice, for guidelines to be conservative,” Dr. McDonagh said. “They’re mainly concerned with looking at evidence and safety.”

A version of this article first appeared on Medscape.com.

Researchers have identified clusters of blood-based metabolites, molecules produced by cells during metabolism, that appear to predict subsequent dementia risk in new findings that may provide a prevention target.

Investigators found one of the clusters includes small high-density lipoprotein (HDL) metabolites associated with vascular dementia, while another cluster involves ketone bodies and citrate that are primarily associated with Alzheimer’s disease.

Ketone bodies, or ketones, are three related compounds – acetone, acetoacetic acid, and beta-hydroxybutyric acid (BHB) – produced by the liver during fat metabolism. Citrate is a salt or ester of citric acid.

Weight loss before dementia explained?

For the study, investigators included 125,000 patients from the UK Biobank, which includes 51,031 who were over age 60 at baseline. Of these, 1,188 developed dementia during a follow-up of about 10 years; 553 were diagnosed with Alzheimer’s disease and 298 with vascular dementia.

Researchers used a platform that covers 249 metabolic measures, including small molecules, fatty acids, and lipoprotein lipids.

They estimated risk associated with these metabolites, adjusting for age, sex, body mass index, technical variables, ethnicity, smoking, alcohol, education, metabolic and neuropsychiatric medication, and APOE4 genotypes.

Of the 249 metabolites, 47 (19%) were associated with dementia risk in those over age 60, after adjustment.

The investigators examined effect estimates for associations of metabolites with both Alzheimer’s disease and vascular dementia over age 60 versus hippocampal volume under age 60. They found a “very strong, very significant” association for Alzheimer’s disease, and a “marginally significant” association for vascular dementia, said Dr. van Duijn.

This would be expected, as there is a much stronger correlation between hippocampal and Alzheimer’s disease versus vascular dementia, she added.

“We not only see that the metabolites predict dementia, but also early pathology. This makes these findings rather interesting for targeting prevention,” she said. An analysis of total brain volume showed “very strong, very similar, very significant associations” for both Alzheimer’s disease and vascular dementia,” added Dr. van Duijn.

The researchers found a major shift in various metabolites involved in energy metabolism in the 10-year period before the diagnosis of Alzheimer’s disease. These changes include low levels of branched-chain amino acids and omega-3 fatty acids and high levels of glucose, citrate, acetone, beta-hydroxybutyrate, and acetate. “This finding is in line with that in APOE models that show reduced energy metabolism over age in the brain,” said Dr. van Duijn.

She added that high levels of some of these metabolites are associated with low body weight before dementia onset, which may explain the weight loss seen in patients before developing the disease. “Our hypothesis is that the liver is burning the fat reserves of the patients in order to provide the brain with fuel,” she explained.
 

Diet a prevention target?

The results also showed ketone bodies increase with age, which may represent the aging brain’s “compensation mechanism” to deal with an energy shortage, said Dr. van Duijn. “Supplementation of ketone bodies, branched-chain amino and omega-3 fatty acids may help support brain function.”

The fact that ketone bodies were positively associated with the risk of dementia is “a very important finding,” she said.

Following this and other presentations, session cochair Rima Kaddurah-Daouk, PhD, professor in psychiatry and behavioral sciences, Institute for Brain Sciences, Duke University, Durham, N.C., noted the research is “an important part of trying to decipher some of the mysteries in Alzheimer’s disease.”

The research contributes to the understanding of how nutrition and diet could influence metabolism and then the brain and is “opening the horizon” for thinking about “strategies for therapeutic interventions,” she said.

The study received funding support from the National Institute on Aging. The investigators have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Researchers have identified clusters of blood-based metabolites, molecules produced by cells during metabolism, that appear to predict subsequent dementia risk in new findings that may provide a prevention target.

Investigators found one of the clusters includes small high-density lipoprotein (HDL) metabolites associated with vascular dementia, while another cluster involves ketone bodies and citrate that are primarily associated with Alzheimer’s disease.

Ketone bodies, or ketones, are three related compounds – acetone, acetoacetic acid, and beta-hydroxybutyric acid (BHB) – produced by the liver during fat metabolism. Citrate is a salt or ester of citric acid.

Weight loss before dementia explained?

For the study, investigators included 125,000 patients from the UK Biobank, which includes 51,031 who were over age 60 at baseline. Of these, 1,188 developed dementia during a follow-up of about 10 years; 553 were diagnosed with Alzheimer’s disease and 298 with vascular dementia.

Researchers used a platform that covers 249 metabolic measures, including small molecules, fatty acids, and lipoprotein lipids.

They estimated risk associated with these metabolites, adjusting for age, sex, body mass index, technical variables, ethnicity, smoking, alcohol, education, metabolic and neuropsychiatric medication, and APOE4 genotypes.

Of the 249 metabolites, 47 (19%) were associated with dementia risk in those over age 60, after adjustment.

The investigators examined effect estimates for associations of metabolites with both Alzheimer’s disease and vascular dementia over age 60 versus hippocampal volume under age 60. They found a “very strong, very significant” association for Alzheimer’s disease, and a “marginally significant” association for vascular dementia, said Dr. van Duijn.

This would be expected, as there is a much stronger correlation between hippocampal and Alzheimer’s disease versus vascular dementia, she added.

“We not only see that the metabolites predict dementia, but also early pathology. This makes these findings rather interesting for targeting prevention,” she said. An analysis of total brain volume showed “very strong, very similar, very significant associations” for both Alzheimer’s disease and vascular dementia,” added Dr. van Duijn.

The researchers found a major shift in various metabolites involved in energy metabolism in the 10-year period before the diagnosis of Alzheimer’s disease. These changes include low levels of branched-chain amino acids and omega-3 fatty acids and high levels of glucose, citrate, acetone, beta-hydroxybutyrate, and acetate. “This finding is in line with that in APOE models that show reduced energy metabolism over age in the brain,” said Dr. van Duijn.

She added that high levels of some of these metabolites are associated with low body weight before dementia onset, which may explain the weight loss seen in patients before developing the disease. “Our hypothesis is that the liver is burning the fat reserves of the patients in order to provide the brain with fuel,” she explained.
 

Diet a prevention target?

The results also showed ketone bodies increase with age, which may represent the aging brain’s “compensation mechanism” to deal with an energy shortage, said Dr. van Duijn. “Supplementation of ketone bodies, branched-chain amino and omega-3 fatty acids may help support brain function.”

The fact that ketone bodies were positively associated with the risk of dementia is “a very important finding,” she said.

Following this and other presentations, session cochair Rima Kaddurah-Daouk, PhD, professor in psychiatry and behavioral sciences, Institute for Brain Sciences, Duke University, Durham, N.C., noted the research is “an important part of trying to decipher some of the mysteries in Alzheimer’s disease.”

The research contributes to the understanding of how nutrition and diet could influence metabolism and then the brain and is “opening the horizon” for thinking about “strategies for therapeutic interventions,” she said.

The study received funding support from the National Institute on Aging. The investigators have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Researchers have identified clusters of blood-based metabolites, molecules produced by cells during metabolism, that appear to predict subsequent dementia risk in new findings that may provide a prevention target.

Investigators found one of the clusters includes small high-density lipoprotein (HDL) metabolites associated with vascular dementia, while another cluster involves ketone bodies and citrate that are primarily associated with Alzheimer’s disease.

Ketone bodies, or ketones, are three related compounds – acetone, acetoacetic acid, and beta-hydroxybutyric acid (BHB) – produced by the liver during fat metabolism. Citrate is a salt or ester of citric acid.

Weight loss before dementia explained?

For the study, investigators included 125,000 patients from the UK Biobank, which includes 51,031 who were over age 60 at baseline. Of these, 1,188 developed dementia during a follow-up of about 10 years; 553 were diagnosed with Alzheimer’s disease and 298 with vascular dementia.

Researchers used a platform that covers 249 metabolic measures, including small molecules, fatty acids, and lipoprotein lipids.

They estimated risk associated with these metabolites, adjusting for age, sex, body mass index, technical variables, ethnicity, smoking, alcohol, education, metabolic and neuropsychiatric medication, and APOE4 genotypes.

Of the 249 metabolites, 47 (19%) were associated with dementia risk in those over age 60, after adjustment.

The investigators examined effect estimates for associations of metabolites with both Alzheimer’s disease and vascular dementia over age 60 versus hippocampal volume under age 60. They found a “very strong, very significant” association for Alzheimer’s disease, and a “marginally significant” association for vascular dementia, said Dr. van Duijn.

This would be expected, as there is a much stronger correlation between hippocampal and Alzheimer’s disease versus vascular dementia, she added.

“We not only see that the metabolites predict dementia, but also early pathology. This makes these findings rather interesting for targeting prevention,” she said. An analysis of total brain volume showed “very strong, very similar, very significant associations” for both Alzheimer’s disease and vascular dementia,” added Dr. van Duijn.

The researchers found a major shift in various metabolites involved in energy metabolism in the 10-year period before the diagnosis of Alzheimer’s disease. These changes include low levels of branched-chain amino acids and omega-3 fatty acids and high levels of glucose, citrate, acetone, beta-hydroxybutyrate, and acetate. “This finding is in line with that in APOE models that show reduced energy metabolism over age in the brain,” said Dr. van Duijn.

She added that high levels of some of these metabolites are associated with low body weight before dementia onset, which may explain the weight loss seen in patients before developing the disease. “Our hypothesis is that the liver is burning the fat reserves of the patients in order to provide the brain with fuel,” she explained.
 

Diet a prevention target?

The results also showed ketone bodies increase with age, which may represent the aging brain’s “compensation mechanism” to deal with an energy shortage, said Dr. van Duijn. “Supplementation of ketone bodies, branched-chain amino and omega-3 fatty acids may help support brain function.”

The fact that ketone bodies were positively associated with the risk of dementia is “a very important finding,” she said.

Following this and other presentations, session cochair Rima Kaddurah-Daouk, PhD, professor in psychiatry and behavioral sciences, Institute for Brain Sciences, Duke University, Durham, N.C., noted the research is “an important part of trying to decipher some of the mysteries in Alzheimer’s disease.”

The research contributes to the understanding of how nutrition and diet could influence metabolism and then the brain and is “opening the horizon” for thinking about “strategies for therapeutic interventions,” she said.

The study received funding support from the National Institute on Aging. The investigators have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Around the world, cases of dementia are projected to hit 153 million in 2050, up from around 57 million in 2019, new global prevalence data show. “These extreme increases are due largely to demographic trends, including population growth and aging,” said study investigator Emma Nichols, MPH, a researcher at the Institute for Health Metrics and Evaluation at the University of Washington in Seattle.

“Our estimates of expected increases can and should inform policy and planning efforts that will be needed to address the needs of the growing number of individuals with dementia in the future,” Ms. Nichols said.

The latest global prevalence data were reported at the 2021 Alzheimer’s Association International Conference.

“The numbers are staggering: Nearly 153 million cases of dementia are predicted worldwide by the year 2050. To put that in context, that number is equal to approximately half of the U.S. population in 2020,” Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, said in a statement.
 

Prevalence by country

To more accurately forecast global dementia prevalence and produce country-level estimates, the investigators leveraged data from 1999 to 2019 from the Global Burden of Disease study, a comprehensive set of estimates of worldwide health trends.

These data suggest global dementia cases will increase from 57.4 million (50.4 to 65.1) in 2019 to 152.8 million (130.8 to 175.9) in 2050.

Regions that will experience the worst of the increase are eastern Sub-Saharan Africa, North Africa, and the Middle East.

The researchers also factored into the forecasts expected trends in obesity, diabetes, smoking, and educational attainment.

Increases in better education around the world are projected to decrease dementia prevalence by 6.2 million cases worldwide by 2050. However, anticipated trends in smoking, high body mass index, and diabetes will offset this gain, increasing global dementia cases by 6.8 million cases.

“A reversal of these expected trends in cardiovascular risks would be necessary to alter the anticipated trends,” Ms. Nichols said. “Interventions targeted at modifiable risk factors for dementia represent a viable strategy to help address the anticipated trends in dementia burden,” she added.
 

Need for effective prevention, treatment

Commenting on the research, Rebecca M. Edelmayer, PhD, senior director of scientific engagement at the Alzheimer’s Association, said the global increase in dementia cases is something the association has been following for many years. “We know that if we do not find effective treatments that are going to stop, slow, or prevent Alzheimer’s disease, this number will continue to grow and it will continue to impact people globally,” Dr. Edelmayer said.

She noted that although there are some positive trends, including the fact that increased education may drive down dementia risk, other factors, such as smoking, high body mass index, and high blood sugar level, are predicted to increase in prevalence.

“Some of these factors are actually counterbalancing each other, and in the end, if we don’t continue to develop culturally tailored interventions or even risk reduction strategies for individuals across the globe, we will continue to see those numbers rise overall,” Dr. Edelmayer said.

A version of this article first appeared on Medscape.com.

Around the world, cases of dementia are projected to hit 153 million in 2050, up from around 57 million in 2019, new global prevalence data show. “These extreme increases are due largely to demographic trends, including population growth and aging,” said study investigator Emma Nichols, MPH, a researcher at the Institute for Health Metrics and Evaluation at the University of Washington in Seattle.

“Our estimates of expected increases can and should inform policy and planning efforts that will be needed to address the needs of the growing number of individuals with dementia in the future,” Ms. Nichols said.

The latest global prevalence data were reported at the 2021 Alzheimer’s Association International Conference.

“The numbers are staggering: Nearly 153 million cases of dementia are predicted worldwide by the year 2050. To put that in context, that number is equal to approximately half of the U.S. population in 2020,” Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, said in a statement.
 

Prevalence by country

To more accurately forecast global dementia prevalence and produce country-level estimates, the investigators leveraged data from 1999 to 2019 from the Global Burden of Disease study, a comprehensive set of estimates of worldwide health trends.

These data suggest global dementia cases will increase from 57.4 million (50.4 to 65.1) in 2019 to 152.8 million (130.8 to 175.9) in 2050.

Regions that will experience the worst of the increase are eastern Sub-Saharan Africa, North Africa, and the Middle East.

The researchers also factored into the forecasts expected trends in obesity, diabetes, smoking, and educational attainment.

Increases in better education around the world are projected to decrease dementia prevalence by 6.2 million cases worldwide by 2050. However, anticipated trends in smoking, high body mass index, and diabetes will offset this gain, increasing global dementia cases by 6.8 million cases.

“A reversal of these expected trends in cardiovascular risks would be necessary to alter the anticipated trends,” Ms. Nichols said. “Interventions targeted at modifiable risk factors for dementia represent a viable strategy to help address the anticipated trends in dementia burden,” she added.
 

Need for effective prevention, treatment

Commenting on the research, Rebecca M. Edelmayer, PhD, senior director of scientific engagement at the Alzheimer’s Association, said the global increase in dementia cases is something the association has been following for many years. “We know that if we do not find effective treatments that are going to stop, slow, or prevent Alzheimer’s disease, this number will continue to grow and it will continue to impact people globally,” Dr. Edelmayer said.

She noted that although there are some positive trends, including the fact that increased education may drive down dementia risk, other factors, such as smoking, high body mass index, and high blood sugar level, are predicted to increase in prevalence.

“Some of these factors are actually counterbalancing each other, and in the end, if we don’t continue to develop culturally tailored interventions or even risk reduction strategies for individuals across the globe, we will continue to see those numbers rise overall,” Dr. Edelmayer said.

A version of this article first appeared on Medscape.com.

Around the world, cases of dementia are projected to hit 153 million in 2050, up from around 57 million in 2019, new global prevalence data show. “These extreme increases are due largely to demographic trends, including population growth and aging,” said study investigator Emma Nichols, MPH, a researcher at the Institute for Health Metrics and Evaluation at the University of Washington in Seattle.

“Our estimates of expected increases can and should inform policy and planning efforts that will be needed to address the needs of the growing number of individuals with dementia in the future,” Ms. Nichols said.

The latest global prevalence data were reported at the 2021 Alzheimer’s Association International Conference.

“The numbers are staggering: Nearly 153 million cases of dementia are predicted worldwide by the year 2050. To put that in context, that number is equal to approximately half of the U.S. population in 2020,” Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, said in a statement.
 

Prevalence by country

To more accurately forecast global dementia prevalence and produce country-level estimates, the investigators leveraged data from 1999 to 2019 from the Global Burden of Disease study, a comprehensive set of estimates of worldwide health trends.

These data suggest global dementia cases will increase from 57.4 million (50.4 to 65.1) in 2019 to 152.8 million (130.8 to 175.9) in 2050.

Regions that will experience the worst of the increase are eastern Sub-Saharan Africa, North Africa, and the Middle East.

The researchers also factored into the forecasts expected trends in obesity, diabetes, smoking, and educational attainment.

Increases in better education around the world are projected to decrease dementia prevalence by 6.2 million cases worldwide by 2050. However, anticipated trends in smoking, high body mass index, and diabetes will offset this gain, increasing global dementia cases by 6.8 million cases.

“A reversal of these expected trends in cardiovascular risks would be necessary to alter the anticipated trends,” Ms. Nichols said. “Interventions targeted at modifiable risk factors for dementia represent a viable strategy to help address the anticipated trends in dementia burden,” she added.
 

Need for effective prevention, treatment

Commenting on the research, Rebecca M. Edelmayer, PhD, senior director of scientific engagement at the Alzheimer’s Association, said the global increase in dementia cases is something the association has been following for many years. “We know that if we do not find effective treatments that are going to stop, slow, or prevent Alzheimer’s disease, this number will continue to grow and it will continue to impact people globally,” Dr. Edelmayer said.

She noted that although there are some positive trends, including the fact that increased education may drive down dementia risk, other factors, such as smoking, high body mass index, and high blood sugar level, are predicted to increase in prevalence.

“Some of these factors are actually counterbalancing each other, and in the end, if we don’t continue to develop culturally tailored interventions or even risk reduction strategies for individuals across the globe, we will continue to see those numbers rise overall,” Dr. Edelmayer said.

A version of this article first appeared on Medscape.com.

Remote cognitive tests often rival in-person tests with respect to reliability. That is the message behind numerous publications in recent years, and the COVID-19 pandemic has accelerated that trend.

“The publications have just skyrocketed since 2018, but I think there are still some additional tests that we need to validate using this medium of assessment. Also, I think we need to kind of put on our thinking caps as a field and think outside the box. What novel tests can we develop that will capitalize upon the telehealth environment – interactive tests that are monitoring [the individuals’] performance in real time and giving the examiner feedback, things like that,” said Munro Cullum, PhD, in an interview. Dr. Cullum spoke on the topic at the 2021 Alzheimer’s Association International Conference.

Still, challenges remain, especially factors in the home environment that can adversely affect testing. “Some of our tests are a question-answer, pencil-paper sort of tests that can be well suited to a telemedicine environment, [but] other tests don’t translate as well. So we still have a ways to go to kind of get our test to the next generation when being administered during this type of assessment. But a lot of the verbal tests work extremely well,” said Dr. Cullum, who is a professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas.
 

Preliminary evidence of equivalence

Some years ago, Dr. Cullum was interested in getting a better understanding of what existing tests could best be performed remotely, and what populations could most benefit from remote assessments. Existing studies were generally supportive of remote testing, but varied significantly in their methodology and design. He went on to publish a study in 2014 showing equivalency of existing tests in the in-person and remote environment, and that helped pave the way for a wave of more recent studies that seem to confirm equivalence of in-person methods.

“If you look at the literature overall, there is a nice, growing body of evidence suggesting support for a host of neuropsychological test instruments. For the most part, almost all have shown good reliability across test conditions,” Dr. Cullum said during the talk.

He said that he is often asked if different test norms will be required for remote tests, but that doesn’t seem to be a concern. “It looks like the regular old neuropsych test norms should serve as well in this remote assessment environment. Although as within hospital testing of patients, conservative use of norms is always an order. They are interpretive guidelines,” he added.

One concern is potential threats to validity within the home environment. He posted an image of a woman at home, taking a remote cognitive test. The desk she sat at overlooked a wooded scene, and had a sewing machine on it. A small dog lay in her lap. “So assessing the home environment, ensuring that it is as close to a clinical standard setting as possible, is certainly advised,” said Dr. Cullum.

Although much progress has been made in studying existing tests in a telemedicine environment, many commonly used tests still haven’t been studied. The risk of intrusions and distractions, and even connectivity issues, can be limiting factors. Some tests may be ineligible for remote use due to copyright issues that might prevent required materials from being displayed online. For those reasons and others, not all individuals are suited for a remote test.

Finally, remote tests should be viewed with healthy skepticism. “In doing clinical evaluations this way, we have to be extra careful to not mis- or overinterpret the findings in case there were any distractions or glitches in the examination that came up during the test,” said Dr. Cullum.
 

Looking toward the future

Moving forward, Dr. Cullum called for more research to design new tests to exploit the telehealth format. “I think this is a really important opportunity for new test development in neuropsychology with increasing incorporation of computerized measures and integration with more cognitive neuroscience and clinical neuropsychology principles.”

He also suggested that remote testing could be combined with neuroimaging, neuromodulation, and even portable magnetoencephalography. “These opportunities for research can enhance compliance, enhance large-scale studies to allow for the inclusion of brief cognitive outcome metrics that might not have other otherwise been [possible],” said Dr. Cullum.

During the question-and-answer session, someone asked if the momentum towards telehealth will continue once the COVID-19 pandemic recedes. “We believe telehealth is here to stay, or at least I do,” said session moderator Allison Lindauer, PhD, who was asked to comment. Dr. Lindauer is an associate professor at the Layton Aging and Alzheimer’s Disease Center in Portland, Ore.

Dr. Lindauer has also conducted studies on telehealth-delivered assessments and also found encouraging results. “Work like this says, we have confidence in our work, we can believe that what we’re assessing and what we’re doing – if we did it face to face, we would get similar results,” Dr. Lindauer said in an interview.

Plenty of challenges remain, and the most important is widely available broadband internet, said Dr. Lindauer. “We need a huge push to get broadband everywhere. Granted, you’re going to have people that don’t want to use the computer, or they’re nervous about doing it online. But in my experience, most people with enough coaching can do it and are fine with it.”

Dr. Cullum and Dr. Lindauer have no relevant financial disclosures.

Remote cognitive tests often rival in-person tests with respect to reliability. That is the message behind numerous publications in recent years, and the COVID-19 pandemic has accelerated that trend.

“The publications have just skyrocketed since 2018, but I think there are still some additional tests that we need to validate using this medium of assessment. Also, I think we need to kind of put on our thinking caps as a field and think outside the box. What novel tests can we develop that will capitalize upon the telehealth environment – interactive tests that are monitoring [the individuals’] performance in real time and giving the examiner feedback, things like that,” said Munro Cullum, PhD, in an interview. Dr. Cullum spoke on the topic at the 2021 Alzheimer’s Association International Conference.

Still, challenges remain, especially factors in the home environment that can adversely affect testing. “Some of our tests are a question-answer, pencil-paper sort of tests that can be well suited to a telemedicine environment, [but] other tests don’t translate as well. So we still have a ways to go to kind of get our test to the next generation when being administered during this type of assessment. But a lot of the verbal tests work extremely well,” said Dr. Cullum, who is a professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas.
 

Preliminary evidence of equivalence

Some years ago, Dr. Cullum was interested in getting a better understanding of what existing tests could best be performed remotely, and what populations could most benefit from remote assessments. Existing studies were generally supportive of remote testing, but varied significantly in their methodology and design. He went on to publish a study in 2014 showing equivalency of existing tests in the in-person and remote environment, and that helped pave the way for a wave of more recent studies that seem to confirm equivalence of in-person methods.

“If you look at the literature overall, there is a nice, growing body of evidence suggesting support for a host of neuropsychological test instruments. For the most part, almost all have shown good reliability across test conditions,” Dr. Cullum said during the talk.

He said that he is often asked if different test norms will be required for remote tests, but that doesn’t seem to be a concern. “It looks like the regular old neuropsych test norms should serve as well in this remote assessment environment. Although as within hospital testing of patients, conservative use of norms is always an order. They are interpretive guidelines,” he added.

One concern is potential threats to validity within the home environment. He posted an image of a woman at home, taking a remote cognitive test. The desk she sat at overlooked a wooded scene, and had a sewing machine on it. A small dog lay in her lap. “So assessing the home environment, ensuring that it is as close to a clinical standard setting as possible, is certainly advised,” said Dr. Cullum.

Although much progress has been made in studying existing tests in a telemedicine environment, many commonly used tests still haven’t been studied. The risk of intrusions and distractions, and even connectivity issues, can be limiting factors. Some tests may be ineligible for remote use due to copyright issues that might prevent required materials from being displayed online. For those reasons and others, not all individuals are suited for a remote test.

Finally, remote tests should be viewed with healthy skepticism. “In doing clinical evaluations this way, we have to be extra careful to not mis- or overinterpret the findings in case there were any distractions or glitches in the examination that came up during the test,” said Dr. Cullum.
 

Looking toward the future

Moving forward, Dr. Cullum called for more research to design new tests to exploit the telehealth format. “I think this is a really important opportunity for new test development in neuropsychology with increasing incorporation of computerized measures and integration with more cognitive neuroscience and clinical neuropsychology principles.”

He also suggested that remote testing could be combined with neuroimaging, neuromodulation, and even portable magnetoencephalography. “These opportunities for research can enhance compliance, enhance large-scale studies to allow for the inclusion of brief cognitive outcome metrics that might not have other otherwise been [possible],” said Dr. Cullum.

During the question-and-answer session, someone asked if the momentum towards telehealth will continue once the COVID-19 pandemic recedes. “We believe telehealth is here to stay, or at least I do,” said session moderator Allison Lindauer, PhD, who was asked to comment. Dr. Lindauer is an associate professor at the Layton Aging and Alzheimer’s Disease Center in Portland, Ore.

Dr. Lindauer has also conducted studies on telehealth-delivered assessments and also found encouraging results. “Work like this says, we have confidence in our work, we can believe that what we’re assessing and what we’re doing – if we did it face to face, we would get similar results,” Dr. Lindauer said in an interview.

Plenty of challenges remain, and the most important is widely available broadband internet, said Dr. Lindauer. “We need a huge push to get broadband everywhere. Granted, you’re going to have people that don’t want to use the computer, or they’re nervous about doing it online. But in my experience, most people with enough coaching can do it and are fine with it.”

Dr. Cullum and Dr. Lindauer have no relevant financial disclosures.

Remote cognitive tests often rival in-person tests with respect to reliability. That is the message behind numerous publications in recent years, and the COVID-19 pandemic has accelerated that trend.

“The publications have just skyrocketed since 2018, but I think there are still some additional tests that we need to validate using this medium of assessment. Also, I think we need to kind of put on our thinking caps as a field and think outside the box. What novel tests can we develop that will capitalize upon the telehealth environment – interactive tests that are monitoring [the individuals’] performance in real time and giving the examiner feedback, things like that,” said Munro Cullum, PhD, in an interview. Dr. Cullum spoke on the topic at the 2021 Alzheimer’s Association International Conference.

Still, challenges remain, especially factors in the home environment that can adversely affect testing. “Some of our tests are a question-answer, pencil-paper sort of tests that can be well suited to a telemedicine environment, [but] other tests don’t translate as well. So we still have a ways to go to kind of get our test to the next generation when being administered during this type of assessment. But a lot of the verbal tests work extremely well,” said Dr. Cullum, who is a professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas.
 

Preliminary evidence of equivalence

Some years ago, Dr. Cullum was interested in getting a better understanding of what existing tests could best be performed remotely, and what populations could most benefit from remote assessments. Existing studies were generally supportive of remote testing, but varied significantly in their methodology and design. He went on to publish a study in 2014 showing equivalency of existing tests in the in-person and remote environment, and that helped pave the way for a wave of more recent studies that seem to confirm equivalence of in-person methods.

“If you look at the literature overall, there is a nice, growing body of evidence suggesting support for a host of neuropsychological test instruments. For the most part, almost all have shown good reliability across test conditions,” Dr. Cullum said during the talk.

He said that he is often asked if different test norms will be required for remote tests, but that doesn’t seem to be a concern. “It looks like the regular old neuropsych test norms should serve as well in this remote assessment environment. Although as within hospital testing of patients, conservative use of norms is always an order. They are interpretive guidelines,” he added.

One concern is potential threats to validity within the home environment. He posted an image of a woman at home, taking a remote cognitive test. The desk she sat at overlooked a wooded scene, and had a sewing machine on it. A small dog lay in her lap. “So assessing the home environment, ensuring that it is as close to a clinical standard setting as possible, is certainly advised,” said Dr. Cullum.

Although much progress has been made in studying existing tests in a telemedicine environment, many commonly used tests still haven’t been studied. The risk of intrusions and distractions, and even connectivity issues, can be limiting factors. Some tests may be ineligible for remote use due to copyright issues that might prevent required materials from being displayed online. For those reasons and others, not all individuals are suited for a remote test.

Finally, remote tests should be viewed with healthy skepticism. “In doing clinical evaluations this way, we have to be extra careful to not mis- or overinterpret the findings in case there were any distractions or glitches in the examination that came up during the test,” said Dr. Cullum.
 

Looking toward the future

Moving forward, Dr. Cullum called for more research to design new tests to exploit the telehealth format. “I think this is a really important opportunity for new test development in neuropsychology with increasing incorporation of computerized measures and integration with more cognitive neuroscience and clinical neuropsychology principles.”

He also suggested that remote testing could be combined with neuroimaging, neuromodulation, and even portable magnetoencephalography. “These opportunities for research can enhance compliance, enhance large-scale studies to allow for the inclusion of brief cognitive outcome metrics that might not have other otherwise been [possible],” said Dr. Cullum.

During the question-and-answer session, someone asked if the momentum towards telehealth will continue once the COVID-19 pandemic recedes. “We believe telehealth is here to stay, or at least I do,” said session moderator Allison Lindauer, PhD, who was asked to comment. Dr. Lindauer is an associate professor at the Layton Aging and Alzheimer’s Disease Center in Portland, Ore.

Dr. Lindauer has also conducted studies on telehealth-delivered assessments and also found encouraging results. “Work like this says, we have confidence in our work, we can believe that what we’re assessing and what we’re doing – if we did it face to face, we would get similar results,” Dr. Lindauer said in an interview.

Plenty of challenges remain, and the most important is widely available broadband internet, said Dr. Lindauer. “We need a huge push to get broadband everywhere. Granted, you’re going to have people that don’t want to use the computer, or they’re nervous about doing it online. But in my experience, most people with enough coaching can do it and are fine with it.”

Dr. Cullum and Dr. Lindauer have no relevant financial disclosures.

Reducing exposure to air pollution may slow brain aging and reduce the risk of dementia, new research reveals. The findings have implications for individual behaviors, such as avoiding areas with poor air quality, but they also have implications for public policy, said study investigator, Xinhui Wang, PhD, assistant professor of research neurology, department of neurology, University of Southern California, Los Angeles.

“Controlling air quality has great benefits not only for the short-term, for example for pulmonary function or very broadly mortality, but can impact brain function and slow memory function decline and in the long run may reduce dementia cases.”

The findings were presented at the 2021 Alzheimer’s Association International Conference.
 

New approach

Previous research examining the impact of reducing air pollution, which has primarily examined respiratory illnesses and mortality, showed it is beneficial. However, no previous studies have examined the impact of improved air quality on cognitive function.

The current study used a subset of participants from the Women’s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO), which evaluated whether postmenopausal women derive cognitive benefit from hormone therapy.

The analysis included 2,232 community-dwelling older women aged 74-92 (mean age, 81.5 years) who did not have dementia at study enrollment.

Researchers obtained measures of participants’ annual cognitive function from 2008 to 2018. These measures included general cognitive status assessed using the Telephone Interview for Cognitive Status-modified (TICSm) and episodic memory assessed by the telephone-based California Verbal Learning Test (CVLT).

The investigators used complex geographical covariates to estimate exposure to fine particulate matter (PM_2.5) and nitrogen dioxide (NO₂), in areas where individual participants lived from 1996 to 2012. The investigators averaged measures over 3-year periods immediately preceding (recent exposure) and 10 years prior to (remote exposure) enrollment, then calculated individual-level improvements in air quality as the reduction from remote to recent exposures.

The researchers examined pollution exposure and cognitive outcomes at different times to determine causation.

“Maybe the relationship isn’t causal and is just an association, so we tried to separate the timeframe for exposure and outcome and make sure the exposure was before we measured the outcome,” said Dr. Wang.

The investigators adjusted for multiple sociodemographic, lifestyle, and clinical characteristics.
 

Reduced dementia risk

The analysis showed air quality improved significantly for both PM_2.5 and NO₂ before study enrollment. “For almost 95% of the subjects in our study, air quality improved over the 10 years,” said Dr. Wang.

During a median follow-up of 6.2 years, there was a significant decline in cognitive status and episodic memory in study participants, which makes sense, said Dr. Wang, because cognitive function naturally declines with age.

However, a 10% improvement in air quality PM_2.5 and NO₂ resulted in a respective 14% and 26% decreased risk for dementia. This translates into a level of risk seen in women 2 to 3 years younger.

Greater air quality improvement was associated with slower decline in both general cognitive status and episodic memory.

“Participants all declined in cognitive function, but living in areas with the greatest air quality improvement slowed this decline,” said Dr. Wang.

“Whether you look at global cognitive function or memory-specific function, and whether you look at PM_2.5 or NO₂, slower decline was in the range of someone who is 1-2 years younger.”

The associations did not significantly differ by age, region, education, APOE ε4 genotypes, or cardiovascular risk factors.

Patients concerned about cognitive decline can take steps to avoid exposure to pollution by wearing a mask; avoiding heavy traffic, fires, and smoke; or moving to an area with better air quality, said Dr. Wang.

“But our study mainly tried to provide some evidence for policymakers and regulators,” she added.

Another study carried out by the same investigators suggests pollution may affect various cognitive functions differently. This analysis used the same cohort, timeframe, and air quality improvement indicators as the first study but examined the association with specific cognitive domains, including episodic memory, working memory, attention/executive function, and language.

The investigators found women living in locations with greater PM_2.5 improvement performed better on tests of episodic memory (P = .002), working memory (P = .01) and attention/executive function (P = .01), but not language. Findings were similar for improved NO₂.

When looking at air quality improvement and trajectory slopes of decline across cognitive functions, only the association between improved NO₂ and slower episodic memory decline was statistically significant (P < 0.001). “The other domains were marginal or not significant,” said Dr. Wang.

“This suggests that brain regions are impacted differently,” she said, adding that various brain areas oversee different cognitive functions.
 

Important policy implications

Commenting on the research, Rebecca Edelmayer, PhD, senior director of scientific engagement, Alzheimer’s Association, said she welcomes new research on environmental factors that affect Alzheimer’s disease.

Whereas previous studies have linked longterm air pollution exposure to accumulation of Alzheimer’s disease-related brain plaques and increased risk of dementia, “these newer studies provide some of the first evidence to suggest that actually reducing pollution is associated with lower risk of all-cause dementia,” said Dr. Edelmayer.

Individuals can control some factors that contribute to dementia risk, such as exercise, diet, and physical activity, but it’s more difficult for them to control exposure to smog and pollution, she said.

“This is probably going to require changes to policy from federal and local governments and businesses, to start addressing the need to improve air quality to help reduce risk for dementia.”

A version of this article first appeared on Medscape.com.

Reducing exposure to air pollution may slow brain aging and reduce the risk of dementia, new research reveals. The findings have implications for individual behaviors, such as avoiding areas with poor air quality, but they also have implications for public policy, said study investigator, Xinhui Wang, PhD, assistant professor of research neurology, department of neurology, University of Southern California, Los Angeles.

“Controlling air quality has great benefits not only for the short-term, for example for pulmonary function or very broadly mortality, but can impact brain function and slow memory function decline and in the long run may reduce dementia cases.”

The findings were presented at the 2021 Alzheimer’s Association International Conference.
 

New approach

Previous research examining the impact of reducing air pollution, which has primarily examined respiratory illnesses and mortality, showed it is beneficial. However, no previous studies have examined the impact of improved air quality on cognitive function.

The current study used a subset of participants from the Women’s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO), which evaluated whether postmenopausal women derive cognitive benefit from hormone therapy.

The analysis included 2,232 community-dwelling older women aged 74-92 (mean age, 81.5 years) who did not have dementia at study enrollment.

Researchers obtained measures of participants’ annual cognitive function from 2008 to 2018. These measures included general cognitive status assessed using the Telephone Interview for Cognitive Status-modified (TICSm) and episodic memory assessed by the telephone-based California Verbal Learning Test (CVLT).

The investigators used complex geographical covariates to estimate exposure to fine particulate matter (PM_2.5) and nitrogen dioxide (NO₂), in areas where individual participants lived from 1996 to 2012. The investigators averaged measures over 3-year periods immediately preceding (recent exposure) and 10 years prior to (remote exposure) enrollment, then calculated individual-level improvements in air quality as the reduction from remote to recent exposures.

The researchers examined pollution exposure and cognitive outcomes at different times to determine causation.

“Maybe the relationship isn’t causal and is just an association, so we tried to separate the timeframe for exposure and outcome and make sure the exposure was before we measured the outcome,” said Dr. Wang.

The investigators adjusted for multiple sociodemographic, lifestyle, and clinical characteristics.
 

Reduced dementia risk

The analysis showed air quality improved significantly for both PM_2.5 and NO₂ before study enrollment. “For almost 95% of the subjects in our study, air quality improved over the 10 years,” said Dr. Wang.

During a median follow-up of 6.2 years, there was a significant decline in cognitive status and episodic memory in study participants, which makes sense, said Dr. Wang, because cognitive function naturally declines with age.

However, a 10% improvement in air quality PM_2.5 and NO₂ resulted in a respective 14% and 26% decreased risk for dementia. This translates into a level of risk seen in women 2 to 3 years younger.

Greater air quality improvement was associated with slower decline in both general cognitive status and episodic memory.

“Participants all declined in cognitive function, but living in areas with the greatest air quality improvement slowed this decline,” said Dr. Wang.

“Whether you look at global cognitive function or memory-specific function, and whether you look at PM_2.5 or NO₂, slower decline was in the range of someone who is 1-2 years younger.”

The associations did not significantly differ by age, region, education, APOE ε4 genotypes, or cardiovascular risk factors.

Patients concerned about cognitive decline can take steps to avoid exposure to pollution by wearing a mask; avoiding heavy traffic, fires, and smoke; or moving to an area with better air quality, said Dr. Wang.

“But our study mainly tried to provide some evidence for policymakers and regulators,” she added.

Another study carried out by the same investigators suggests pollution may affect various cognitive functions differently. This analysis used the same cohort, timeframe, and air quality improvement indicators as the first study but examined the association with specific cognitive domains, including episodic memory, working memory, attention/executive function, and language.

The investigators found women living in locations with greater PM_2.5 improvement performed better on tests of episodic memory (P = .002), working memory (P = .01) and attention/executive function (P = .01), but not language. Findings were similar for improved NO₂.

When looking at air quality improvement and trajectory slopes of decline across cognitive functions, only the association between improved NO₂ and slower episodic memory decline was statistically significant (P < 0.001). “The other domains were marginal or not significant,” said Dr. Wang.

“This suggests that brain regions are impacted differently,” she said, adding that various brain areas oversee different cognitive functions.
 

Important policy implications

Commenting on the research, Rebecca Edelmayer, PhD, senior director of scientific engagement, Alzheimer’s Association, said she welcomes new research on environmental factors that affect Alzheimer’s disease.

Whereas previous studies have linked longterm air pollution exposure to accumulation of Alzheimer’s disease-related brain plaques and increased risk of dementia, “these newer studies provide some of the first evidence to suggest that actually reducing pollution is associated with lower risk of all-cause dementia,” said Dr. Edelmayer.

Individuals can control some factors that contribute to dementia risk, such as exercise, diet, and physical activity, but it’s more difficult for them to control exposure to smog and pollution, she said.

“This is probably going to require changes to policy from federal and local governments and businesses, to start addressing the need to improve air quality to help reduce risk for dementia.”

A version of this article first appeared on Medscape.com.

Reducing exposure to air pollution may slow brain aging and reduce the risk of dementia, new research reveals. The findings have implications for individual behaviors, such as avoiding areas with poor air quality, but they also have implications for public policy, said study investigator, Xinhui Wang, PhD, assistant professor of research neurology, department of neurology, University of Southern California, Los Angeles.

“Controlling air quality has great benefits not only for the short-term, for example for pulmonary function or very broadly mortality, but can impact brain function and slow memory function decline and in the long run may reduce dementia cases.”

The findings were presented at the 2021 Alzheimer’s Association International Conference.
 

New approach

Previous research examining the impact of reducing air pollution, which has primarily examined respiratory illnesses and mortality, showed it is beneficial. However, no previous studies have examined the impact of improved air quality on cognitive function.

The current study used a subset of participants from the Women’s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO), which evaluated whether postmenopausal women derive cognitive benefit from hormone therapy.

The analysis included 2,232 community-dwelling older women aged 74-92 (mean age, 81.5 years) who did not have dementia at study enrollment.

Researchers obtained measures of participants’ annual cognitive function from 2008 to 2018. These measures included general cognitive status assessed using the Telephone Interview for Cognitive Status-modified (TICSm) and episodic memory assessed by the telephone-based California Verbal Learning Test (CVLT).

The investigators used complex geographical covariates to estimate exposure to fine particulate matter (PM_2.5) and nitrogen dioxide (NO₂), in areas where individual participants lived from 1996 to 2012. The investigators averaged measures over 3-year periods immediately preceding (recent exposure) and 10 years prior to (remote exposure) enrollment, then calculated individual-level improvements in air quality as the reduction from remote to recent exposures.

The researchers examined pollution exposure and cognitive outcomes at different times to determine causation.

“Maybe the relationship isn’t causal and is just an association, so we tried to separate the timeframe for exposure and outcome and make sure the exposure was before we measured the outcome,” said Dr. Wang.

The investigators adjusted for multiple sociodemographic, lifestyle, and clinical characteristics.
 

Reduced dementia risk

The analysis showed air quality improved significantly for both PM_2.5 and NO₂ before study enrollment. “For almost 95% of the subjects in our study, air quality improved over the 10 years,” said Dr. Wang.

During a median follow-up of 6.2 years, there was a significant decline in cognitive status and episodic memory in study participants, which makes sense, said Dr. Wang, because cognitive function naturally declines with age.

However, a 10% improvement in air quality PM_2.5 and NO₂ resulted in a respective 14% and 26% decreased risk for dementia. This translates into a level of risk seen in women 2 to 3 years younger.

Greater air quality improvement was associated with slower decline in both general cognitive status and episodic memory.

“Participants all declined in cognitive function, but living in areas with the greatest air quality improvement slowed this decline,” said Dr. Wang.

“Whether you look at global cognitive function or memory-specific function, and whether you look at PM_2.5 or NO₂, slower decline was in the range of someone who is 1-2 years younger.”

The associations did not significantly differ by age, region, education, APOE ε4 genotypes, or cardiovascular risk factors.

Patients concerned about cognitive decline can take steps to avoid exposure to pollution by wearing a mask; avoiding heavy traffic, fires, and smoke; or moving to an area with better air quality, said Dr. Wang.

“But our study mainly tried to provide some evidence for policymakers and regulators,” she added.

Another study carried out by the same investigators suggests pollution may affect various cognitive functions differently. This analysis used the same cohort, timeframe, and air quality improvement indicators as the first study but examined the association with specific cognitive domains, including episodic memory, working memory, attention/executive function, and language.

The investigators found women living in locations with greater PM_2.5 improvement performed better on tests of episodic memory (P = .002), working memory (P = .01) and attention/executive function (P = .01), but not language. Findings were similar for improved NO₂.

When looking at air quality improvement and trajectory slopes of decline across cognitive functions, only the association between improved NO₂ and slower episodic memory decline was statistically significant (P < 0.001). “The other domains were marginal or not significant,” said Dr. Wang.

“This suggests that brain regions are impacted differently,” she said, adding that various brain areas oversee different cognitive functions.
 

Important policy implications

Commenting on the research, Rebecca Edelmayer, PhD, senior director of scientific engagement, Alzheimer’s Association, said she welcomes new research on environmental factors that affect Alzheimer’s disease.

Whereas previous studies have linked longterm air pollution exposure to accumulation of Alzheimer’s disease-related brain plaques and increased risk of dementia, “these newer studies provide some of the first evidence to suggest that actually reducing pollution is associated with lower risk of all-cause dementia,” said Dr. Edelmayer.

Individuals can control some factors that contribute to dementia risk, such as exercise, diet, and physical activity, but it’s more difficult for them to control exposure to smog and pollution, she said.

“This is probably going to require changes to policy from federal and local governments and businesses, to start addressing the need to improve air quality to help reduce risk for dementia.”

A version of this article first appeared on Medscape.com.

An expert panel has released the first recommendations on the appropriate use of aducanumab (Aduhelm), the controversial anti-amyloid drug that was approved by the U.S. Food and Drug Administration in June for adults with early Alzheimer’s disease.

“There are incredible gaps between the FDA label and what most of us in the field feel needs to happen in terms of detailed guidance on using this drug,” said panel member Alireza Atri, MD, PhD, director of the Banner Sun Health Research Institute (Banner Health) in Sun City, Arizona.

“This is a first-in-class drug where the vast majority of clinicians have no experience with it, and patients and their caregivers are already asking for it, and there are some really important conversations to be had – not only about who may qualify to begin with and also about potential effectiveness and safety,” Dr. Atri added.

The aducanumab recommendations were published online July 27 in the Journal of Prevention of Alzheimer’s Disease to coincide with their presentation at the 2021 Alzheimer’s Association International Conference.

A separate article outlining the key recommendations was published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions.
 

Patient-centered focus

The panel recommends that aducanumab only be used for patients with clinical features similar to those of the patients who took part in the clinical trials that led to the drug’s approval – patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease dementia who have brain amyloid, as confirmed on amyloid positron-emission tomography (PET) or with cerebrospinal fluid (CSF) findings consistent with Alzheimer’s disease.

“You’re giving a drug that’s been approved on accelerated status for lowering amyloid, so amyloid status needs to be verified either by an amyloid PET scan or spinal fluid,” said Dr. Atri.

The panel also recommends that patients under consideration for aducanumab treatment have no psychiatric problems; that they be medically stable with no cardiovascular or cardiopulmonary conditions; that they are not taking anticoagulants; that they have no organ failure; and that they have no active cancer except for low-grade basal and squamous cell carcinomas. Current treatment with cholinesterase inhibitors and memantine is acceptable.

Dr. Atri noted that the prescribing label for the drug provides “broad strokes about titration.” The panel recommends that the drug be titrated to the highest dose to maximize opportunity for efficacy.

Monthly infusions should begin with a dose of 1 mg/kg for the first and second infusions. They should be increased to 3 mg/kg for infusions three and four and to 6 mg/kg for the fifth and sixth infusions. The intended dose of 10 mg/kg should be administered on the seventh infusion. The target dose level of 10 mg/kg should then be continued for the foreseeable future, the panel notes.

Safety monitoring is critically important. The panel recommends structured monitoring for amyloid-related imaging abnormalities of the effusion (ARIA-E) or hemorrhagic (ARIA-H) type. Patients should undergo MRI at least 1 year before aducanumab treatment is initiated or at baseline if there are any suggestions of a focal brain event since the last MRI. MRI should again be conducted before the fifth, seventh, and 12th infusions.

The panel says the “best practice” for providing aducanumab therapy is to adopt a patient-centered focus.
 

‘Not a cure’

“There should be comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits,” said Dr. Atri.

“Patients need to know that this is not a cure. It’s not going to actually make their cognition better, but by removing amyloid, there is a reasonable chance it’s going to slow down clinical decline,” he added.

“You could have two identical twins who would qualify, and when you have this discussion with them, based on the risk and reward calculus, one may reasonably decide, ‘this is not for me,’ and that’s really important,” Dr. Atri added.

He cautioned that these initial recommendations are “a starting point, not a finishing point,” and will be updated as needed.

“This paper takes no stance on advocating for this treatment. But now that it’s available, let’s put up some guardrails and use it appropriately and safety,” Dr. Atri said.

“Clinicians are requesting clarity and more specific information about the appropriate use of this new treatment,” Rebecca Edelmayer, PhD, senior director of scientific engagement, the Alzheimer’s Association, said in an interview.

These first appropriate-use recommendations are “a first step and will certainly evolve over time as the medication is prescribed,” Dr. Edelmayer said.

The research had no specific funding. Dr. Atri has received honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Sunovion, and Suven. Dr. Edelmayer has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An expert panel has released the first recommendations on the appropriate use of aducanumab (Aduhelm), the controversial anti-amyloid drug that was approved by the U.S. Food and Drug Administration in June for adults with early Alzheimer’s disease.

“There are incredible gaps between the FDA label and what most of us in the field feel needs to happen in terms of detailed guidance on using this drug,” said panel member Alireza Atri, MD, PhD, director of the Banner Sun Health Research Institute (Banner Health) in Sun City, Arizona.

“This is a first-in-class drug where the vast majority of clinicians have no experience with it, and patients and their caregivers are already asking for it, and there are some really important conversations to be had – not only about who may qualify to begin with and also about potential effectiveness and safety,” Dr. Atri added.

The aducanumab recommendations were published online July 27 in the Journal of Prevention of Alzheimer’s Disease to coincide with their presentation at the 2021 Alzheimer’s Association International Conference.

A separate article outlining the key recommendations was published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions.
 

Patient-centered focus

The panel recommends that aducanumab only be used for patients with clinical features similar to those of the patients who took part in the clinical trials that led to the drug’s approval – patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease dementia who have brain amyloid, as confirmed on amyloid positron-emission tomography (PET) or with cerebrospinal fluid (CSF) findings consistent with Alzheimer’s disease.

“You’re giving a drug that’s been approved on accelerated status for lowering amyloid, so amyloid status needs to be verified either by an amyloid PET scan or spinal fluid,” said Dr. Atri.

The panel also recommends that patients under consideration for aducanumab treatment have no psychiatric problems; that they be medically stable with no cardiovascular or cardiopulmonary conditions; that they are not taking anticoagulants; that they have no organ failure; and that they have no active cancer except for low-grade basal and squamous cell carcinomas. Current treatment with cholinesterase inhibitors and memantine is acceptable.

Dr. Atri noted that the prescribing label for the drug provides “broad strokes about titration.” The panel recommends that the drug be titrated to the highest dose to maximize opportunity for efficacy.

Monthly infusions should begin with a dose of 1 mg/kg for the first and second infusions. They should be increased to 3 mg/kg for infusions three and four and to 6 mg/kg for the fifth and sixth infusions. The intended dose of 10 mg/kg should be administered on the seventh infusion. The target dose level of 10 mg/kg should then be continued for the foreseeable future, the panel notes.

Safety monitoring is critically important. The panel recommends structured monitoring for amyloid-related imaging abnormalities of the effusion (ARIA-E) or hemorrhagic (ARIA-H) type. Patients should undergo MRI at least 1 year before aducanumab treatment is initiated or at baseline if there are any suggestions of a focal brain event since the last MRI. MRI should again be conducted before the fifth, seventh, and 12th infusions.

The panel says the “best practice” for providing aducanumab therapy is to adopt a patient-centered focus.
 

‘Not a cure’

“There should be comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits,” said Dr. Atri.

“Patients need to know that this is not a cure. It’s not going to actually make their cognition better, but by removing amyloid, there is a reasonable chance it’s going to slow down clinical decline,” he added.

“You could have two identical twins who would qualify, and when you have this discussion with them, based on the risk and reward calculus, one may reasonably decide, ‘this is not for me,’ and that’s really important,” Dr. Atri added.

He cautioned that these initial recommendations are “a starting point, not a finishing point,” and will be updated as needed.

“This paper takes no stance on advocating for this treatment. But now that it’s available, let’s put up some guardrails and use it appropriately and safety,” Dr. Atri said.

“Clinicians are requesting clarity and more specific information about the appropriate use of this new treatment,” Rebecca Edelmayer, PhD, senior director of scientific engagement, the Alzheimer’s Association, said in an interview.

These first appropriate-use recommendations are “a first step and will certainly evolve over time as the medication is prescribed,” Dr. Edelmayer said.

The research had no specific funding. Dr. Atri has received honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Sunovion, and Suven. Dr. Edelmayer has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An expert panel has released the first recommendations on the appropriate use of aducanumab (Aduhelm), the controversial anti-amyloid drug that was approved by the U.S. Food and Drug Administration in June for adults with early Alzheimer’s disease.

“There are incredible gaps between the FDA label and what most of us in the field feel needs to happen in terms of detailed guidance on using this drug,” said panel member Alireza Atri, MD, PhD, director of the Banner Sun Health Research Institute (Banner Health) in Sun City, Arizona.

“This is a first-in-class drug where the vast majority of clinicians have no experience with it, and patients and their caregivers are already asking for it, and there are some really important conversations to be had – not only about who may qualify to begin with and also about potential effectiveness and safety,” Dr. Atri added.

The aducanumab recommendations were published online July 27 in the Journal of Prevention of Alzheimer’s Disease to coincide with their presentation at the 2021 Alzheimer’s Association International Conference.

A separate article outlining the key recommendations was published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions.
 

Patient-centered focus

The panel recommends that aducanumab only be used for patients with clinical features similar to those of the patients who took part in the clinical trials that led to the drug’s approval – patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease dementia who have brain amyloid, as confirmed on amyloid positron-emission tomography (PET) or with cerebrospinal fluid (CSF) findings consistent with Alzheimer’s disease.

“You’re giving a drug that’s been approved on accelerated status for lowering amyloid, so amyloid status needs to be verified either by an amyloid PET scan or spinal fluid,” said Dr. Atri.

The panel also recommends that patients under consideration for aducanumab treatment have no psychiatric problems; that they be medically stable with no cardiovascular or cardiopulmonary conditions; that they are not taking anticoagulants; that they have no organ failure; and that they have no active cancer except for low-grade basal and squamous cell carcinomas. Current treatment with cholinesterase inhibitors and memantine is acceptable.

Dr. Atri noted that the prescribing label for the drug provides “broad strokes about titration.” The panel recommends that the drug be titrated to the highest dose to maximize opportunity for efficacy.

Monthly infusions should begin with a dose of 1 mg/kg for the first and second infusions. They should be increased to 3 mg/kg for infusions three and four and to 6 mg/kg for the fifth and sixth infusions. The intended dose of 10 mg/kg should be administered on the seventh infusion. The target dose level of 10 mg/kg should then be continued for the foreseeable future, the panel notes.

Safety monitoring is critically important. The panel recommends structured monitoring for amyloid-related imaging abnormalities of the effusion (ARIA-E) or hemorrhagic (ARIA-H) type. Patients should undergo MRI at least 1 year before aducanumab treatment is initiated or at baseline if there are any suggestions of a focal brain event since the last MRI. MRI should again be conducted before the fifth, seventh, and 12th infusions.

The panel says the “best practice” for providing aducanumab therapy is to adopt a patient-centered focus.
 

‘Not a cure’

“There should be comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits,” said Dr. Atri.

“Patients need to know that this is not a cure. It’s not going to actually make their cognition better, but by removing amyloid, there is a reasonable chance it’s going to slow down clinical decline,” he added.

“You could have two identical twins who would qualify, and when you have this discussion with them, based on the risk and reward calculus, one may reasonably decide, ‘this is not for me,’ and that’s really important,” Dr. Atri added.

He cautioned that these initial recommendations are “a starting point, not a finishing point,” and will be updated as needed.

“This paper takes no stance on advocating for this treatment. But now that it’s available, let’s put up some guardrails and use it appropriately and safety,” Dr. Atri said.

“Clinicians are requesting clarity and more specific information about the appropriate use of this new treatment,” Rebecca Edelmayer, PhD, senior director of scientific engagement, the Alzheimer’s Association, said in an interview.

These first appropriate-use recommendations are “a first step and will certainly evolve over time as the medication is prescribed,” Dr. Edelmayer said.

The research had no specific funding. Dr. Atri has received honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Sunovion, and Suven. Dr. Edelmayer has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

When used for appropriate patients, MRI imaging is helpful in congenital melanocytic nevus (CMN) management and may help predict neurologic outcomes or drive neurosurgical intervention, results from a small multi-institutional study showed.

“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”

One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.

“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.

To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.

The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).

“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.

The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.

All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”

The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.

Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.

“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”

Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.

Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.

dbrunk@mdedge.com

When used for appropriate patients, MRI imaging is helpful in congenital melanocytic nevus (CMN) management and may help predict neurologic outcomes or drive neurosurgical intervention, results from a small multi-institutional study showed.

“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”

One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.

“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.

To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.

The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).

“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.

The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.

All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”

The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.

Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.

“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”

Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.

Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.

dbrunk@mdedge.com

When used for appropriate patients, MRI imaging is helpful in congenital melanocytic nevus (CMN) management and may help predict neurologic outcomes or drive neurosurgical intervention, results from a small multi-institutional study showed.

“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”

One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.

“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.

To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.

The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).

“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.

The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.

All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”

The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.

Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.

“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”

Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.

Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.

dbrunk@mdedge.com

Many validation studies of clinician- and patient-reported outcome measures for atopic dermatitis (AD) lack adequate reporting of race, ethnicity, and skin tone, according to results from a systematic review.

“AD is associated with considerable heterogeneity across different races and skin tones,” presenting study author Trisha Kaundinya said at the Revolutionizing Atopic Dermatitis symposium. “Compared with lighter skin tones, darker skin tones more commonly have diffuse xerosis, Dennis-Morgan lines, hyperlinearity of the palms, periorbital dark circles, lichenification, and prurigo nodularis. This heterogeneity can be challenging to assess in clinical trials and in practice.”

The Harmonizing Outcome Measures for Eczema (HOME) group has selected several scales by international consensus. For clinical trials, the group recommends the Patient-Oriented Eczema Measure (POEM), Eczema Area and Severity Index (EASI), and Dermatology Life Quality Index (DLQI). In clinical practice, the HOME group recommends the POEM, Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD), and the Numeric Rating Scale (NRS)-itch measures. “The psychometric validity and reliability of these outcome measures have undergone robust investigation before, but the validity and reliability of these outcome measures remains uncertain across different races, ethnicities, and skin tones,” Ms. Kaundinya said.

Jonathan Silverberg, MD, PhD, associate professor of dermatology at George Washington University, Washington, in collaboration with Andrew F. Alexis, MD, MPH, vice-chair for diversity and inclusion for the department of dermatology at Weill-Cornell Medicine, New York, and Jacob P. Thyssen, MD, PhD, at the University of Copenhagen, Denmark, sought to examine reporting of race, ethnicity, and skin tone, and to compare results across these groups from studies of psychometric properties for outcome measures in AD. Under the mentorship of Dr. Silverberg, Ms. Kaundinya, a medical student at Northwestern University, Chicago, and her research associates conducted a systematic review that searched PubMed and Embase and identified 165 relevant published studies of 41,146 individuals.

Of the individuals participating in these 165 studies, 73% had an unspecified racial background, 18% were White, 4% were Asian, 2% were Black, 2% were Hispanic, 1% were multiracial/other, and the remainder were American Indian/Alaskan Native. Only 55 of the studies (33%) reported the distribution of race or ethnicity, 5 (3%) reported the distribution of skin tone, and 16 (10%) reported psychometric differences in patients with different races, ethnicities, or skin tones. In addition, only 5 of 113 (4%) studies that did not report race, ethnicity, or skin tone–based differences acknowledged absence of stratification as a limitation.

Of note, significant differential item functioning was found between race subgroups for one or more items of the PO-SCORAD, the Patient-Reported Outcomes Measurement Information System (PROMIS) Itch Questionnaire (PIQ) Short Forms, POEM, DLQI, Hospital Anxiety and Depression Scale (HADS), Itchy Quality of Life (ItchyQOL) scale, 5-dimensions (5D) itch scale, Short Form (SF)-12, and NRS-itch. “Correlations of the POEM with the Investigator’s Global Assessment (IGA) differed the most between skin of color and lighter skin,” Ms. Kaundinya said.

“The POEM did seem to correlate similarly with the DLQI and the EASI in both white and nonwhite participants, which may indicate why this trifecta of instruments is recommended by the HOME group. One study found that substituting the erythema component of the EASI scale with greyness for darker skin, in which erythema is more challenging to assess, did not significantly improve the reliability of EASI. This indicates that further research is needed to investigate how EASI can be modified to perform better in darker skin tones.”

She pointed out that some studies of clinician-reported outcome measures were underpowered to detect meaningful differences between patient subgroups. “There were also insufficient data to perform meta-regression of differences between patient subgroups,” she said. “Overall, future studies are needed to determine whether outcome measures recommended by the HOME and other tools perform equally well across diverse patient populations. This systematic review indicates significant reporting and knowledge gaps for psychometric properties of outcome measures by race, ethnicity, or skin tone in AD.”

Ms. Kaundinya reported having no relevant financial disclosures. Dr. Silverberg, the study’s senior author, is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

dbrunk@mdedge.com

Many validation studies of clinician- and patient-reported outcome measures for atopic dermatitis (AD) lack adequate reporting of race, ethnicity, and skin tone, according to results from a systematic review.

“AD is associated with considerable heterogeneity across different races and skin tones,” presenting study author Trisha Kaundinya said at the Revolutionizing Atopic Dermatitis symposium. “Compared with lighter skin tones, darker skin tones more commonly have diffuse xerosis, Dennis-Morgan lines, hyperlinearity of the palms, periorbital dark circles, lichenification, and prurigo nodularis. This heterogeneity can be challenging to assess in clinical trials and in practice.”

The Harmonizing Outcome Measures for Eczema (HOME) group has selected several scales by international consensus. For clinical trials, the group recommends the Patient-Oriented Eczema Measure (POEM), Eczema Area and Severity Index (EASI), and Dermatology Life Quality Index (DLQI). In clinical practice, the HOME group recommends the POEM, Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD), and the Numeric Rating Scale (NRS)-itch measures. “The psychometric validity and reliability of these outcome measures have undergone robust investigation before, but the validity and reliability of these outcome measures remains uncertain across different races, ethnicities, and skin tones,” Ms. Kaundinya said.

Jonathan Silverberg, MD, PhD, associate professor of dermatology at George Washington University, Washington, in collaboration with Andrew F. Alexis, MD, MPH, vice-chair for diversity and inclusion for the department of dermatology at Weill-Cornell Medicine, New York, and Jacob P. Thyssen, MD, PhD, at the University of Copenhagen, Denmark, sought to examine reporting of race, ethnicity, and skin tone, and to compare results across these groups from studies of psychometric properties for outcome measures in AD. Under the mentorship of Dr. Silverberg, Ms. Kaundinya, a medical student at Northwestern University, Chicago, and her research associates conducted a systematic review that searched PubMed and Embase and identified 165 relevant published studies of 41,146 individuals.

Of the individuals participating in these 165 studies, 73% had an unspecified racial background, 18% were White, 4% were Asian, 2% were Black, 2% were Hispanic, 1% were multiracial/other, and the remainder were American Indian/Alaskan Native. Only 55 of the studies (33%) reported the distribution of race or ethnicity, 5 (3%) reported the distribution of skin tone, and 16 (10%) reported psychometric differences in patients with different races, ethnicities, or skin tones. In addition, only 5 of 113 (4%) studies that did not report race, ethnicity, or skin tone–based differences acknowledged absence of stratification as a limitation.

Of note, significant differential item functioning was found between race subgroups for one or more items of the PO-SCORAD, the Patient-Reported Outcomes Measurement Information System (PROMIS) Itch Questionnaire (PIQ) Short Forms, POEM, DLQI, Hospital Anxiety and Depression Scale (HADS), Itchy Quality of Life (ItchyQOL) scale, 5-dimensions (5D) itch scale, Short Form (SF)-12, and NRS-itch. “Correlations of the POEM with the Investigator’s Global Assessment (IGA) differed the most between skin of color and lighter skin,” Ms. Kaundinya said.

“The POEM did seem to correlate similarly with the DLQI and the EASI in both white and nonwhite participants, which may indicate why this trifecta of instruments is recommended by the HOME group. One study found that substituting the erythema component of the EASI scale with greyness for darker skin, in which erythema is more challenging to assess, did not significantly improve the reliability of EASI. This indicates that further research is needed to investigate how EASI can be modified to perform better in darker skin tones.”

She pointed out that some studies of clinician-reported outcome measures were underpowered to detect meaningful differences between patient subgroups. “There were also insufficient data to perform meta-regression of differences between patient subgroups,” she said. “Overall, future studies are needed to determine whether outcome measures recommended by the HOME and other tools perform equally well across diverse patient populations. This systematic review indicates significant reporting and knowledge gaps for psychometric properties of outcome measures by race, ethnicity, or skin tone in AD.”

Ms. Kaundinya reported having no relevant financial disclosures. Dr. Silverberg, the study’s senior author, is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

dbrunk@mdedge.com

Many validation studies of clinician- and patient-reported outcome measures for atopic dermatitis (AD) lack adequate reporting of race, ethnicity, and skin tone, according to results from a systematic review.

“AD is associated with considerable heterogeneity across different races and skin tones,” presenting study author Trisha Kaundinya said at the Revolutionizing Atopic Dermatitis symposium. “Compared with lighter skin tones, darker skin tones more commonly have diffuse xerosis, Dennis-Morgan lines, hyperlinearity of the palms, periorbital dark circles, lichenification, and prurigo nodularis. This heterogeneity can be challenging to assess in clinical trials and in practice.”

The Harmonizing Outcome Measures for Eczema (HOME) group has selected several scales by international consensus. For clinical trials, the group recommends the Patient-Oriented Eczema Measure (POEM), Eczema Area and Severity Index (EASI), and Dermatology Life Quality Index (DLQI). In clinical practice, the HOME group recommends the POEM, Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD), and the Numeric Rating Scale (NRS)-itch measures. “The psychometric validity and reliability of these outcome measures have undergone robust investigation before, but the validity and reliability of these outcome measures remains uncertain across different races, ethnicities, and skin tones,” Ms. Kaundinya said.

Jonathan Silverberg, MD, PhD, associate professor of dermatology at George Washington University, Washington, in collaboration with Andrew F. Alexis, MD, MPH, vice-chair for diversity and inclusion for the department of dermatology at Weill-Cornell Medicine, New York, and Jacob P. Thyssen, MD, PhD, at the University of Copenhagen, Denmark, sought to examine reporting of race, ethnicity, and skin tone, and to compare results across these groups from studies of psychometric properties for outcome measures in AD. Under the mentorship of Dr. Silverberg, Ms. Kaundinya, a medical student at Northwestern University, Chicago, and her research associates conducted a systematic review that searched PubMed and Embase and identified 165 relevant published studies of 41,146 individuals.

Of the individuals participating in these 165 studies, 73% had an unspecified racial background, 18% were White, 4% were Asian, 2% were Black, 2% were Hispanic, 1% were multiracial/other, and the remainder were American Indian/Alaskan Native. Only 55 of the studies (33%) reported the distribution of race or ethnicity, 5 (3%) reported the distribution of skin tone, and 16 (10%) reported psychometric differences in patients with different races, ethnicities, or skin tones. In addition, only 5 of 113 (4%) studies that did not report race, ethnicity, or skin tone–based differences acknowledged absence of stratification as a limitation.

Of note, significant differential item functioning was found between race subgroups for one or more items of the PO-SCORAD, the Patient-Reported Outcomes Measurement Information System (PROMIS) Itch Questionnaire (PIQ) Short Forms, POEM, DLQI, Hospital Anxiety and Depression Scale (HADS), Itchy Quality of Life (ItchyQOL) scale, 5-dimensions (5D) itch scale, Short Form (SF)-12, and NRS-itch. “Correlations of the POEM with the Investigator’s Global Assessment (IGA) differed the most between skin of color and lighter skin,” Ms. Kaundinya said.

“The POEM did seem to correlate similarly with the DLQI and the EASI in both white and nonwhite participants, which may indicate why this trifecta of instruments is recommended by the HOME group. One study found that substituting the erythema component of the EASI scale with greyness for darker skin, in which erythema is more challenging to assess, did not significantly improve the reliability of EASI. This indicates that further research is needed to investigate how EASI can be modified to perform better in darker skin tones.”

She pointed out that some studies of clinician-reported outcome measures were underpowered to detect meaningful differences between patient subgroups. “There were also insufficient data to perform meta-regression of differences between patient subgroups,” she said. “Overall, future studies are needed to determine whether outcome measures recommended by the HOME and other tools perform equally well across diverse patient populations. This systematic review indicates significant reporting and knowledge gaps for psychometric properties of outcome measures by race, ethnicity, or skin tone in AD.”

Ms. Kaundinya reported having no relevant financial disclosures. Dr. Silverberg, the study’s senior author, is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

dbrunk@mdedge.com

A dyadic telehealth intervention to help people with dementia and their caregivers can achieve outcomes similar to those of traditional, in-person approaches. The program combines information, education, and skills training to help participants overcome specific challenges.

“It focuses on individualized problem solving and is tailored to the needs of the person. The focus is not just on educating caregivers, but working on strategies to maintain independence in the person with dementia and support them to remain active and engaged,” said Kate Laver, PhD, who presented the study at the annual meeting of the Alzheimer’s Association International Conference. Dr. Laver is an associate professor in the College of Medicine and Public Health at Flinders University in Adelaide, South Australia.

The program is called Care of Persons with Dementia in Their Environments (COPE), and has previously been demonstrated to improve outcomes when conducted through in-person home visits. Over a maximum of ten sessions in 4 months, COPE employs occupational therapists and individuals with nursing skills to identify environmental stressors that can be modified to reduce sensory, physical, and cognitive demands. It also looks for comorbidities in the person with dementia that could be contributing to poor functioning. The goal of COPE is to encourage the person with dementia to reengage in daily activities, and to reduce caregiver burden as a result.

In a 2020 study, Dr. Laver and colleagues showed that COPE is noninferior when delivered by telehealth compared with in-person delivery. They randomized 63 caregiver-patient dyads to telehealth or home visit delivery of the COPE program. Sixty percent of the persons with dementia were male, and the mean caregiver time was 32 months.

Similar improvements in outcomes were seen in both groups, with no statistically significant differences for the primary outcome of change in Caregiver Mastery Index score at 4 months (mean difference, 0.09; 95% confidence interval, –1.26 to 1.45). Similar changes were also seen in the Perceived Change Scale, which is a 13-item caregiver questionnaire that covers day-to-day care challenges, including feeling overwhelmed or upset, sleeping patterns, and availability of personal time.

Not surprisingly, telehealth implementation led to reduced mean travel time (77.2 minutes vs. 255.9 minutes; P < .0001). The face-to-face time was shorter in the telehealth group (308 vs. 337 minutes), though the difference was not statistically significant. Dr. Laver noted that the consent rate was high at 75%, but there were some missed sessions.
 

Lessons learned

During the presentation, Dr. Laver emphasized some lessons learned from conversion to a telehealth model. These included providing a tablet and stand on loan, a user guide with pictures, and an initial on-site training session. The first two sessions were conducted on site to do an in-person demonstration and to assess the participants and the home environment.

She noted that it was important to have an IT support person on call to help participants use the provided tablet if needed, though this was rarely used.

“Although few people (at the time) had their own devices, they were able to quickly master videoconferencing. We felt that it was important to ensure that the first couple of consultations were in person – this enabled the therapist to develop rapport, practice use of videoconferencing, and get a good idea of the person’s environment and relationship with the person with dementia,” said Dr. Laver.

She noted that telehealth can be more efficient, and even preferred, during times like the COVID-19 pandemic, as well as in rural settings. But home visits will always be needed. “They are important for developing rapport and enabling a comprehensive assessment of the person with dementia, relationships, and environment. They are also preferred by some caregivers,” said Dr. Laver.

The demonstration of equivalence to in-person delivery was welcome, said Ingo Kilimann, MD, who comoderated the session where Dr. Laver presented. “We have to bring help to the families where they are, and not just tell them where they can get the help, because some people are just not able to actually come to some specialists’ centers. So it’s very important information that it does work,” said Dr. Kilimann, who is a dementia neurologist and head of the memory clinic at the The German Center for Neurodegenerative Diseases in Bonn.

He added that mixing of on-site and remote sessions is a good model. “I think that is the way to be most effective – to have someone in person at the person with dementia’s house, and then have online support for the rest of the time, and then it can be as successful as a total in-person intervention,” said Dr. Kilimann.

Dr. Laver had no relevant financial disclosures.

A dyadic telehealth intervention to help people with dementia and their caregivers can achieve outcomes similar to those of traditional, in-person approaches. The program combines information, education, and skills training to help participants overcome specific challenges.

“It focuses on individualized problem solving and is tailored to the needs of the person. The focus is not just on educating caregivers, but working on strategies to maintain independence in the person with dementia and support them to remain active and engaged,” said Kate Laver, PhD, who presented the study at the annual meeting of the Alzheimer’s Association International Conference. Dr. Laver is an associate professor in the College of Medicine and Public Health at Flinders University in Adelaide, South Australia.

The program is called Care of Persons with Dementia in Their Environments (COPE), and has previously been demonstrated to improve outcomes when conducted through in-person home visits. Over a maximum of ten sessions in 4 months, COPE employs occupational therapists and individuals with nursing skills to identify environmental stressors that can be modified to reduce sensory, physical, and cognitive demands. It also looks for comorbidities in the person with dementia that could be contributing to poor functioning. The goal of COPE is to encourage the person with dementia to reengage in daily activities, and to reduce caregiver burden as a result.

In a 2020 study, Dr. Laver and colleagues showed that COPE is noninferior when delivered by telehealth compared with in-person delivery. They randomized 63 caregiver-patient dyads to telehealth or home visit delivery of the COPE program. Sixty percent of the persons with dementia were male, and the mean caregiver time was 32 months.

Similar improvements in outcomes were seen in both groups, with no statistically significant differences for the primary outcome of change in Caregiver Mastery Index score at 4 months (mean difference, 0.09; 95% confidence interval, –1.26 to 1.45). Similar changes were also seen in the Perceived Change Scale, which is a 13-item caregiver questionnaire that covers day-to-day care challenges, including feeling overwhelmed or upset, sleeping patterns, and availability of personal time.

Not surprisingly, telehealth implementation led to reduced mean travel time (77.2 minutes vs. 255.9 minutes; P < .0001). The face-to-face time was shorter in the telehealth group (308 vs. 337 minutes), though the difference was not statistically significant. Dr. Laver noted that the consent rate was high at 75%, but there were some missed sessions.
 

Lessons learned

During the presentation, Dr. Laver emphasized some lessons learned from conversion to a telehealth model. These included providing a tablet and stand on loan, a user guide with pictures, and an initial on-site training session. The first two sessions were conducted on site to do an in-person demonstration and to assess the participants and the home environment.

She noted that it was important to have an IT support person on call to help participants use the provided tablet if needed, though this was rarely used.

“Although few people (at the time) had their own devices, they were able to quickly master videoconferencing. We felt that it was important to ensure that the first couple of consultations were in person – this enabled the therapist to develop rapport, practice use of videoconferencing, and get a good idea of the person’s environment and relationship with the person with dementia,” said Dr. Laver.

She noted that telehealth can be more efficient, and even preferred, during times like the COVID-19 pandemic, as well as in rural settings. But home visits will always be needed. “They are important for developing rapport and enabling a comprehensive assessment of the person with dementia, relationships, and environment. They are also preferred by some caregivers,” said Dr. Laver.

The demonstration of equivalence to in-person delivery was welcome, said Ingo Kilimann, MD, who comoderated the session where Dr. Laver presented. “We have to bring help to the families where they are, and not just tell them where they can get the help, because some people are just not able to actually come to some specialists’ centers. So it’s very important information that it does work,” said Dr. Kilimann, who is a dementia neurologist and head of the memory clinic at the The German Center for Neurodegenerative Diseases in Bonn.

He added that mixing of on-site and remote sessions is a good model. “I think that is the way to be most effective – to have someone in person at the person with dementia’s house, and then have online support for the rest of the time, and then it can be as successful as a total in-person intervention,” said Dr. Kilimann.

Dr. Laver had no relevant financial disclosures.

A dyadic telehealth intervention to help people with dementia and their caregivers can achieve outcomes similar to those of traditional, in-person approaches. The program combines information, education, and skills training to help participants overcome specific challenges.

“It focuses on individualized problem solving and is tailored to the needs of the person. The focus is not just on educating caregivers, but working on strategies to maintain independence in the person with dementia and support them to remain active and engaged,” said Kate Laver, PhD, who presented the study at the annual meeting of the Alzheimer’s Association International Conference. Dr. Laver is an associate professor in the College of Medicine and Public Health at Flinders University in Adelaide, South Australia.

The program is called Care of Persons with Dementia in Their Environments (COPE), and has previously been demonstrated to improve outcomes when conducted through in-person home visits. Over a maximum of ten sessions in 4 months, COPE employs occupational therapists and individuals with nursing skills to identify environmental stressors that can be modified to reduce sensory, physical, and cognitive demands. It also looks for comorbidities in the person with dementia that could be contributing to poor functioning. The goal of COPE is to encourage the person with dementia to reengage in daily activities, and to reduce caregiver burden as a result.

In a 2020 study, Dr. Laver and colleagues showed that COPE is noninferior when delivered by telehealth compared with in-person delivery. They randomized 63 caregiver-patient dyads to telehealth or home visit delivery of the COPE program. Sixty percent of the persons with dementia were male, and the mean caregiver time was 32 months.

Similar improvements in outcomes were seen in both groups, with no statistically significant differences for the primary outcome of change in Caregiver Mastery Index score at 4 months (mean difference, 0.09; 95% confidence interval, –1.26 to 1.45). Similar changes were also seen in the Perceived Change Scale, which is a 13-item caregiver questionnaire that covers day-to-day care challenges, including feeling overwhelmed or upset, sleeping patterns, and availability of personal time.

Not surprisingly, telehealth implementation led to reduced mean travel time (77.2 minutes vs. 255.9 minutes; P < .0001). The face-to-face time was shorter in the telehealth group (308 vs. 337 minutes), though the difference was not statistically significant. Dr. Laver noted that the consent rate was high at 75%, but there were some missed sessions.
 

Lessons learned

During the presentation, Dr. Laver emphasized some lessons learned from conversion to a telehealth model. These included providing a tablet and stand on loan, a user guide with pictures, and an initial on-site training session. The first two sessions were conducted on site to do an in-person demonstration and to assess the participants and the home environment.

She noted that it was important to have an IT support person on call to help participants use the provided tablet if needed, though this was rarely used.

“Although few people (at the time) had their own devices, they were able to quickly master videoconferencing. We felt that it was important to ensure that the first couple of consultations were in person – this enabled the therapist to develop rapport, practice use of videoconferencing, and get a good idea of the person’s environment and relationship with the person with dementia,” said Dr. Laver.

She noted that telehealth can be more efficient, and even preferred, during times like the COVID-19 pandemic, as well as in rural settings. But home visits will always be needed. “They are important for developing rapport and enabling a comprehensive assessment of the person with dementia, relationships, and environment. They are also preferred by some caregivers,” said Dr. Laver.

The demonstration of equivalence to in-person delivery was welcome, said Ingo Kilimann, MD, who comoderated the session where Dr. Laver presented. “We have to bring help to the families where they are, and not just tell them where they can get the help, because some people are just not able to actually come to some specialists’ centers. So it’s very important information that it does work,” said Dr. Kilimann, who is a dementia neurologist and head of the memory clinic at the The German Center for Neurodegenerative Diseases in Bonn.

He added that mixing of on-site and remote sessions is a good model. “I think that is the way to be most effective – to have someone in person at the person with dementia’s house, and then have online support for the rest of the time, and then it can be as successful as a total in-person intervention,” said Dr. Kilimann.

Dr. Laver had no relevant financial disclosures.

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

dbrunk@mdedge.com

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

dbrunk@mdedge.com

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

dbrunk@mdedge.com