Expert Perspective

Dr. Messoud Ashina is a Professor of Neurology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. He is Director of the Human Migraine Research Unit at the Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup. He serves an associate editor for Cephalalgia, Journal of Headache and Pain, and Brain.

Dr. Faisal Mohammad Amin is an Associate Professor, Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Denmark. He is an associate editor for Headache Medicine and is President of the Danish Headache Society.

Dr. Ashina reports that he has received fees and grants from and/or has served as a principal trial investigator for AbbVie, Amgen, Eli Lilly, Lundbeck Pharmaceuticals, Lundbeck Foundation, Novartis, Novo Nordisk Foundation, and Teva.

Dr. Amin reports that he has worked as a consultant, speaker, and/or primary investigator Eli Lilly, Lundbeck, Novartis, and Teva. Both authors have reported that they have no ownership interest nor own any stocks in a pharmaceutical company.

Since the time of the Neanderthals, humankind has looked for ways to rid the brain of migraine headache. There is evidence that trepanation–removing a portion of bone from the skull–was performed on Neolithic skulls. Did it work for that poor individual? We will never know.

What is known is that the often circuitous hunt for effective treatments has taken centuries. And while this search led to the successful introduction of calcitonin gene-related peptides (CGRPs) a few years ago, the search is nowhere near finished, as efforts to pinpoint the source of migraine continue, as does the search for other possible therapies.

The nearly 39 million people with migraine in the United States  would be grateful; they often experience a perplexing, frustrating, and unsatisfactory search for a pain-free existence. Migraine is estimated to cost more than $20 million per year in direct medical expenses and lost productivity in the United States. People with migraine, meanwhile, face the prospect of significant disability. More than 8 in every 10 participants in the American Migraine Study had at least some headache-related disability. More than half said their pain has caused severe impairment.

The search to find relief for these patients is focused on understanding the pathophysiology of migraine. Approaches include in vitro application of mediators, direct electrical stimulation of trigeminal neurons in vivo, administration of vasoactive substances in vivo, and introduction of exogenous pain-inducing substances in vivo. In 2021, investigators at AstraZeneca and the University of Arizona College of Medicine described their development of an injury-free murine model to be used to study migraine-like pain. Animal research has led to a few interventional studies involving new and existing medications. 

How the field has evolved from using a chisel to make a cranial hole to using magnetic resonance imaging and other technologies to examine the trigeminovascular system’s role in the pathophysiology of migraine headache is a tale worth telling.

From crocodiles to nitroglycerin to allergies

The search for an effective remedy for migraine has proved to be torturously slow. In addition to trepanation, another procedure thought to have been used during prehistoric times involved a religious ritual whereby a clay crocodile was attached tightly with a strip of linen to an individual’s head. Though the gods were credited if the headache pain receded, relief likely came from the resulting compression on the scalp. Centuries later, in the Middle Ages, treatments included soaking bandages in drugs and then applying them to the head or mixing elixirs with vinegar (which opened scalp pores) and opium (which traveled into the scalp through the open pores).

The Persian scholar Ibn Sina (980-1032), also known as Avicenna, postulated that the pain could emanate from the bones that comprise the skull or within the parenchyma or from veins and arteries outside the cranium. The medicinal plants he investigated for the treatment of migraine have components that resonate today: antineuroinflammatory agents, analgesics, and even cyclooxegenase-2 inhibitors.

Six hundred years later, English physician Thomas Willis discussed how the vascular system perpetrated migraine, and in the next century, Erasmus Darwin, Charles’ grandfather, proposed that individuals with migraine be spun around so that blood from the head would be forced down toward the feet. In the 1800s, English physician Edward Liveing abandoned vascular theory, instead proposing that migraine resulted from discharges of the central nervous system.

British neurologist William Gowers thought migraine could be a derangement of neurons, but ultimately wrote in his Manual of Diseases (p. 852) that, “When all has been that can be, mystery still envelops the mechanism of migraine.” Gowers advocated continuous treatment with drugs to minimize the frequency of attacks, as well as treating the attacks themselves. His preferred treatments were nitroglycerin in alcohol, combined with other agents, as well as marijuana. His choice of nitroglycerin is an interesting one, given that modern medicine considers nitroglycerin an important neurochemical in migraine initiation.

The concept of neuronal involvement retained support into the 20th century, solidified by German physician Paul Ehrlich’s Nobel Prize–winning work involving immunology and brain receptors. In the 1920s, thoughts turned to allergy as the source of migraine, as an association between migraine, asthma, and urticaria emerged, but this connection was eventually proved to be incidental, not causal.

In the 1930s, the vascular theory again was vogue -- aided by studies performed by US physician Harold G. Wolff. His work, the first to assess headache in a laboratory setting, along with observations about changes in vasculature and evolving treatment, appeared to support the vascular nature of headache. In the 1940s and 1950s, psychosomatic disorders crept into the mix of possible causes. Some categorized migraine as a so-called stress disease.

Puzzles and irony

In 1979, Moskowitz and colleagues introduced a new hypothesis focused on the importance of the neuropeptide-containing trigeminal nerve. CGRP is stored in vesicles in sensory nerve terminals, where it is released along with the vasodilating peptide, substance P, when the trigeminal nerve is activated.

At about the same time, researchers in England were working on a discovery with ancestral roots going back hundreds of years. In the 18th century, scientists learned that rye ergot was a constrictor of blood vessels. In time, ergot became ergotamine and hence more valuable because it could reduce vascular headaches. But the adverse effects, prominent in those with cardiovascular disease, kept researchers in the lab.

So, while Moskowitz and colleagues were focused on CGRPs, Humphrey et al were focused on a receptor they found in cranial blood vessels that came to be called serotonin (5-HT_1B). An agonist soon followed. In 1991, sumatriptan became available in Europe, and 2 years later, it was available in the United States. But sumatriptan is for acute care treatment, not a preventive therapy. It was Moskowitz’s work that led to studies demonstrating that antisera could neutralize CGRP and substance P.

For those with chronic migraine, preventive therapy was exactly what they needed because, while the triptans helped, they were insufficient for many. In a 2-year longitudinal analysis conducted in Italy involving 82,446 individuals prescribed at least 1 triptan, 31,515 had an unmet medical need in migraine (3.1 per 1000 patients).

In February 2022, a team of researchers published the results of a genome-wide association study involving over 100,000 cases. The results were 125 risk loci linked to migraine within the vascular and central nervous systems, thereby firmly establishing that the pathophysiology of migraine exists in neurovascular mechanisms. 

The fact that it has taken technology to prove that migraine exists and that it is organically rooted is obviously satisfying but also frustrating. For centuries, people with migraine were considered to have caused their own illness or were exaggerating the pain.

In March 2022, a large German population-based study found that people with migraine still struggled with bias, stigma, and undermedication. Fifty-four percent said they were not seeing a physician for their migraine, and 33% said they had not received information on medication overuse risks.

With captured images of what happens inside the brains of these patients during an attack, now the focus can be on helping them and not questioning the validity of their reported symptoms.

Coming next month, a discussion about migraine therapies.

Dr. Messoud Ashina is a Professor of Neurology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. He is Director of the Human Migraine Research Unit at the Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup. He serves an associate editor for Cephalalgia, Journal of Headache and Pain, and Brain.

Dr. Faisal Mohammad Amin is an Associate Professor, Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Denmark. He is an associate editor for Headache Medicine and is President of the Danish Headache Society.

Dr. Ashina reports that he has received fees and grants from and/or has served as a principal trial investigator for AbbVie, Amgen, Eli Lilly, Lundbeck Pharmaceuticals, Lundbeck Foundation, Novartis, Novo Nordisk Foundation, and Teva.

Dr. Amin reports that he has worked as a consultant, speaker, and/or primary investigator Eli Lilly, Lundbeck, Novartis, and Teva. Both authors have reported that they have no ownership interest nor own any stocks in a pharmaceutical company.

Since the time of the Neanderthals, humankind has looked for ways to rid the brain of migraine headache. There is evidence that trepanation–removing a portion of bone from the skull–was performed on Neolithic skulls. Did it work for that poor individual? We will never know.

What is known is that the often circuitous hunt for effective treatments has taken centuries. And while this search led to the successful introduction of calcitonin gene-related peptides (CGRPs) a few years ago, the search is nowhere near finished, as efforts to pinpoint the source of migraine continue, as does the search for other possible therapies.

The nearly 39 million people with migraine in the United States  would be grateful; they often experience a perplexing, frustrating, and unsatisfactory search for a pain-free existence. Migraine is estimated to cost more than $20 million per year in direct medical expenses and lost productivity in the United States. People with migraine, meanwhile, face the prospect of significant disability. More than 8 in every 10 participants in the American Migraine Study had at least some headache-related disability. More than half said their pain has caused severe impairment.

The search to find relief for these patients is focused on understanding the pathophysiology of migraine. Approaches include in vitro application of mediators, direct electrical stimulation of trigeminal neurons in vivo, administration of vasoactive substances in vivo, and introduction of exogenous pain-inducing substances in vivo. In 2021, investigators at AstraZeneca and the University of Arizona College of Medicine described their development of an injury-free murine model to be used to study migraine-like pain. Animal research has led to a few interventional studies involving new and existing medications. 

How the field has evolved from using a chisel to make a cranial hole to using magnetic resonance imaging and other technologies to examine the trigeminovascular system’s role in the pathophysiology of migraine headache is a tale worth telling.

From crocodiles to nitroglycerin to allergies

The search for an effective remedy for migraine has proved to be torturously slow. In addition to trepanation, another procedure thought to have been used during prehistoric times involved a religious ritual whereby a clay crocodile was attached tightly with a strip of linen to an individual’s head. Though the gods were credited if the headache pain receded, relief likely came from the resulting compression on the scalp. Centuries later, in the Middle Ages, treatments included soaking bandages in drugs and then applying them to the head or mixing elixirs with vinegar (which opened scalp pores) and opium (which traveled into the scalp through the open pores).

The Persian scholar Ibn Sina (980-1032), also known as Avicenna, postulated that the pain could emanate from the bones that comprise the skull or within the parenchyma or from veins and arteries outside the cranium. The medicinal plants he investigated for the treatment of migraine have components that resonate today: antineuroinflammatory agents, analgesics, and even cyclooxegenase-2 inhibitors.

Six hundred years later, English physician Thomas Willis discussed how the vascular system perpetrated migraine, and in the next century, Erasmus Darwin, Charles’ grandfather, proposed that individuals with migraine be spun around so that blood from the head would be forced down toward the feet. In the 1800s, English physician Edward Liveing abandoned vascular theory, instead proposing that migraine resulted from discharges of the central nervous system.

British neurologist William Gowers thought migraine could be a derangement of neurons, but ultimately wrote in his Manual of Diseases (p. 852) that, “When all has been that can be, mystery still envelops the mechanism of migraine.” Gowers advocated continuous treatment with drugs to minimize the frequency of attacks, as well as treating the attacks themselves. His preferred treatments were nitroglycerin in alcohol, combined with other agents, as well as marijuana. His choice of nitroglycerin is an interesting one, given that modern medicine considers nitroglycerin an important neurochemical in migraine initiation.

The concept of neuronal involvement retained support into the 20th century, solidified by German physician Paul Ehrlich’s Nobel Prize–winning work involving immunology and brain receptors. In the 1920s, thoughts turned to allergy as the source of migraine, as an association between migraine, asthma, and urticaria emerged, but this connection was eventually proved to be incidental, not causal.

In the 1930s, the vascular theory again was vogue -- aided by studies performed by US physician Harold G. Wolff. His work, the first to assess headache in a laboratory setting, along with observations about changes in vasculature and evolving treatment, appeared to support the vascular nature of headache. In the 1940s and 1950s, psychosomatic disorders crept into the mix of possible causes. Some categorized migraine as a so-called stress disease.

Puzzles and irony

In 1979, Moskowitz and colleagues introduced a new hypothesis focused on the importance of the neuropeptide-containing trigeminal nerve. CGRP is stored in vesicles in sensory nerve terminals, where it is released along with the vasodilating peptide, substance P, when the trigeminal nerve is activated.

At about the same time, researchers in England were working on a discovery with ancestral roots going back hundreds of years. In the 18th century, scientists learned that rye ergot was a constrictor of blood vessels. In time, ergot became ergotamine and hence more valuable because it could reduce vascular headaches. But the adverse effects, prominent in those with cardiovascular disease, kept researchers in the lab.

So, while Moskowitz and colleagues were focused on CGRPs, Humphrey et al were focused on a receptor they found in cranial blood vessels that came to be called serotonin (5-HT_1B). An agonist soon followed. In 1991, sumatriptan became available in Europe, and 2 years later, it was available in the United States. But sumatriptan is for acute care treatment, not a preventive therapy. It was Moskowitz’s work that led to studies demonstrating that antisera could neutralize CGRP and substance P.

For those with chronic migraine, preventive therapy was exactly what they needed because, while the triptans helped, they were insufficient for many. In a 2-year longitudinal analysis conducted in Italy involving 82,446 individuals prescribed at least 1 triptan, 31,515 had an unmet medical need in migraine (3.1 per 1000 patients).

In February 2022, a team of researchers published the results of a genome-wide association study involving over 100,000 cases. The results were 125 risk loci linked to migraine within the vascular and central nervous systems, thereby firmly establishing that the pathophysiology of migraine exists in neurovascular mechanisms. 

The fact that it has taken technology to prove that migraine exists and that it is organically rooted is obviously satisfying but also frustrating. For centuries, people with migraine were considered to have caused their own illness or were exaggerating the pain.

In March 2022, a large German population-based study found that people with migraine still struggled with bias, stigma, and undermedication. Fifty-four percent said they were not seeing a physician for their migraine, and 33% said they had not received information on medication overuse risks.

With captured images of what happens inside the brains of these patients during an attack, now the focus can be on helping them and not questioning the validity of their reported symptoms.

Coming next month, a discussion about migraine therapies.

Dr. Messoud Ashina is a Professor of Neurology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. He is Director of the Human Migraine Research Unit at the Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup. He serves an associate editor for Cephalalgia, Journal of Headache and Pain, and Brain.

Dr. Faisal Mohammad Amin is an Associate Professor, Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Denmark. He is an associate editor for Headache Medicine and is President of the Danish Headache Society.

Dr. Ashina reports that he has received fees and grants from and/or has served as a principal trial investigator for AbbVie, Amgen, Eli Lilly, Lundbeck Pharmaceuticals, Lundbeck Foundation, Novartis, Novo Nordisk Foundation, and Teva.

Dr. Amin reports that he has worked as a consultant, speaker, and/or primary investigator Eli Lilly, Lundbeck, Novartis, and Teva. Both authors have reported that they have no ownership interest nor own any stocks in a pharmaceutical company.

Since the time of the Neanderthals, humankind has looked for ways to rid the brain of migraine headache. There is evidence that trepanation–removing a portion of bone from the skull–was performed on Neolithic skulls. Did it work for that poor individual? We will never know.

What is known is that the often circuitous hunt for effective treatments has taken centuries. And while this search led to the successful introduction of calcitonin gene-related peptides (CGRPs) a few years ago, the search is nowhere near finished, as efforts to pinpoint the source of migraine continue, as does the search for other possible therapies.

The nearly 39 million people with migraine in the United States  would be grateful; they often experience a perplexing, frustrating, and unsatisfactory search for a pain-free existence. Migraine is estimated to cost more than $20 million per year in direct medical expenses and lost productivity in the United States. People with migraine, meanwhile, face the prospect of significant disability. More than 8 in every 10 participants in the American Migraine Study had at least some headache-related disability. More than half said their pain has caused severe impairment.

The search to find relief for these patients is focused on understanding the pathophysiology of migraine. Approaches include in vitro application of mediators, direct electrical stimulation of trigeminal neurons in vivo, administration of vasoactive substances in vivo, and introduction of exogenous pain-inducing substances in vivo. In 2021, investigators at AstraZeneca and the University of Arizona College of Medicine described their development of an injury-free murine model to be used to study migraine-like pain. Animal research has led to a few interventional studies involving new and existing medications. 

How the field has evolved from using a chisel to make a cranial hole to using magnetic resonance imaging and other technologies to examine the trigeminovascular system’s role in the pathophysiology of migraine headache is a tale worth telling.

From crocodiles to nitroglycerin to allergies

The search for an effective remedy for migraine has proved to be torturously slow. In addition to trepanation, another procedure thought to have been used during prehistoric times involved a religious ritual whereby a clay crocodile was attached tightly with a strip of linen to an individual’s head. Though the gods were credited if the headache pain receded, relief likely came from the resulting compression on the scalp. Centuries later, in the Middle Ages, treatments included soaking bandages in drugs and then applying them to the head or mixing elixirs with vinegar (which opened scalp pores) and opium (which traveled into the scalp through the open pores).

The Persian scholar Ibn Sina (980-1032), also known as Avicenna, postulated that the pain could emanate from the bones that comprise the skull or within the parenchyma or from veins and arteries outside the cranium. The medicinal plants he investigated for the treatment of migraine have components that resonate today: antineuroinflammatory agents, analgesics, and even cyclooxegenase-2 inhibitors.

Six hundred years later, English physician Thomas Willis discussed how the vascular system perpetrated migraine, and in the next century, Erasmus Darwin, Charles’ grandfather, proposed that individuals with migraine be spun around so that blood from the head would be forced down toward the feet. In the 1800s, English physician Edward Liveing abandoned vascular theory, instead proposing that migraine resulted from discharges of the central nervous system.

British neurologist William Gowers thought migraine could be a derangement of neurons, but ultimately wrote in his Manual of Diseases (p. 852) that, “When all has been that can be, mystery still envelops the mechanism of migraine.” Gowers advocated continuous treatment with drugs to minimize the frequency of attacks, as well as treating the attacks themselves. His preferred treatments were nitroglycerin in alcohol, combined with other agents, as well as marijuana. His choice of nitroglycerin is an interesting one, given that modern medicine considers nitroglycerin an important neurochemical in migraine initiation.

The concept of neuronal involvement retained support into the 20th century, solidified by German physician Paul Ehrlich’s Nobel Prize–winning work involving immunology and brain receptors. In the 1920s, thoughts turned to allergy as the source of migraine, as an association between migraine, asthma, and urticaria emerged, but this connection was eventually proved to be incidental, not causal.

In the 1930s, the vascular theory again was vogue -- aided by studies performed by US physician Harold G. Wolff. His work, the first to assess headache in a laboratory setting, along with observations about changes in vasculature and evolving treatment, appeared to support the vascular nature of headache. In the 1940s and 1950s, psychosomatic disorders crept into the mix of possible causes. Some categorized migraine as a so-called stress disease.

Puzzles and irony

In 1979, Moskowitz and colleagues introduced a new hypothesis focused on the importance of the neuropeptide-containing trigeminal nerve. CGRP is stored in vesicles in sensory nerve terminals, where it is released along with the vasodilating peptide, substance P, when the trigeminal nerve is activated.

At about the same time, researchers in England were working on a discovery with ancestral roots going back hundreds of years. In the 18th century, scientists learned that rye ergot was a constrictor of blood vessels. In time, ergot became ergotamine and hence more valuable because it could reduce vascular headaches. But the adverse effects, prominent in those with cardiovascular disease, kept researchers in the lab.

So, while Moskowitz and colleagues were focused on CGRPs, Humphrey et al were focused on a receptor they found in cranial blood vessels that came to be called serotonin (5-HT_1B). An agonist soon followed. In 1991, sumatriptan became available in Europe, and 2 years later, it was available in the United States. But sumatriptan is for acute care treatment, not a preventive therapy. It was Moskowitz’s work that led to studies demonstrating that antisera could neutralize CGRP and substance P.

For those with chronic migraine, preventive therapy was exactly what they needed because, while the triptans helped, they were insufficient for many. In a 2-year longitudinal analysis conducted in Italy involving 82,446 individuals prescribed at least 1 triptan, 31,515 had an unmet medical need in migraine (3.1 per 1000 patients).

In February 2022, a team of researchers published the results of a genome-wide association study involving over 100,000 cases. The results were 125 risk loci linked to migraine within the vascular and central nervous systems, thereby firmly establishing that the pathophysiology of migraine exists in neurovascular mechanisms. 

The fact that it has taken technology to prove that migraine exists and that it is organically rooted is obviously satisfying but also frustrating. For centuries, people with migraine were considered to have caused their own illness or were exaggerating the pain.

In March 2022, a large German population-based study found that people with migraine still struggled with bias, stigma, and undermedication. Fifty-four percent said they were not seeing a physician for their migraine, and 33% said they had not received information on medication overuse risks.

With captured images of what happens inside the brains of these patients during an attack, now the focus can be on helping them and not questioning the validity of their reported symptoms.

Coming next month, a discussion about migraine therapies.

The 2022 Pediatric Academic Societies meeting included an excellent session on the acute and delayed effects of COVID-19 on children’s hearts. Data on the risk for cardiac injury during acute COVID-19, return-to-play guidelines after COVID-19–related heart injury, and post–vaccine-associated myocarditis were reviewed.

COVID-induced cardiac injury

The risk for COVID-induced cardiac injury is directly associated with age. Recent Centers for Disease Control and Prevention data revealed a “myocarditis or pericarditis” rate in the range of 12-17 cases per 100,000 SARS-CoV-2 infections among male children aged 5-11 years (lower rates for females); the rate jumps to 50-65 cases per 100,000 infections among male children aged 12-17 years. So cardiac injury caused by acute COVID-19 appears rare, but the risk is clearly associated with male sex and adolescent age.

Return to play after COVID-19

Clinicians may be pressed by patients and parents for advice on return to play after illness with COVID-19. In July 2020, the American College of Cardiology published an algorithm that has been adjusted over time, most recently in 2022 by the American Academy of Pediatrics. These algorithms stratify recommendations by degree of illness. One rule of thumb: Patients with severe COVID-19 (ICU care or multisystem inflammatory syndrome in children [MIS-C]) have only one box on the algorithm, and that is to rest for 3-6 months and only return to usual activity after cardiac clearance. Moderate disease (defined as ≥ 4 days of fever > 100.4 °F; ≥ 1 week of myalgia, chills, lethargy, or any non-ICU hospital stay; and no evidence of MIS-C) require undergoing an ECG to look for cardiac dysfunction, followed by at least 10 days of rest if the ECG is negative or referral for cardiac evaluation if either ECG or exam by a pediatric cardiologist is abnormal.

Clinicians can perhaps be more permissible with patients who are younger or who have had less severe disease. For example, if a patient aged younger than 12 years is asymptomatic with routine activity at the time of evaluation, an ECG is not indicated. For patients aged 12-15 years who are asymptomatic at the time of evaluation but participate in a high-intensity sport, clinicians might consider obtaining an ECG. As few as 3 days of rest might be enough for select patients who are asymptomatic at presentation. For other patients, clinicians should work with parents to introduce activity gradually and make it clear to parents that any activity intolerance requires quick reevaluation. On existing athlete registries, no deaths that are attributable to post–COVID-19 cardiac effects have been confirmed in children; however, all data presented during the session were from prior to the Omicron variant surge in early 2022, so more information may be forthcoming.
 

Considerations for MIS-C

Among children experiencing MIS-C, 35% had ECG changes, 40% exhibited left ventricular systolic or diastolic dysfunction, and 30% had mitral regurgitation, meaning that a large percentage of patients with MIS-C show some degree of cardiac dysfunction. Unfortunately, we are still in the data-gathering phase for long-term outcomes. Functional parameters tend to improve within a week, and most patients will return to normal cardiac function by 3-4 months.

Return to play after MIS-C is quite different from that for acute COVID-19. Patients with MIS-C should be treated much like other patients with myocarditis with an expected return to play in 3-6 months and only after cardiac follow-up. Another good-to-remember recommendation is to delay COVID-19 vaccination for at least 90 days after an episode of MIS-C.
 

Vaccine-related myocarditis

Once again, older age appears to be a risk factor because most patients with postvaccine myocarditis have been in their mid-teens to early 20s, with events more likely after the second vaccine dose and also more likely in male children (4:1 ratio to female children). No deaths have occurred from postvaccination myocarditis in patients younger than 30 years. Still, many individuals have exhibited residual MRI enhancement in the cardiac tissue for some time after experiencing postvaccination myocarditis; it’s currently unclear whether that has clinical implications. By comparison, CDC data demonstrates convincingly that the risk for cardiac effects is much greater after acute COVID-19 than after COVID-19 vaccination, with risk ratios often higher than 20, depending on age and condition (for example, myocarditis vs. pericarditis). Data are still insufficient to determine whether clinicians should recommend or avoid COVID-19 vaccination in children with congenital heart disease.

In summary, administering COVID-19 vaccines requires a great deal of shared decision-making with parents, and the clinician’s role is to educate parents about all potential risks related to both the vaccine and COVID-19 illness. Research has consistently shown that acute COVID-19 myocarditis and myocarditis associated with MIS-C are much more likely to occur in unvaccinated youth and more likely than postvaccination myocarditis, regardless of age.

William T. Basco, Jr., MD, MS, is a professor of pediatrics at the Medical University of South Carolina, Charleston, and director of the division of general pediatrics. He is an active health services researcher and has published more than 60 manuscripts in the peer-reviewed literature.

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

The 2022 Pediatric Academic Societies meeting included an excellent session on the acute and delayed effects of COVID-19 on children’s hearts. Data on the risk for cardiac injury during acute COVID-19, return-to-play guidelines after COVID-19–related heart injury, and post–vaccine-associated myocarditis were reviewed.

COVID-induced cardiac injury

The risk for COVID-induced cardiac injury is directly associated with age. Recent Centers for Disease Control and Prevention data revealed a “myocarditis or pericarditis” rate in the range of 12-17 cases per 100,000 SARS-CoV-2 infections among male children aged 5-11 years (lower rates for females); the rate jumps to 50-65 cases per 100,000 infections among male children aged 12-17 years. So cardiac injury caused by acute COVID-19 appears rare, but the risk is clearly associated with male sex and adolescent age.

Return to play after COVID-19

Clinicians may be pressed by patients and parents for advice on return to play after illness with COVID-19. In July 2020, the American College of Cardiology published an algorithm that has been adjusted over time, most recently in 2022 by the American Academy of Pediatrics. These algorithms stratify recommendations by degree of illness. One rule of thumb: Patients with severe COVID-19 (ICU care or multisystem inflammatory syndrome in children [MIS-C]) have only one box on the algorithm, and that is to rest for 3-6 months and only return to usual activity after cardiac clearance. Moderate disease (defined as ≥ 4 days of fever > 100.4 °F; ≥ 1 week of myalgia, chills, lethargy, or any non-ICU hospital stay; and no evidence of MIS-C) require undergoing an ECG to look for cardiac dysfunction, followed by at least 10 days of rest if the ECG is negative or referral for cardiac evaluation if either ECG or exam by a pediatric cardiologist is abnormal.

Clinicians can perhaps be more permissible with patients who are younger or who have had less severe disease. For example, if a patient aged younger than 12 years is asymptomatic with routine activity at the time of evaluation, an ECG is not indicated. For patients aged 12-15 years who are asymptomatic at the time of evaluation but participate in a high-intensity sport, clinicians might consider obtaining an ECG. As few as 3 days of rest might be enough for select patients who are asymptomatic at presentation. For other patients, clinicians should work with parents to introduce activity gradually and make it clear to parents that any activity intolerance requires quick reevaluation. On existing athlete registries, no deaths that are attributable to post–COVID-19 cardiac effects have been confirmed in children; however, all data presented during the session were from prior to the Omicron variant surge in early 2022, so more information may be forthcoming.
 

Considerations for MIS-C

Among children experiencing MIS-C, 35% had ECG changes, 40% exhibited left ventricular systolic or diastolic dysfunction, and 30% had mitral regurgitation, meaning that a large percentage of patients with MIS-C show some degree of cardiac dysfunction. Unfortunately, we are still in the data-gathering phase for long-term outcomes. Functional parameters tend to improve within a week, and most patients will return to normal cardiac function by 3-4 months.

Return to play after MIS-C is quite different from that for acute COVID-19. Patients with MIS-C should be treated much like other patients with myocarditis with an expected return to play in 3-6 months and only after cardiac follow-up. Another good-to-remember recommendation is to delay COVID-19 vaccination for at least 90 days after an episode of MIS-C.
 

Vaccine-related myocarditis

Once again, older age appears to be a risk factor because most patients with postvaccine myocarditis have been in their mid-teens to early 20s, with events more likely after the second vaccine dose and also more likely in male children (4:1 ratio to female children). No deaths have occurred from postvaccination myocarditis in patients younger than 30 years. Still, many individuals have exhibited residual MRI enhancement in the cardiac tissue for some time after experiencing postvaccination myocarditis; it’s currently unclear whether that has clinical implications. By comparison, CDC data demonstrates convincingly that the risk for cardiac effects is much greater after acute COVID-19 than after COVID-19 vaccination, with risk ratios often higher than 20, depending on age and condition (for example, myocarditis vs. pericarditis). Data are still insufficient to determine whether clinicians should recommend or avoid COVID-19 vaccination in children with congenital heart disease.

In summary, administering COVID-19 vaccines requires a great deal of shared decision-making with parents, and the clinician’s role is to educate parents about all potential risks related to both the vaccine and COVID-19 illness. Research has consistently shown that acute COVID-19 myocarditis and myocarditis associated with MIS-C are much more likely to occur in unvaccinated youth and more likely than postvaccination myocarditis, regardless of age.

William T. Basco, Jr., MD, MS, is a professor of pediatrics at the Medical University of South Carolina, Charleston, and director of the division of general pediatrics. He is an active health services researcher and has published more than 60 manuscripts in the peer-reviewed literature.

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

The 2022 Pediatric Academic Societies meeting included an excellent session on the acute and delayed effects of COVID-19 on children’s hearts. Data on the risk for cardiac injury during acute COVID-19, return-to-play guidelines after COVID-19–related heart injury, and post–vaccine-associated myocarditis were reviewed.

COVID-induced cardiac injury

The risk for COVID-induced cardiac injury is directly associated with age. Recent Centers for Disease Control and Prevention data revealed a “myocarditis or pericarditis” rate in the range of 12-17 cases per 100,000 SARS-CoV-2 infections among male children aged 5-11 years (lower rates for females); the rate jumps to 50-65 cases per 100,000 infections among male children aged 12-17 years. So cardiac injury caused by acute COVID-19 appears rare, but the risk is clearly associated with male sex and adolescent age.

Return to play after COVID-19

Clinicians may be pressed by patients and parents for advice on return to play after illness with COVID-19. In July 2020, the American College of Cardiology published an algorithm that has been adjusted over time, most recently in 2022 by the American Academy of Pediatrics. These algorithms stratify recommendations by degree of illness. One rule of thumb: Patients with severe COVID-19 (ICU care or multisystem inflammatory syndrome in children [MIS-C]) have only one box on the algorithm, and that is to rest for 3-6 months and only return to usual activity after cardiac clearance. Moderate disease (defined as ≥ 4 days of fever > 100.4 °F; ≥ 1 week of myalgia, chills, lethargy, or any non-ICU hospital stay; and no evidence of MIS-C) require undergoing an ECG to look for cardiac dysfunction, followed by at least 10 days of rest if the ECG is negative or referral for cardiac evaluation if either ECG or exam by a pediatric cardiologist is abnormal.

Clinicians can perhaps be more permissible with patients who are younger or who have had less severe disease. For example, if a patient aged younger than 12 years is asymptomatic with routine activity at the time of evaluation, an ECG is not indicated. For patients aged 12-15 years who are asymptomatic at the time of evaluation but participate in a high-intensity sport, clinicians might consider obtaining an ECG. As few as 3 days of rest might be enough for select patients who are asymptomatic at presentation. For other patients, clinicians should work with parents to introduce activity gradually and make it clear to parents that any activity intolerance requires quick reevaluation. On existing athlete registries, no deaths that are attributable to post–COVID-19 cardiac effects have been confirmed in children; however, all data presented during the session were from prior to the Omicron variant surge in early 2022, so more information may be forthcoming.
 

Considerations for MIS-C

Among children experiencing MIS-C, 35% had ECG changes, 40% exhibited left ventricular systolic or diastolic dysfunction, and 30% had mitral regurgitation, meaning that a large percentage of patients with MIS-C show some degree of cardiac dysfunction. Unfortunately, we are still in the data-gathering phase for long-term outcomes. Functional parameters tend to improve within a week, and most patients will return to normal cardiac function by 3-4 months.

Return to play after MIS-C is quite different from that for acute COVID-19. Patients with MIS-C should be treated much like other patients with myocarditis with an expected return to play in 3-6 months and only after cardiac follow-up. Another good-to-remember recommendation is to delay COVID-19 vaccination for at least 90 days after an episode of MIS-C.
 

Vaccine-related myocarditis

Once again, older age appears to be a risk factor because most patients with postvaccine myocarditis have been in their mid-teens to early 20s, with events more likely after the second vaccine dose and also more likely in male children (4:1 ratio to female children). No deaths have occurred from postvaccination myocarditis in patients younger than 30 years. Still, many individuals have exhibited residual MRI enhancement in the cardiac tissue for some time after experiencing postvaccination myocarditis; it’s currently unclear whether that has clinical implications. By comparison, CDC data demonstrates convincingly that the risk for cardiac effects is much greater after acute COVID-19 than after COVID-19 vaccination, with risk ratios often higher than 20, depending on age and condition (for example, myocarditis vs. pericarditis). Data are still insufficient to determine whether clinicians should recommend or avoid COVID-19 vaccination in children with congenital heart disease.

In summary, administering COVID-19 vaccines requires a great deal of shared decision-making with parents, and the clinician’s role is to educate parents about all potential risks related to both the vaccine and COVID-19 illness. Research has consistently shown that acute COVID-19 myocarditis and myocarditis associated with MIS-C are much more likely to occur in unvaccinated youth and more likely than postvaccination myocarditis, regardless of age.

William T. Basco, Jr., MD, MS, is a professor of pediatrics at the Medical University of South Carolina, Charleston, and director of the division of general pediatrics. He is an active health services researcher and has published more than 60 manuscripts in the peer-reviewed literature.

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

This transcript has been edited for clarity.

Does having had a COVID-19 infection increase your risk for the development of diabetes subsequently? Some data say yes and other data say no. No matter what, it’s obviously important to screen people for diabetes routinely, pandemic or not. Remember, screening should start at age 35.

For over a decade, we have known that SARS-type viruses bind to beta cells. This could cause either direct damage to the beta cell or in some way trigger beta cell autoimmunity. We also know that COVID-19 infection increases the levels of inflammatory mediators, which could cause damage to beta cells and potentially to insulin receptors. There is a potential that having had a COVID-19 infection could increase rates of developing type 1 and/or type 2 diabetes.

However, there are other possible causes for people to develop diabetes after having a COVID-19 infection. A COVID-19 infection could cause one to seek medical care, unmasking latent type 1 and/or type 2 diabetes by causing infection-related insulin resistance and worsening preexisting mild hypoglycemia. In addition, people could have sought more medical care in the years since the pandemic has been ebbing, which may make it look like cases have increased.

For example, during the worst of the pandemic, I had multiple referrals for “COVID-19–caused new-onset diabetes” only to find that the patient had an A1c level above 10% and a history of mildly elevated blood glucose levels. This suggests to me that COVID-19 did not cause the diabetes per se but rather worsened an underlying glucose abnormality.

Since the pandemic has improved, I have also seen people diagnosed with type 2 diabetes that I think is associated with pandemic-related weight gain and inactivity.

The bigger issue is what is happening to people after COVID-19 infection who lack risk factors. What about those who we didn’t think were at high risk to get diabetes to begin with and didn’t have prediabetes?

An article by Xie and Al-Aly in The Lancet Diabetes & Endocrinology showed an increase in rates of diabetes in a large VA cohort among those who had a COVID-19 infection compared with both a contemporaneous control who did not have COVID-19 and a historical control. The researchers looked at the patient data 1 year after they’d had COVID-19, so it wasn’t the immediate post–COVID-19 phase but several months later.

They found that the risk for incident type 2 diabetes development was increased by 40% after adjusting for many risk factors. This included individuals who didn’t have traditional risk factors before they developed type 2 diabetes.

What does this mean clinically? First, pandemic or not, people need screening for diabetes and encouragement to have a healthy lifestyle. There may be an increased risk for the diagnosis of type 2 diabetes after COVID-19 infection due to a variety of different mechanisms.

As for people with type 1 diabetes, we also don’t know if having a COVID-19 infection increases their risk. We do know that there was an increase in the severity of diabetic ketoacidosis presentation during the pandemic, so we need to be sure that we reinforce sick-day rules with our patients with type 1 diabetes and that all individuals with type 1 diabetes have the ability to test their ketone levels at home.

In people with new-onset diabetes, whether type 1 or type 2, caused by COVID-19 or not, we need to treat appropriately based on their clinical situation.

Data from registries started during the pandemic will provide more definitive answers and help us find out if there is a relationship between having had COVID-19 infection and developing diabetes.

Perhaps that can help us better understand the mechanisms behind the development of diabetes overall.

Dr. Peters is professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She disclosed ties with Abbott Diabetes Care, AstraZeneca, Becton Dickinson, Boehringer Ingelheim Pharmaceuticals, Dexcom, Eli Lilly, Lexicon Pharmaceuticals, Livongo, MannKind Corporation, Medscape, Merck, Novo Nordisk, Omada Health, OptumHealth, Sanofi, and Zafgen. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Does having had a COVID-19 infection increase your risk for the development of diabetes subsequently? Some data say yes and other data say no. No matter what, it’s obviously important to screen people for diabetes routinely, pandemic or not. Remember, screening should start at age 35.

For over a decade, we have known that SARS-type viruses bind to beta cells. This could cause either direct damage to the beta cell or in some way trigger beta cell autoimmunity. We also know that COVID-19 infection increases the levels of inflammatory mediators, which could cause damage to beta cells and potentially to insulin receptors. There is a potential that having had a COVID-19 infection could increase rates of developing type 1 and/or type 2 diabetes.

However, there are other possible causes for people to develop diabetes after having a COVID-19 infection. A COVID-19 infection could cause one to seek medical care, unmasking latent type 1 and/or type 2 diabetes by causing infection-related insulin resistance and worsening preexisting mild hypoglycemia. In addition, people could have sought more medical care in the years since the pandemic has been ebbing, which may make it look like cases have increased.

For example, during the worst of the pandemic, I had multiple referrals for “COVID-19–caused new-onset diabetes” only to find that the patient had an A1c level above 10% and a history of mildly elevated blood glucose levels. This suggests to me that COVID-19 did not cause the diabetes per se but rather worsened an underlying glucose abnormality.

Since the pandemic has improved, I have also seen people diagnosed with type 2 diabetes that I think is associated with pandemic-related weight gain and inactivity.

The bigger issue is what is happening to people after COVID-19 infection who lack risk factors. What about those who we didn’t think were at high risk to get diabetes to begin with and didn’t have prediabetes?

An article by Xie and Al-Aly in The Lancet Diabetes & Endocrinology showed an increase in rates of diabetes in a large VA cohort among those who had a COVID-19 infection compared with both a contemporaneous control who did not have COVID-19 and a historical control. The researchers looked at the patient data 1 year after they’d had COVID-19, so it wasn’t the immediate post–COVID-19 phase but several months later.

They found that the risk for incident type 2 diabetes development was increased by 40% after adjusting for many risk factors. This included individuals who didn’t have traditional risk factors before they developed type 2 diabetes.

What does this mean clinically? First, pandemic or not, people need screening for diabetes and encouragement to have a healthy lifestyle. There may be an increased risk for the diagnosis of type 2 diabetes after COVID-19 infection due to a variety of different mechanisms.

As for people with type 1 diabetes, we also don’t know if having a COVID-19 infection increases their risk. We do know that there was an increase in the severity of diabetic ketoacidosis presentation during the pandemic, so we need to be sure that we reinforce sick-day rules with our patients with type 1 diabetes and that all individuals with type 1 diabetes have the ability to test their ketone levels at home.

In people with new-onset diabetes, whether type 1 or type 2, caused by COVID-19 or not, we need to treat appropriately based on their clinical situation.

Data from registries started during the pandemic will provide more definitive answers and help us find out if there is a relationship between having had COVID-19 infection and developing diabetes.

Perhaps that can help us better understand the mechanisms behind the development of diabetes overall.

Dr. Peters is professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She disclosed ties with Abbott Diabetes Care, AstraZeneca, Becton Dickinson, Boehringer Ingelheim Pharmaceuticals, Dexcom, Eli Lilly, Lexicon Pharmaceuticals, Livongo, MannKind Corporation, Medscape, Merck, Novo Nordisk, Omada Health, OptumHealth, Sanofi, and Zafgen. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Does having had a COVID-19 infection increase your risk for the development of diabetes subsequently? Some data say yes and other data say no. No matter what, it’s obviously important to screen people for diabetes routinely, pandemic or not. Remember, screening should start at age 35.

For over a decade, we have known that SARS-type viruses bind to beta cells. This could cause either direct damage to the beta cell or in some way trigger beta cell autoimmunity. We also know that COVID-19 infection increases the levels of inflammatory mediators, which could cause damage to beta cells and potentially to insulin receptors. There is a potential that having had a COVID-19 infection could increase rates of developing type 1 and/or type 2 diabetes.

However, there are other possible causes for people to develop diabetes after having a COVID-19 infection. A COVID-19 infection could cause one to seek medical care, unmasking latent type 1 and/or type 2 diabetes by causing infection-related insulin resistance and worsening preexisting mild hypoglycemia. In addition, people could have sought more medical care in the years since the pandemic has been ebbing, which may make it look like cases have increased.

For example, during the worst of the pandemic, I had multiple referrals for “COVID-19–caused new-onset diabetes” only to find that the patient had an A1c level above 10% and a history of mildly elevated blood glucose levels. This suggests to me that COVID-19 did not cause the diabetes per se but rather worsened an underlying glucose abnormality.

Since the pandemic has improved, I have also seen people diagnosed with type 2 diabetes that I think is associated with pandemic-related weight gain and inactivity.

The bigger issue is what is happening to people after COVID-19 infection who lack risk factors. What about those who we didn’t think were at high risk to get diabetes to begin with and didn’t have prediabetes?

An article by Xie and Al-Aly in The Lancet Diabetes & Endocrinology showed an increase in rates of diabetes in a large VA cohort among those who had a COVID-19 infection compared with both a contemporaneous control who did not have COVID-19 and a historical control. The researchers looked at the patient data 1 year after they’d had COVID-19, so it wasn’t the immediate post–COVID-19 phase but several months later.

They found that the risk for incident type 2 diabetes development was increased by 40% after adjusting for many risk factors. This included individuals who didn’t have traditional risk factors before they developed type 2 diabetes.

What does this mean clinically? First, pandemic or not, people need screening for diabetes and encouragement to have a healthy lifestyle. There may be an increased risk for the diagnosis of type 2 diabetes after COVID-19 infection due to a variety of different mechanisms.

As for people with type 1 diabetes, we also don’t know if having a COVID-19 infection increases their risk. We do know that there was an increase in the severity of diabetic ketoacidosis presentation during the pandemic, so we need to be sure that we reinforce sick-day rules with our patients with type 1 diabetes and that all individuals with type 1 diabetes have the ability to test their ketone levels at home.

In people with new-onset diabetes, whether type 1 or type 2, caused by COVID-19 or not, we need to treat appropriately based on their clinical situation.

Data from registries started during the pandemic will provide more definitive answers and help us find out if there is a relationship between having had COVID-19 infection and developing diabetes.

Perhaps that can help us better understand the mechanisms behind the development of diabetes overall.

Dr. Peters is professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She disclosed ties with Abbott Diabetes Care, AstraZeneca, Becton Dickinson, Boehringer Ingelheim Pharmaceuticals, Dexcom, Eli Lilly, Lexicon Pharmaceuticals, Livongo, MannKind Corporation, Medscape, Merck, Novo Nordisk, Omada Health, OptumHealth, Sanofi, and Zafgen. A version of this article first appeared on Medscape.com.

Davida F. Kruger, MSN, APN-BC, BC-ADM
Ms. Kruger has been a certified nurse practitioner in diabetes at Henry Ford Health System in Detroit, MI, for more than 35 years. Ms. Kruger has been a co-investigator on numerous studies of diabetes interventions and care, including the National Institutes of Health–funded multicenter EDIC and ACCORD trials.

She is a past Chair of the American Diabetes Association (ADA) Research Foundation and has served on the ADA Research Policy Committee. She is also an ADA Past President (Health Care and Education). She has also served as editor-in-chief of 2 American Diabetes Association (ADA) journals, Diabetes Spectrum and Clinical Diabetes.

Our diabetes clinic in Detroit is ground zero for diabetes care and education.

High-risk obstetrician gynecologists, cardiologists, nephrologists, and primary care providers, which are all specialties seeing more patients with type 2 diabetes (T2D) comorbidities, are coming to us or sharing patient cases to learn more about diabetes care, newer medications, and the technology needed to help disease management. Considering the complexity of the disease, its comorbidities, the long list of medications, and the human skills required to help these individuals, our clinic has long considered that patients are better served by a team of providers with experience in the intricacies and nuances of this chronic disease.

With over 40 years in the trenches, I can write without equivocation that the treatment of patients with diabetes requires a team approach involving diabetes educators, nurse practitioners, physician assistants, pharmacists, physicians, and nutritionists, who have long known that diabetes is a serious, deadly disease. 

Some facts to prove my point: 
When I started treating people with  diabetes, 4% of the US population had the disease. Life expectancy was about 74 years. Today, 11% of the population has diabetes, and life expectancy is closer to 78 years. Longer life, for someone with diabetes, means more time with kidney disease, cardiovascular problems, neuropathy, macular degeneration, and more.T2D is no longer just an adult disease. We are treating T2D in a much younger population. The Centers for Disease Control and Prevention says from 2002 to 2015, the incidence rate for people <20 years rose 4.8% per year. 
In 2019, the World Health Organization said that 16,300 people < 25 years old died from diabetes, and most of these deaths were from type 1 diabetes.
If we maintain the status quo, between now and 2050, 33% of the adult population in this country could have this disease. 
Our clinic has enrolled  at least 3500 patients with some type of diabetes. 

The list of therapies ─ and more importantly the different classes of therapies ─ has grown significantly since the time when sulfonylureas, metformin, and insulin were the only therapies available. Today, there are at least 9 classes of medications to treat type 2 diabetes. 

Considering that patients with T2D, most of whom are overweight or obese, also have heart disease, kidney disease, and more, the collective input from various kinds of healthcare providers to discuss how these medications can work together, or not, is beyond beneficial. The literature shows that a multidisciplinary team improves patient outcomes in the T2D population. The literature also shows that despite therapeutic advances, most of these patients have disease that is not well controlled, for a variety of reasons.

Patients and Attitudes
I was riding in an elevator with a rheumatologist a few years ago. He told me that my patients were all “fat” and “responsible for their situation.” I told him an elevator ride could not cover the amount of education he needed, so I invited him to call me. There are many reasons why people develop T2D and carrying too much weight is a significant one. We tell our patients that this extra weight puts stress on the natural production of insulin. The result is that less organic insulin is produced so more manufactured insulin is prescribed, and this puts weight on the patient. 

Patients have busy lives, and those with diabetes are no different; their lives get in the way of managing their disease. Some need to remember to take 3 or 4 injections a day. They forget an injection at lunch because their routine has been disrupted; they forget at bedtime because they fell asleep on the sofa. Or they had to feed their children dinner quickly to make it to a teacher’s meeting, so they forgot their medication. But it is vital that they maintain their insulin injection schedule. Research says missing 2.1 meal-related injections a week increases glycated hemoglobin (A1c) by 0.3% to 0.4%.

Most people with T2D will eventually need insulin. For someone with diabetes – and for their family members – hypoglycemia is a real fear. Hypoglycemia has significant physical (eg, irregular heartbeat, shakiness) and mental (eg, anxiety, irritability) effects. In response, patients can treat themselves with glucose tablets or simple carbohydrates (between 15 and 30 g). If the patient is unconscious, the family may need to use injectable glucagon. This is where the benefits of a continuous glucose monitor come in.
Patients can see the hypoglycemic state they are approaching so they can treat a low blood glucose level on their own before others need to. 

Our clinic members focus on having open, honest conversations with our patients about how their lives affect their diabetes. We encourage them to choose a nutrition plan or see our dietitian. Some do phenomenally well with plans like Weight Watchers, but others do not. Whatever they choose, our dietitians aim to help them stay on it, with weekly check-ins, teleconferences, and appointments.

Communication goes both ways. Our patients tell us constantly that they do not want another medication. Diabetes is an expensive disease, and most of our patients take at least 5 medications, prescribed by nephrologists, cardiologists, endocrinologists, and family physicians. Our clinical pharmacists and other team members try to find ways to bring those costs down; sometimes we cannot.

Some Pointers
It is not a bad idea to keep a flowchart on your phone that details which diabetes drug is applicable under which circumstances, and when it is not applicable. While most are complementary, a list would detail how each of the new medications work, how they work together and how they benefit patients.

Some wisdom learned in the trenches: 

• Do not shy away from starting a newly diagnosed patient on metformin and a second agent. The American Diabetes Association guidelines say that more intensive initial treatment can be beneficial. If the patient’s  A1c is elevated, consider using 2 medications upon diagnosis. 
• Using a sulfonylurea, which stimulates insulin secretion, as a second-line therapy alone can increase risk of myocardial infarction, all-cause mortality, and severe hypoglycemia (hazard ratios, 1.26, 1.28, and 7.60, respectively); these medications also cause weight gain. The sulfonylureas put pressure on the beta cells to work harder. More importantly, we do not know what these medications do to the cardiovascular system in the long term.
• If the patient has cardiovascular disease, then, in combination with metformin, use a glucagon-like peptide 1 receptor agonist (GLP-1) or a sodium-glucose cotransporter 2 (SGLT2) inhibitor. If the patient has kidney disease, start with an SGLT2 inhibitor. And yes, you can prescribe both at the same time. 
• SGLT2 inhibitors lower glucose levels by preventing the kidneys from reabsorbing glucose. The GLP-1 agonists encourage insulin production and inhibit glucagon secretion  after meals. Neither of these medications are known to add weight; they are linked with weight loss. 
• If your patient is on a dipeptidyl peptidase 4 (DPP-4) inhibitor and is moving to a GLP-1 receptor agonist, stop the DDP-4 before starting the GLP-1 since both target the incretin system to control blood glucose levels.

While years in the making, new medications and technologies now available for T2D have given healthcare providers more options for their patients, and patients have better opportunities to achieve their treatment goals. 
 

Davida F. Kruger, MSN, APN-BC, BC-ADM
Ms. Kruger has been a certified nurse practitioner in diabetes at Henry Ford Health System in Detroit, MI, for more than 35 years. Ms. Kruger has been a co-investigator on numerous studies of diabetes interventions and care, including the National Institutes of Health–funded multicenter EDIC and ACCORD trials.

She is a past Chair of the American Diabetes Association (ADA) Research Foundation and has served on the ADA Research Policy Committee. She is also an ADA Past President (Health Care and Education). She has also served as editor-in-chief of 2 American Diabetes Association (ADA) journals, Diabetes Spectrum and Clinical Diabetes.

Our diabetes clinic in Detroit is ground zero for diabetes care and education.

High-risk obstetrician gynecologists, cardiologists, nephrologists, and primary care providers, which are all specialties seeing more patients with type 2 diabetes (T2D) comorbidities, are coming to us or sharing patient cases to learn more about diabetes care, newer medications, and the technology needed to help disease management. Considering the complexity of the disease, its comorbidities, the long list of medications, and the human skills required to help these individuals, our clinic has long considered that patients are better served by a team of providers with experience in the intricacies and nuances of this chronic disease.

With over 40 years in the trenches, I can write without equivocation that the treatment of patients with diabetes requires a team approach involving diabetes educators, nurse practitioners, physician assistants, pharmacists, physicians, and nutritionists, who have long known that diabetes is a serious, deadly disease. 

Some facts to prove my point: 
When I started treating people with  diabetes, 4% of the US population had the disease. Life expectancy was about 74 years. Today, 11% of the population has diabetes, and life expectancy is closer to 78 years. Longer life, for someone with diabetes, means more time with kidney disease, cardiovascular problems, neuropathy, macular degeneration, and more.T2D is no longer just an adult disease. We are treating T2D in a much younger population. The Centers for Disease Control and Prevention says from 2002 to 2015, the incidence rate for people <20 years rose 4.8% per year. 
In 2019, the World Health Organization said that 16,300 people < 25 years old died from diabetes, and most of these deaths were from type 1 diabetes.
If we maintain the status quo, between now and 2050, 33% of the adult population in this country could have this disease. 
Our clinic has enrolled  at least 3500 patients with some type of diabetes. 

The list of therapies ─ and more importantly the different classes of therapies ─ has grown significantly since the time when sulfonylureas, metformin, and insulin were the only therapies available. Today, there are at least 9 classes of medications to treat type 2 diabetes. 

Considering that patients with T2D, most of whom are overweight or obese, also have heart disease, kidney disease, and more, the collective input from various kinds of healthcare providers to discuss how these medications can work together, or not, is beyond beneficial. The literature shows that a multidisciplinary team improves patient outcomes in the T2D population. The literature also shows that despite therapeutic advances, most of these patients have disease that is not well controlled, for a variety of reasons.

Patients and Attitudes
I was riding in an elevator with a rheumatologist a few years ago. He told me that my patients were all “fat” and “responsible for their situation.” I told him an elevator ride could not cover the amount of education he needed, so I invited him to call me. There are many reasons why people develop T2D and carrying too much weight is a significant one. We tell our patients that this extra weight puts stress on the natural production of insulin. The result is that less organic insulin is produced so more manufactured insulin is prescribed, and this puts weight on the patient. 

Patients have busy lives, and those with diabetes are no different; their lives get in the way of managing their disease. Some need to remember to take 3 or 4 injections a day. They forget an injection at lunch because their routine has been disrupted; they forget at bedtime because they fell asleep on the sofa. Or they had to feed their children dinner quickly to make it to a teacher’s meeting, so they forgot their medication. But it is vital that they maintain their insulin injection schedule. Research says missing 2.1 meal-related injections a week increases glycated hemoglobin (A1c) by 0.3% to 0.4%.

Most people with T2D will eventually need insulin. For someone with diabetes – and for their family members – hypoglycemia is a real fear. Hypoglycemia has significant physical (eg, irregular heartbeat, shakiness) and mental (eg, anxiety, irritability) effects. In response, patients can treat themselves with glucose tablets or simple carbohydrates (between 15 and 30 g). If the patient is unconscious, the family may need to use injectable glucagon. This is where the benefits of a continuous glucose monitor come in.
Patients can see the hypoglycemic state they are approaching so they can treat a low blood glucose level on their own before others need to. 

Our clinic members focus on having open, honest conversations with our patients about how their lives affect their diabetes. We encourage them to choose a nutrition plan or see our dietitian. Some do phenomenally well with plans like Weight Watchers, but others do not. Whatever they choose, our dietitians aim to help them stay on it, with weekly check-ins, teleconferences, and appointments.

Communication goes both ways. Our patients tell us constantly that they do not want another medication. Diabetes is an expensive disease, and most of our patients take at least 5 medications, prescribed by nephrologists, cardiologists, endocrinologists, and family physicians. Our clinical pharmacists and other team members try to find ways to bring those costs down; sometimes we cannot.

Some Pointers
It is not a bad idea to keep a flowchart on your phone that details which diabetes drug is applicable under which circumstances, and when it is not applicable. While most are complementary, a list would detail how each of the new medications work, how they work together and how they benefit patients.

Some wisdom learned in the trenches: 

• Do not shy away from starting a newly diagnosed patient on metformin and a second agent. The American Diabetes Association guidelines say that more intensive initial treatment can be beneficial. If the patient’s  A1c is elevated, consider using 2 medications upon diagnosis. 
• Using a sulfonylurea, which stimulates insulin secretion, as a second-line therapy alone can increase risk of myocardial infarction, all-cause mortality, and severe hypoglycemia (hazard ratios, 1.26, 1.28, and 7.60, respectively); these medications also cause weight gain. The sulfonylureas put pressure on the beta cells to work harder. More importantly, we do not know what these medications do to the cardiovascular system in the long term.
• If the patient has cardiovascular disease, then, in combination with metformin, use a glucagon-like peptide 1 receptor agonist (GLP-1) or a sodium-glucose cotransporter 2 (SGLT2) inhibitor. If the patient has kidney disease, start with an SGLT2 inhibitor. And yes, you can prescribe both at the same time. 
• SGLT2 inhibitors lower glucose levels by preventing the kidneys from reabsorbing glucose. The GLP-1 agonists encourage insulin production and inhibit glucagon secretion  after meals. Neither of these medications are known to add weight; they are linked with weight loss. 
• If your patient is on a dipeptidyl peptidase 4 (DPP-4) inhibitor and is moving to a GLP-1 receptor agonist, stop the DDP-4 before starting the GLP-1 since both target the incretin system to control blood glucose levels.

While years in the making, new medications and technologies now available for T2D have given healthcare providers more options for their patients, and patients have better opportunities to achieve their treatment goals. 
 

Davida F. Kruger, MSN, APN-BC, BC-ADM
Ms. Kruger has been a certified nurse practitioner in diabetes at Henry Ford Health System in Detroit, MI, for more than 35 years. Ms. Kruger has been a co-investigator on numerous studies of diabetes interventions and care, including the National Institutes of Health–funded multicenter EDIC and ACCORD trials.

She is a past Chair of the American Diabetes Association (ADA) Research Foundation and has served on the ADA Research Policy Committee. She is also an ADA Past President (Health Care and Education). She has also served as editor-in-chief of 2 American Diabetes Association (ADA) journals, Diabetes Spectrum and Clinical Diabetes.

Our diabetes clinic in Detroit is ground zero for diabetes care and education.

High-risk obstetrician gynecologists, cardiologists, nephrologists, and primary care providers, which are all specialties seeing more patients with type 2 diabetes (T2D) comorbidities, are coming to us or sharing patient cases to learn more about diabetes care, newer medications, and the technology needed to help disease management. Considering the complexity of the disease, its comorbidities, the long list of medications, and the human skills required to help these individuals, our clinic has long considered that patients are better served by a team of providers with experience in the intricacies and nuances of this chronic disease.

With over 40 years in the trenches, I can write without equivocation that the treatment of patients with diabetes requires a team approach involving diabetes educators, nurse practitioners, physician assistants, pharmacists, physicians, and nutritionists, who have long known that diabetes is a serious, deadly disease. 

Some facts to prove my point: 
When I started treating people with  diabetes, 4% of the US population had the disease. Life expectancy was about 74 years. Today, 11% of the population has diabetes, and life expectancy is closer to 78 years. Longer life, for someone with diabetes, means more time with kidney disease, cardiovascular problems, neuropathy, macular degeneration, and more.T2D is no longer just an adult disease. We are treating T2D in a much younger population. The Centers for Disease Control and Prevention says from 2002 to 2015, the incidence rate for people <20 years rose 4.8% per year. 
In 2019, the World Health Organization said that 16,300 people < 25 years old died from diabetes, and most of these deaths were from type 1 diabetes.
If we maintain the status quo, between now and 2050, 33% of the adult population in this country could have this disease. 
Our clinic has enrolled  at least 3500 patients with some type of diabetes. 

The list of therapies ─ and more importantly the different classes of therapies ─ has grown significantly since the time when sulfonylureas, metformin, and insulin were the only therapies available. Today, there are at least 9 classes of medications to treat type 2 diabetes. 

Considering that patients with T2D, most of whom are overweight or obese, also have heart disease, kidney disease, and more, the collective input from various kinds of healthcare providers to discuss how these medications can work together, or not, is beyond beneficial. The literature shows that a multidisciplinary team improves patient outcomes in the T2D population. The literature also shows that despite therapeutic advances, most of these patients have disease that is not well controlled, for a variety of reasons.

Patients and Attitudes
I was riding in an elevator with a rheumatologist a few years ago. He told me that my patients were all “fat” and “responsible for their situation.” I told him an elevator ride could not cover the amount of education he needed, so I invited him to call me. There are many reasons why people develop T2D and carrying too much weight is a significant one. We tell our patients that this extra weight puts stress on the natural production of insulin. The result is that less organic insulin is produced so more manufactured insulin is prescribed, and this puts weight on the patient. 

Patients have busy lives, and those with diabetes are no different; their lives get in the way of managing their disease. Some need to remember to take 3 or 4 injections a day. They forget an injection at lunch because their routine has been disrupted; they forget at bedtime because they fell asleep on the sofa. Or they had to feed their children dinner quickly to make it to a teacher’s meeting, so they forgot their medication. But it is vital that they maintain their insulin injection schedule. Research says missing 2.1 meal-related injections a week increases glycated hemoglobin (A1c) by 0.3% to 0.4%.

Most people with T2D will eventually need insulin. For someone with diabetes – and for their family members – hypoglycemia is a real fear. Hypoglycemia has significant physical (eg, irregular heartbeat, shakiness) and mental (eg, anxiety, irritability) effects. In response, patients can treat themselves with glucose tablets or simple carbohydrates (between 15 and 30 g). If the patient is unconscious, the family may need to use injectable glucagon. This is where the benefits of a continuous glucose monitor come in.
Patients can see the hypoglycemic state they are approaching so they can treat a low blood glucose level on their own before others need to. 

Our clinic members focus on having open, honest conversations with our patients about how their lives affect their diabetes. We encourage them to choose a nutrition plan or see our dietitian. Some do phenomenally well with plans like Weight Watchers, but others do not. Whatever they choose, our dietitians aim to help them stay on it, with weekly check-ins, teleconferences, and appointments.

Communication goes both ways. Our patients tell us constantly that they do not want another medication. Diabetes is an expensive disease, and most of our patients take at least 5 medications, prescribed by nephrologists, cardiologists, endocrinologists, and family physicians. Our clinical pharmacists and other team members try to find ways to bring those costs down; sometimes we cannot.

Some Pointers
It is not a bad idea to keep a flowchart on your phone that details which diabetes drug is applicable under which circumstances, and when it is not applicable. While most are complementary, a list would detail how each of the new medications work, how they work together and how they benefit patients.

Some wisdom learned in the trenches: 

• Do not shy away from starting a newly diagnosed patient on metformin and a second agent. The American Diabetes Association guidelines say that more intensive initial treatment can be beneficial. If the patient’s  A1c is elevated, consider using 2 medications upon diagnosis. 
• Using a sulfonylurea, which stimulates insulin secretion, as a second-line therapy alone can increase risk of myocardial infarction, all-cause mortality, and severe hypoglycemia (hazard ratios, 1.26, 1.28, and 7.60, respectively); these medications also cause weight gain. The sulfonylureas put pressure on the beta cells to work harder. More importantly, we do not know what these medications do to the cardiovascular system in the long term.
• If the patient has cardiovascular disease, then, in combination with metformin, use a glucagon-like peptide 1 receptor agonist (GLP-1) or a sodium-glucose cotransporter 2 (SGLT2) inhibitor. If the patient has kidney disease, start with an SGLT2 inhibitor. And yes, you can prescribe both at the same time. 
• SGLT2 inhibitors lower glucose levels by preventing the kidneys from reabsorbing glucose. The GLP-1 agonists encourage insulin production and inhibit glucagon secretion  after meals. Neither of these medications are known to add weight; they are linked with weight loss. 
• If your patient is on a dipeptidyl peptidase 4 (DPP-4) inhibitor and is moving to a GLP-1 receptor agonist, stop the DDP-4 before starting the GLP-1 since both target the incretin system to control blood glucose levels.

While years in the making, new medications and technologies now available for T2D have given healthcare providers more options for their patients, and patients have better opportunities to achieve their treatment goals. 
 

A few years ago I tracked down my medical school interviewer to thank him for giving me the opportunity to do what I felt I was called to do. I was surprised that, after 15 years, he actually remembered me and remembered details like walking to the courtyard to meet my father who’d driven me to the interview.

Gratitude throughout my career has grounded me in moments of hardship and highlighted joyful times that give me peace. Sharing my gratitude and letting him know I was happy felt important to me.

Choosing to practice family medicine has a lot to do with why I am happy in my career today.

One of my frustrations with health care had been its emphasis on treatment of sickness, rather than a broader one that incorporated prevention of sickness. During my third year of medical school, I was following a family and sports medicine faculty member who was focusing on aspects of lifestyle medicine to help a patient remain active and age gracefully. Seeing opportunities to practice preventative medicine in family medicine made me realize the specialty was the perfect fit for me.
 

Food as medicine

While participating in rotations I also realized you can find a subspecialty within family medicine.

During my fourth year of medical school, I followed an attending who was seeing a patient for hypertension, prediabetes and hypercholesterolemia. The attending told the patient to eat “healthier,” gave her a handout, and scheduled a follow up appointment for 6 months later.

My thoughts were: “That’s it? That’s how we counsel patients to improve their dietary habits?”

As the patient was leaving the exam room, I asked her what type of oil she cooked with, and I proceeded to share culinary tips from my mother – who was a self-taught and early adopter of the food-as-medicine movement.

Once I started my residency, I knew I’d want to incorporate lifestyle and dietary approaches at many of my patient visits.

I scheduled patients every month to monitor their weight, follow up on chronic conditions, but more importantly, to engage them in their health and empower them to make small lifestyle changes each month and report their efforts. I felt like I was their health coach and cheerleader.
 

My career in family medicine

Entering the job market allowed me to form my philosophy of treating patients with a mind, body, and spirit approach. I chose to practice value-based care, which aligns with my lifestyle and preventative medicine approach .

I currently practice in a small family medicine–only clinic that is part of a larger multispecialty system. Primary care specialties in my organization are valued, respected and central to a patient’s well being and care. We are encouraged to spend time with patients, assess barriers to care and work collaboratively with our healthcare team, so that preventative medicine approaches take the lead in a patient’s health. This supportive culture and environment is one where my passion for food as medicine has thrived.

One day I forgot to pack a lunch and instead brought a grocery bag of items to make a salad. When I realized I made too much, I sent an email to my staff to get some “free salad in my office.” This serendipitous moment started an informal office “salad club” each week. Continued support from my staff and leadership, allowed me to consider further extending this teaching to my patients and my colleagues.

Three years ago, I helped adopt a sustainable plant-forward menu for our physician meetings, complete with a recipe from the menu for physicians to replicate at home or give to their patients.

I also pursued adoption of shared medical appointments for our medical group. These appointments apply the “see one, do one, teach one” model in medicine, but with culinary medicine as the focus.

Knowing that my patients are all connected to their families through food, I sought this as an opportunity to dive in further with wellness opportunities at their next meal. After almost 2 years of working on this project, I was able to host my first shared medical appointment with a group of patients on March 12, 2020. The next day schools closed, lockdowns occurred, and the world changed.
 

Opportunities highlighted by the pandemic

We always knew health care was broken but adding the increasingly longer hours and COVID vaccine–hesitant patients that the pandemic brought made everything look dark at times. What has helped me stay hopeful and energetic for system changes is feeling gratitude and seeking bright lights.

My experiences seeing patients in telehealth visits are examples of some of the bright lights I found in the pandemic. During these visits, patients showed me something from their pantry, and we’d go over nutritional labels together.

Additionally, my patients became engaged with their own conditions and wanted to improve them because of news articles highlighting risk factors for COVID-19, such as obesity. I had an active audience when it came to talking about food-as-medicine approaches to improving risk factors and immunity. And since everyone was listening, I didn’t stop at food. I also talked about physical health, stress resiliency, planetary diets, sleep, connections, and lastly vaccines!

Once the vaccines were distributed, I naturally gravitated to having those conversations with patients and colleagues and on social media. Plus, the pandemic gave us moments of simple times to slow down, take more rests, be less overscheduled, consider work-life priorities, and, lastly, to be okay with not being totally okay.

In practicing primary care, we have a unique role in seeing medicine from a whole body, whole person, whole family perspective. There is an opportunity to highlight what is broken in medicine and aim to make it whole.

I’m currently looking at shared medical appointments as a new standard way to provide care to all patients, because it improves access, provides better quality visits and aligns my values, mission, and purpose.

In the midst of the pandemic, I helped advocate for a sustainable plant-forward menu that was launched throughout four different hospitals in the Sharp HealthCare system, in California, in 2020. Knowing that patients were served a menu I played a role in, gave me solace.

As part of the hospital food and nutrition team, I am grateful for the opportunity I have to work on a broader mission to address social determinants of health and seek opportunities to help the system work for our patients.

Public health communication has been lacking in the pandemic, but another bright light is that we were still the trusted messengers to our patients and our communities. I’m continually honored and humbled to be trusted with a whole family’s health.

Dr. Neison practices family medicine and culinary medicine at Sharp Rees-Stealy Medical Group in San Diego, and is cochair of climate and planetary health for SRS Medical Group. You can follow her on Instagram, LinkedIn, and Facebook @Flavors4WellnessMD.

A few years ago I tracked down my medical school interviewer to thank him for giving me the opportunity to do what I felt I was called to do. I was surprised that, after 15 years, he actually remembered me and remembered details like walking to the courtyard to meet my father who’d driven me to the interview.

Gratitude throughout my career has grounded me in moments of hardship and highlighted joyful times that give me peace. Sharing my gratitude and letting him know I was happy felt important to me.

Choosing to practice family medicine has a lot to do with why I am happy in my career today.

One of my frustrations with health care had been its emphasis on treatment of sickness, rather than a broader one that incorporated prevention of sickness. During my third year of medical school, I was following a family and sports medicine faculty member who was focusing on aspects of lifestyle medicine to help a patient remain active and age gracefully. Seeing opportunities to practice preventative medicine in family medicine made me realize the specialty was the perfect fit for me.
 

Food as medicine

While participating in rotations I also realized you can find a subspecialty within family medicine.

During my fourth year of medical school, I followed an attending who was seeing a patient for hypertension, prediabetes and hypercholesterolemia. The attending told the patient to eat “healthier,” gave her a handout, and scheduled a follow up appointment for 6 months later.

My thoughts were: “That’s it? That’s how we counsel patients to improve their dietary habits?”

As the patient was leaving the exam room, I asked her what type of oil she cooked with, and I proceeded to share culinary tips from my mother – who was a self-taught and early adopter of the food-as-medicine movement.

Once I started my residency, I knew I’d want to incorporate lifestyle and dietary approaches at many of my patient visits.

I scheduled patients every month to monitor their weight, follow up on chronic conditions, but more importantly, to engage them in their health and empower them to make small lifestyle changes each month and report their efforts. I felt like I was their health coach and cheerleader.
 

My career in family medicine

Entering the job market allowed me to form my philosophy of treating patients with a mind, body, and spirit approach. I chose to practice value-based care, which aligns with my lifestyle and preventative medicine approach .

I currently practice in a small family medicine–only clinic that is part of a larger multispecialty system. Primary care specialties in my organization are valued, respected and central to a patient’s well being and care. We are encouraged to spend time with patients, assess barriers to care and work collaboratively with our healthcare team, so that preventative medicine approaches take the lead in a patient’s health. This supportive culture and environment is one where my passion for food as medicine has thrived.

One day I forgot to pack a lunch and instead brought a grocery bag of items to make a salad. When I realized I made too much, I sent an email to my staff to get some “free salad in my office.” This serendipitous moment started an informal office “salad club” each week. Continued support from my staff and leadership, allowed me to consider further extending this teaching to my patients and my colleagues.

Three years ago, I helped adopt a sustainable plant-forward menu for our physician meetings, complete with a recipe from the menu for physicians to replicate at home or give to their patients.

I also pursued adoption of shared medical appointments for our medical group. These appointments apply the “see one, do one, teach one” model in medicine, but with culinary medicine as the focus.

Knowing that my patients are all connected to their families through food, I sought this as an opportunity to dive in further with wellness opportunities at their next meal. After almost 2 years of working on this project, I was able to host my first shared medical appointment with a group of patients on March 12, 2020. The next day schools closed, lockdowns occurred, and the world changed.
 

Opportunities highlighted by the pandemic

We always knew health care was broken but adding the increasingly longer hours and COVID vaccine–hesitant patients that the pandemic brought made everything look dark at times. What has helped me stay hopeful and energetic for system changes is feeling gratitude and seeking bright lights.

My experiences seeing patients in telehealth visits are examples of some of the bright lights I found in the pandemic. During these visits, patients showed me something from their pantry, and we’d go over nutritional labels together.

Additionally, my patients became engaged with their own conditions and wanted to improve them because of news articles highlighting risk factors for COVID-19, such as obesity. I had an active audience when it came to talking about food-as-medicine approaches to improving risk factors and immunity. And since everyone was listening, I didn’t stop at food. I also talked about physical health, stress resiliency, planetary diets, sleep, connections, and lastly vaccines!

Once the vaccines were distributed, I naturally gravitated to having those conversations with patients and colleagues and on social media. Plus, the pandemic gave us moments of simple times to slow down, take more rests, be less overscheduled, consider work-life priorities, and, lastly, to be okay with not being totally okay.

In practicing primary care, we have a unique role in seeing medicine from a whole body, whole person, whole family perspective. There is an opportunity to highlight what is broken in medicine and aim to make it whole.

I’m currently looking at shared medical appointments as a new standard way to provide care to all patients, because it improves access, provides better quality visits and aligns my values, mission, and purpose.

In the midst of the pandemic, I helped advocate for a sustainable plant-forward menu that was launched throughout four different hospitals in the Sharp HealthCare system, in California, in 2020. Knowing that patients were served a menu I played a role in, gave me solace.

As part of the hospital food and nutrition team, I am grateful for the opportunity I have to work on a broader mission to address social determinants of health and seek opportunities to help the system work for our patients.

Public health communication has been lacking in the pandemic, but another bright light is that we were still the trusted messengers to our patients and our communities. I’m continually honored and humbled to be trusted with a whole family’s health.

Dr. Neison practices family medicine and culinary medicine at Sharp Rees-Stealy Medical Group in San Diego, and is cochair of climate and planetary health for SRS Medical Group. You can follow her on Instagram, LinkedIn, and Facebook @Flavors4WellnessMD.

A few years ago I tracked down my medical school interviewer to thank him for giving me the opportunity to do what I felt I was called to do. I was surprised that, after 15 years, he actually remembered me and remembered details like walking to the courtyard to meet my father who’d driven me to the interview.

Gratitude throughout my career has grounded me in moments of hardship and highlighted joyful times that give me peace. Sharing my gratitude and letting him know I was happy felt important to me.

Choosing to practice family medicine has a lot to do with why I am happy in my career today.

One of my frustrations with health care had been its emphasis on treatment of sickness, rather than a broader one that incorporated prevention of sickness. During my third year of medical school, I was following a family and sports medicine faculty member who was focusing on aspects of lifestyle medicine to help a patient remain active and age gracefully. Seeing opportunities to practice preventative medicine in family medicine made me realize the specialty was the perfect fit for me.
 

Food as medicine

While participating in rotations I also realized you can find a subspecialty within family medicine.

During my fourth year of medical school, I followed an attending who was seeing a patient for hypertension, prediabetes and hypercholesterolemia. The attending told the patient to eat “healthier,” gave her a handout, and scheduled a follow up appointment for 6 months later.

My thoughts were: “That’s it? That’s how we counsel patients to improve their dietary habits?”

As the patient was leaving the exam room, I asked her what type of oil she cooked with, and I proceeded to share culinary tips from my mother – who was a self-taught and early adopter of the food-as-medicine movement.

Once I started my residency, I knew I’d want to incorporate lifestyle and dietary approaches at many of my patient visits.

I scheduled patients every month to monitor their weight, follow up on chronic conditions, but more importantly, to engage them in their health and empower them to make small lifestyle changes each month and report their efforts. I felt like I was their health coach and cheerleader.
 

My career in family medicine

Entering the job market allowed me to form my philosophy of treating patients with a mind, body, and spirit approach. I chose to practice value-based care, which aligns with my lifestyle and preventative medicine approach .

I currently practice in a small family medicine–only clinic that is part of a larger multispecialty system. Primary care specialties in my organization are valued, respected and central to a patient’s well being and care. We are encouraged to spend time with patients, assess barriers to care and work collaboratively with our healthcare team, so that preventative medicine approaches take the lead in a patient’s health. This supportive culture and environment is one where my passion for food as medicine has thrived.

One day I forgot to pack a lunch and instead brought a grocery bag of items to make a salad. When I realized I made too much, I sent an email to my staff to get some “free salad in my office.” This serendipitous moment started an informal office “salad club” each week. Continued support from my staff and leadership, allowed me to consider further extending this teaching to my patients and my colleagues.

Three years ago, I helped adopt a sustainable plant-forward menu for our physician meetings, complete with a recipe from the menu for physicians to replicate at home or give to their patients.

I also pursued adoption of shared medical appointments for our medical group. These appointments apply the “see one, do one, teach one” model in medicine, but with culinary medicine as the focus.

Knowing that my patients are all connected to their families through food, I sought this as an opportunity to dive in further with wellness opportunities at their next meal. After almost 2 years of working on this project, I was able to host my first shared medical appointment with a group of patients on March 12, 2020. The next day schools closed, lockdowns occurred, and the world changed.
 

Opportunities highlighted by the pandemic

We always knew health care was broken but adding the increasingly longer hours and COVID vaccine–hesitant patients that the pandemic brought made everything look dark at times. What has helped me stay hopeful and energetic for system changes is feeling gratitude and seeking bright lights.

My experiences seeing patients in telehealth visits are examples of some of the bright lights I found in the pandemic. During these visits, patients showed me something from their pantry, and we’d go over nutritional labels together.

Additionally, my patients became engaged with their own conditions and wanted to improve them because of news articles highlighting risk factors for COVID-19, such as obesity. I had an active audience when it came to talking about food-as-medicine approaches to improving risk factors and immunity. And since everyone was listening, I didn’t stop at food. I also talked about physical health, stress resiliency, planetary diets, sleep, connections, and lastly vaccines!

Once the vaccines were distributed, I naturally gravitated to having those conversations with patients and colleagues and on social media. Plus, the pandemic gave us moments of simple times to slow down, take more rests, be less overscheduled, consider work-life priorities, and, lastly, to be okay with not being totally okay.

In practicing primary care, we have a unique role in seeing medicine from a whole body, whole person, whole family perspective. There is an opportunity to highlight what is broken in medicine and aim to make it whole.

I’m currently looking at shared medical appointments as a new standard way to provide care to all patients, because it improves access, provides better quality visits and aligns my values, mission, and purpose.

In the midst of the pandemic, I helped advocate for a sustainable plant-forward menu that was launched throughout four different hospitals in the Sharp HealthCare system, in California, in 2020. Knowing that patients were served a menu I played a role in, gave me solace.

As part of the hospital food and nutrition team, I am grateful for the opportunity I have to work on a broader mission to address social determinants of health and seek opportunities to help the system work for our patients.

Public health communication has been lacking in the pandemic, but another bright light is that we were still the trusted messengers to our patients and our communities. I’m continually honored and humbled to be trusted with a whole family’s health.

Dr. Neison practices family medicine and culinary medicine at Sharp Rees-Stealy Medical Group in San Diego, and is cochair of climate and planetary health for SRS Medical Group. You can follow her on Instagram, LinkedIn, and Facebook @Flavors4WellnessMD.

Recently the National Clinical Care Commission provided recommendations to Congress for improving federal diabetes programs in a report. This commission was put together after Congress passed the National Clinical Care Commission Act in 2017.

The report provides a wide range of recommendations that look to combat and prevent diabetes at many levels. An exciting aspect of the recommendations is that they consider how all agencies, including those that are not specifically health care, can fight diabetes. As primary care physicians are increasingly looking at all aspects of our patients’ lives to improve their health, these recommendations provide support for the work on which we are currently embarking.

The report acknowledges that many recent advances in diabetes treatments have made huge differences for clinicians and patients alike. Unfortunately, they have not been translated quickly into practice and when they have been, there have been disparities in the rollouts.

The document also states that many other factors, including housing, health care access, and food access, greatly affect the prevention and control of diabetes, according to a paper published in Annals of Internal Medicine. These factors have led to significant disparities in the population impacted by diabetes.

The topic areas of the recommendations include federal programs and policies; population-level programs to prevent diabetes, facilitate treatments, and promote health equity; type 2 diabetes prevention; insurance coverage; diabetes care delivery; and diabetes research.

Supporting recommendations in clinics

Family physicians, internists, and pediatricians can directly support many of the recommendations in their clinics. For those recommendations that are not directed at primary care clinics specifically, physicians should provide advocacy for their implementation.

If implemented, some of these recommendations will allow primary care physicians to improve at providing treatments to their patients for diabetes prevention and treatment of the disease. For example, the recommendations call for requirements of insurance companies to cover screening for prediabetes with the use of hemoglobin A1c and the participation in Centers for Disease Control and Prevention–recognized diabetes prevention programs.

The recommendations also call for the requirement of high-value diabetes services and treatment to be covered predeductible by insurers. If more consistently covered by insurers, it would be easier for us to implement these opportunities including educational groups in our practices. Additionally, if they were available predeductible, we could recommend these to our patients with less worry about cost.

Within care delivery recommendations, they also highlight the importance of an adequate and sustainable team to enhance care for patients with diabetes. Many of us know that it takes more than just the medications, but also significant counseling on diet, exercise and other lifestyle aspects – which need to be tailored to each patient for both prevention and treatment of diabetes.

The recommendations also call for the education and treatment modalities to be able to be provided and covered via virtual methods, while potentially increasing physicians’ ability to provide and patients’ ability to access. Ensuring both the workforce is available and that insurance provides coverage would make these programs accessible to so many more physician offices and ultimately patients.
 

Importance of social factors

As stated earlier, one of the great aspects of this report is its acknowledgment of the importance of social factors on the prevention and treatment of diabetes.

The report recommends expanding housing opportunities for low-income individuals as individuals cannot focus on their health when worried about housing. It also recommends increasing assistance with programs focused on food security. Primary care physicians should advocate for the adoption of these and other recommendations, because of the potentially meaningful impact these changes could have.

Ensuring adequate housing and access to healthy food would go a long way in the prevention and treatment of diabetes. If there are increases in these resources, team members within primary care physician offices would be wonderful allies to help direct patients to these resources. As these concerns may be top of mind for some patients, linking patients to these resources in the physician’s office may reinforce for patients that physicians understand our patients’ biggest concerns.

Ultimately, if the sweeping recommendations in this report are adopted and enforced, it could mean significant improvements for many patients at risk for and living with diabetes. They would provide payment for these resources making them more accessible for patients and physicians alike.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

Recently the National Clinical Care Commission provided recommendations to Congress for improving federal diabetes programs in a report. This commission was put together after Congress passed the National Clinical Care Commission Act in 2017.

The report provides a wide range of recommendations that look to combat and prevent diabetes at many levels. An exciting aspect of the recommendations is that they consider how all agencies, including those that are not specifically health care, can fight diabetes. As primary care physicians are increasingly looking at all aspects of our patients’ lives to improve their health, these recommendations provide support for the work on which we are currently embarking.

The report acknowledges that many recent advances in diabetes treatments have made huge differences for clinicians and patients alike. Unfortunately, they have not been translated quickly into practice and when they have been, there have been disparities in the rollouts.

The document also states that many other factors, including housing, health care access, and food access, greatly affect the prevention and control of diabetes, according to a paper published in Annals of Internal Medicine. These factors have led to significant disparities in the population impacted by diabetes.

The topic areas of the recommendations include federal programs and policies; population-level programs to prevent diabetes, facilitate treatments, and promote health equity; type 2 diabetes prevention; insurance coverage; diabetes care delivery; and diabetes research.

Supporting recommendations in clinics

Family physicians, internists, and pediatricians can directly support many of the recommendations in their clinics. For those recommendations that are not directed at primary care clinics specifically, physicians should provide advocacy for their implementation.

If implemented, some of these recommendations will allow primary care physicians to improve at providing treatments to their patients for diabetes prevention and treatment of the disease. For example, the recommendations call for requirements of insurance companies to cover screening for prediabetes with the use of hemoglobin A1c and the participation in Centers for Disease Control and Prevention–recognized diabetes prevention programs.

The recommendations also call for the requirement of high-value diabetes services and treatment to be covered predeductible by insurers. If more consistently covered by insurers, it would be easier for us to implement these opportunities including educational groups in our practices. Additionally, if they were available predeductible, we could recommend these to our patients with less worry about cost.

Within care delivery recommendations, they also highlight the importance of an adequate and sustainable team to enhance care for patients with diabetes. Many of us know that it takes more than just the medications, but also significant counseling on diet, exercise and other lifestyle aspects – which need to be tailored to each patient for both prevention and treatment of diabetes.

The recommendations also call for the education and treatment modalities to be able to be provided and covered via virtual methods, while potentially increasing physicians’ ability to provide and patients’ ability to access. Ensuring both the workforce is available and that insurance provides coverage would make these programs accessible to so many more physician offices and ultimately patients.
 

Importance of social factors

As stated earlier, one of the great aspects of this report is its acknowledgment of the importance of social factors on the prevention and treatment of diabetes.

The report recommends expanding housing opportunities for low-income individuals as individuals cannot focus on their health when worried about housing. It also recommends increasing assistance with programs focused on food security. Primary care physicians should advocate for the adoption of these and other recommendations, because of the potentially meaningful impact these changes could have.

Ensuring adequate housing and access to healthy food would go a long way in the prevention and treatment of diabetes. If there are increases in these resources, team members within primary care physician offices would be wonderful allies to help direct patients to these resources. As these concerns may be top of mind for some patients, linking patients to these resources in the physician’s office may reinforce for patients that physicians understand our patients’ biggest concerns.

Ultimately, if the sweeping recommendations in this report are adopted and enforced, it could mean significant improvements for many patients at risk for and living with diabetes. They would provide payment for these resources making them more accessible for patients and physicians alike.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

Recently the National Clinical Care Commission provided recommendations to Congress for improving federal diabetes programs in a report. This commission was put together after Congress passed the National Clinical Care Commission Act in 2017.

The report provides a wide range of recommendations that look to combat and prevent diabetes at many levels. An exciting aspect of the recommendations is that they consider how all agencies, including those that are not specifically health care, can fight diabetes. As primary care physicians are increasingly looking at all aspects of our patients’ lives to improve their health, these recommendations provide support for the work on which we are currently embarking.

The report acknowledges that many recent advances in diabetes treatments have made huge differences for clinicians and patients alike. Unfortunately, they have not been translated quickly into practice and when they have been, there have been disparities in the rollouts.

The document also states that many other factors, including housing, health care access, and food access, greatly affect the prevention and control of diabetes, according to a paper published in Annals of Internal Medicine. These factors have led to significant disparities in the population impacted by diabetes.

The topic areas of the recommendations include federal programs and policies; population-level programs to prevent diabetes, facilitate treatments, and promote health equity; type 2 diabetes prevention; insurance coverage; diabetes care delivery; and diabetes research.

Supporting recommendations in clinics

Family physicians, internists, and pediatricians can directly support many of the recommendations in their clinics. For those recommendations that are not directed at primary care clinics specifically, physicians should provide advocacy for their implementation.

If implemented, some of these recommendations will allow primary care physicians to improve at providing treatments to their patients for diabetes prevention and treatment of the disease. For example, the recommendations call for requirements of insurance companies to cover screening for prediabetes with the use of hemoglobin A1c and the participation in Centers for Disease Control and Prevention–recognized diabetes prevention programs.

The recommendations also call for the requirement of high-value diabetes services and treatment to be covered predeductible by insurers. If more consistently covered by insurers, it would be easier for us to implement these opportunities including educational groups in our practices. Additionally, if they were available predeductible, we could recommend these to our patients with less worry about cost.

Within care delivery recommendations, they also highlight the importance of an adequate and sustainable team to enhance care for patients with diabetes. Many of us know that it takes more than just the medications, but also significant counseling on diet, exercise and other lifestyle aspects – which need to be tailored to each patient for both prevention and treatment of diabetes.

The recommendations also call for the education and treatment modalities to be able to be provided and covered via virtual methods, while potentially increasing physicians’ ability to provide and patients’ ability to access. Ensuring both the workforce is available and that insurance provides coverage would make these programs accessible to so many more physician offices and ultimately patients.
 

Importance of social factors

As stated earlier, one of the great aspects of this report is its acknowledgment of the importance of social factors on the prevention and treatment of diabetes.

The report recommends expanding housing opportunities for low-income individuals as individuals cannot focus on their health when worried about housing. It also recommends increasing assistance with programs focused on food security. Primary care physicians should advocate for the adoption of these and other recommendations, because of the potentially meaningful impact these changes could have.

Ensuring adequate housing and access to healthy food would go a long way in the prevention and treatment of diabetes. If there are increases in these resources, team members within primary care physician offices would be wonderful allies to help direct patients to these resources. As these concerns may be top of mind for some patients, linking patients to these resources in the physician’s office may reinforce for patients that physicians understand our patients’ biggest concerns.

Ultimately, if the sweeping recommendations in this report are adopted and enforced, it could mean significant improvements for many patients at risk for and living with diabetes. They would provide payment for these resources making them more accessible for patients and physicians alike.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked two leading neurologists to present differing views on the use of calcitonin gene-related peptide (CGRPs) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of the CGRP mAbs. To read a counter-argument in which Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class, click here.

Dr. Schim is Co-Director of The Headache Center of Southern California, The Neurology Center.  He is Board Member and past President of the Headache Consortium of the Pacific, Board Member and past President, American Heart Association San Diego, a Past President of the California Neurologic Society, and an active member of the American Academy of Neurology, American Stroke Association, and American Headache Society.

The identification of CGRP as a crucial pain signaling molecule in the trigeminal pathway, thereby establishing its link to migraine pain, has transformed care for patients with episodic and chronic migraine. Since 2018, the FDA has approved 4 monoclonal antibodies (mAbs) that either block the CGRP receptor or bind its ligand to prevent attachment to the receptor. 

These medications are helping patients with medication overuse headache (MOH) and chronic migraine; one study involving 139 patients showed that half the patients saw their headache days per month cut by half, and migraine days per month cut by 62%. In another small study, 23 patients (47%) with medication overuse headache reported having no MOH issues after 3 months. Most of these patients had a history of medication overuse, but no specific diagnosis of MOH.

In a survey, 277 physicians said that nearly half of their patients had resistant migraine, and 29% had refractory migraine. For these patients, the mAbs have helped restore some normalcy in their lives.  

But are these medications safe? Some clinicians posed this question even before the 2018 approval.

It is a valid question. The CGRP neuropeptide is a powerful dilator, establishing vascular homeostasis, organ development in utero, wound healing, and more. It is expressed in the peripheral and central nervous system and found abundantly in neurons and the unmyelinated A-fibers of the peripheral trigeminovascular system and trigeminal ganglion.

So, would blocking CGRP function in one area affect its function in another? So far, I have to say the answer is no. Neither the literature nor my observations say otherwise. 

Trials vs the real world

Finding an answer to this question takes more than reading clinical trials data. Participants in these trials do not necessarily represent the real world – no complicated morbidities, no pregnant or lactating women. And trial lengths are generally short.

Thus, it is important to assess the safety of these medications in the real world.  

In the trials of the subcutaneous mAbs, local injection site reactions were the most common adverse event. More specifically, erenumab showed increased incidence of constipation, and  post-marketing surveillance has revealed some risk of hypertension; pooled analysis from 4 trial phases showed that across treatment groups, 20 people out of 2443 began treatment for hypertension. Some patients enrolled in trials for atogepant, an oral small molecule CGRP receptor agonist, also reported constipation and nausea, suggesting that receptor blockade may result in a higher incidence of GI disturbance. In addition, these medicines on occasion have caused alopecia, fatigue, or achiness. 

Eptinezumab is administered intravenously, every 3 months, and thus does not have injection site reactions as a safety concern. In clinical trials, the most common adverse event was nasopharyngitis and hypersensitivity; Datta et al have provided a summary of safety and efficacy.

Raynaud’s and cluster headaches

A retrospective chart review study from the Mayo Clinic looking at individuals with Raynaud’s disease who were treated with CGRP antagonists showed that 5.3% of 169 patients had microvascular complications such as gangrene or autoimmune necrosis. There was no significant difference in demographic characteristics or rheumatologic history among those with Raynaud's who did or did not experience complications. In addition, microvascular complications of migraine therapies have preceded the use of CGRP modulators, as this has been documented in the past with other vasoactive substances such as ergots, triptans, and beta blockers. 

In a tolerability and safety study of galcanezumab in patients with chronic cluster headache, with up to 15 months of treatment, the most common treatment emergent adverse events were nasopharyngitis and injection site pain. In this population with 11% to 12% of individuals having baseline hypertension and nearly 63% currently using tobacco, less than 2.5% had any abnormalities on ECG.  

Vascular complications including pulmonary embolism, TIA, myocardial infarction, and atrial fibrillation have been reported but with no apparent relation between galcanezumab dosing and onset, with onset following the second to up to the eleventh monthly dose. 

Antidrug antibodies can also occur as a complication of exposure to therapeutic antibodies of this class and have been detected in up to 12% of individuals treated. This might lead to therapeutic failure but would not likely be a safety issue.

Anaphylaxis or serious hypersensitivity reactions are uncommon, and in general are the only contraindication to the use of these agents. 

Pregnancy registry information is just starting to become available. The number of reports on adverse drug reactions remains limited, and thus it is wise to avoid pregnancy and breastfeeding exposures as best as possible.

FAERS

The FDA adverse event reporting system (FAERS) database does contain reports on adverse events of approved medications. However, even the FDA website warns that the information provided regarding individual cases is unverified and wouldn’t establish causation, considering the confounding variables involved, and this information can be duplicated as well as incomplete. In addition, rates of occurrence cannot be established with reports, as the denominator of exposure is uncertain.  

With those caveats established, the most common reports in FAERS concern injection site reactions, more frequent migraine or headache, or drug ineffectiveness. While constipation has been the second most common AE for erenumab, it did not make the top 10 for fremanezumab or galcanezumab, and cardiovascular events have not ranked in the top 10 for any product. Reasons for discontinuing treatment included withdrawal by the patient (147 of 1,890 [8%]) and lack of efficacy (77 of 1,890 [4%]). 

As the reader can ascertain, different studies point out different reasons for discontinuing CGRP therapies. Other studies note that the most frequent reasons for discontinuation are lack of efficacy, constipation, and lack of insurance .

Conclusions

These medications have been well received; I believe. Fremanezumab, manufactured by Teva Pharmaceuticals, was approved in September 2018. According to Teva’s 2021 annual report, Ajovy, fremanezumab’s brand name, reached 21% market share in the US and 21% in Europe.

Aimovig, or erenumab, has been prescribed 620,000 times since its approval, according to the Novartis 2021 annual report. Galcanezumab, or Emgality, was approved in 2019, and had 65,300 prescriptions written in the since then. . Adherence to treatment has generally been very high in clinical practice, with the most common reason for a patient to switch being lack of effectiveness, rather than adverse events.

Of note, adverse events of other migraine therapeutics are not insignificant, and considering the pain that people with migraine endure, side effects must be hard to contend with for individuals to stop taking them. Case in point: A year before erenumab was approved, a study was published that looked at medical records for medication persistence in 8,700 chronic migraine patients, who all had been prescribed beta blockers, anti-seizure medications, or antidepressants. By 6 months, only 1 out of 4 patients were still taking the prescribed medicines. By 12 months, that  was down to 14%. And about one-third of patients who stopped treatment stayed untreated for at least a year. 

The presumed reasons these patients stopped their medications: side effects and-or lack of efficacy. 

Migraine is a disabling disorder, for which the mAb class of medications has been highly beneficial for large numbers of patients, with far greater tolerability than prior oral preventives. While no treatments have absolute safety, the overall safety of this class of medications has been very high, leading to much improved clinical outcomes.

Editors’ note: For the April edition of Expert Perspectives, we asked two leading neurologists to present differing views on the use of calcitonin gene-related peptide (CGRPs) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of the CGRP mAbs. To read a counter-argument in which Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class, click here.

Dr. Schim is Co-Director of The Headache Center of Southern California, The Neurology Center.  He is Board Member and past President of the Headache Consortium of the Pacific, Board Member and past President, American Heart Association San Diego, a Past President of the California Neurologic Society, and an active member of the American Academy of Neurology, American Stroke Association, and American Headache Society.

The identification of CGRP as a crucial pain signaling molecule in the trigeminal pathway, thereby establishing its link to migraine pain, has transformed care for patients with episodic and chronic migraine. Since 2018, the FDA has approved 4 monoclonal antibodies (mAbs) that either block the CGRP receptor or bind its ligand to prevent attachment to the receptor. 

These medications are helping patients with medication overuse headache (MOH) and chronic migraine; one study involving 139 patients showed that half the patients saw their headache days per month cut by half, and migraine days per month cut by 62%. In another small study, 23 patients (47%) with medication overuse headache reported having no MOH issues after 3 months. Most of these patients had a history of medication overuse, but no specific diagnosis of MOH.

In a survey, 277 physicians said that nearly half of their patients had resistant migraine, and 29% had refractory migraine. For these patients, the mAbs have helped restore some normalcy in their lives.  

But are these medications safe? Some clinicians posed this question even before the 2018 approval.

It is a valid question. The CGRP neuropeptide is a powerful dilator, establishing vascular homeostasis, organ development in utero, wound healing, and more. It is expressed in the peripheral and central nervous system and found abundantly in neurons and the unmyelinated A-fibers of the peripheral trigeminovascular system and trigeminal ganglion.

So, would blocking CGRP function in one area affect its function in another? So far, I have to say the answer is no. Neither the literature nor my observations say otherwise. 

Trials vs the real world

Finding an answer to this question takes more than reading clinical trials data. Participants in these trials do not necessarily represent the real world – no complicated morbidities, no pregnant or lactating women. And trial lengths are generally short.

Thus, it is important to assess the safety of these medications in the real world.  

In the trials of the subcutaneous mAbs, local injection site reactions were the most common adverse event. More specifically, erenumab showed increased incidence of constipation, and  post-marketing surveillance has revealed some risk of hypertension; pooled analysis from 4 trial phases showed that across treatment groups, 20 people out of 2443 began treatment for hypertension. Some patients enrolled in trials for atogepant, an oral small molecule CGRP receptor agonist, also reported constipation and nausea, suggesting that receptor blockade may result in a higher incidence of GI disturbance. In addition, these medicines on occasion have caused alopecia, fatigue, or achiness. 

Eptinezumab is administered intravenously, every 3 months, and thus does not have injection site reactions as a safety concern. In clinical trials, the most common adverse event was nasopharyngitis and hypersensitivity; Datta et al have provided a summary of safety and efficacy.

Raynaud’s and cluster headaches

A retrospective chart review study from the Mayo Clinic looking at individuals with Raynaud’s disease who were treated with CGRP antagonists showed that 5.3% of 169 patients had microvascular complications such as gangrene or autoimmune necrosis. There was no significant difference in demographic characteristics or rheumatologic history among those with Raynaud's who did or did not experience complications. In addition, microvascular complications of migraine therapies have preceded the use of CGRP modulators, as this has been documented in the past with other vasoactive substances such as ergots, triptans, and beta blockers. 

In a tolerability and safety study of galcanezumab in patients with chronic cluster headache, with up to 15 months of treatment, the most common treatment emergent adverse events were nasopharyngitis and injection site pain. In this population with 11% to 12% of individuals having baseline hypertension and nearly 63% currently using tobacco, less than 2.5% had any abnormalities on ECG.  

Vascular complications including pulmonary embolism, TIA, myocardial infarction, and atrial fibrillation have been reported but with no apparent relation between galcanezumab dosing and onset, with onset following the second to up to the eleventh monthly dose. 

Antidrug antibodies can also occur as a complication of exposure to therapeutic antibodies of this class and have been detected in up to 12% of individuals treated. This might lead to therapeutic failure but would not likely be a safety issue.

Anaphylaxis or serious hypersensitivity reactions are uncommon, and in general are the only contraindication to the use of these agents. 

Pregnancy registry information is just starting to become available. The number of reports on adverse drug reactions remains limited, and thus it is wise to avoid pregnancy and breastfeeding exposures as best as possible.

FAERS

The FDA adverse event reporting system (FAERS) database does contain reports on adverse events of approved medications. However, even the FDA website warns that the information provided regarding individual cases is unverified and wouldn’t establish causation, considering the confounding variables involved, and this information can be duplicated as well as incomplete. In addition, rates of occurrence cannot be established with reports, as the denominator of exposure is uncertain.  

With those caveats established, the most common reports in FAERS concern injection site reactions, more frequent migraine or headache, or drug ineffectiveness. While constipation has been the second most common AE for erenumab, it did not make the top 10 for fremanezumab or galcanezumab, and cardiovascular events have not ranked in the top 10 for any product. Reasons for discontinuing treatment included withdrawal by the patient (147 of 1,890 [8%]) and lack of efficacy (77 of 1,890 [4%]). 

As the reader can ascertain, different studies point out different reasons for discontinuing CGRP therapies. Other studies note that the most frequent reasons for discontinuation are lack of efficacy, constipation, and lack of insurance .

Conclusions

These medications have been well received; I believe. Fremanezumab, manufactured by Teva Pharmaceuticals, was approved in September 2018. According to Teva’s 2021 annual report, Ajovy, fremanezumab’s brand name, reached 21% market share in the US and 21% in Europe.

Aimovig, or erenumab, has been prescribed 620,000 times since its approval, according to the Novartis 2021 annual report. Galcanezumab, or Emgality, was approved in 2019, and had 65,300 prescriptions written in the since then. . Adherence to treatment has generally been very high in clinical practice, with the most common reason for a patient to switch being lack of effectiveness, rather than adverse events.

Of note, adverse events of other migraine therapeutics are not insignificant, and considering the pain that people with migraine endure, side effects must be hard to contend with for individuals to stop taking them. Case in point: A year before erenumab was approved, a study was published that looked at medical records for medication persistence in 8,700 chronic migraine patients, who all had been prescribed beta blockers, anti-seizure medications, or antidepressants. By 6 months, only 1 out of 4 patients were still taking the prescribed medicines. By 12 months, that  was down to 14%. And about one-third of patients who stopped treatment stayed untreated for at least a year. 

The presumed reasons these patients stopped their medications: side effects and-or lack of efficacy. 

Migraine is a disabling disorder, for which the mAb class of medications has been highly beneficial for large numbers of patients, with far greater tolerability than prior oral preventives. While no treatments have absolute safety, the overall safety of this class of medications has been very high, leading to much improved clinical outcomes.

Editors’ note: For the April edition of Expert Perspectives, we asked two leading neurologists to present differing views on the use of calcitonin gene-related peptide (CGRPs) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of the CGRP mAbs. To read a counter-argument in which Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class, click here.

Dr. Schim is Co-Director of The Headache Center of Southern California, The Neurology Center.  He is Board Member and past President of the Headache Consortium of the Pacific, Board Member and past President, American Heart Association San Diego, a Past President of the California Neurologic Society, and an active member of the American Academy of Neurology, American Stroke Association, and American Headache Society.

The identification of CGRP as a crucial pain signaling molecule in the trigeminal pathway, thereby establishing its link to migraine pain, has transformed care for patients with episodic and chronic migraine. Since 2018, the FDA has approved 4 monoclonal antibodies (mAbs) that either block the CGRP receptor or bind its ligand to prevent attachment to the receptor. 

These medications are helping patients with medication overuse headache (MOH) and chronic migraine; one study involving 139 patients showed that half the patients saw their headache days per month cut by half, and migraine days per month cut by 62%. In another small study, 23 patients (47%) with medication overuse headache reported having no MOH issues after 3 months. Most of these patients had a history of medication overuse, but no specific diagnosis of MOH.

In a survey, 277 physicians said that nearly half of their patients had resistant migraine, and 29% had refractory migraine. For these patients, the mAbs have helped restore some normalcy in their lives.  

But are these medications safe? Some clinicians posed this question even before the 2018 approval.

It is a valid question. The CGRP neuropeptide is a powerful dilator, establishing vascular homeostasis, organ development in utero, wound healing, and more. It is expressed in the peripheral and central nervous system and found abundantly in neurons and the unmyelinated A-fibers of the peripheral trigeminovascular system and trigeminal ganglion.

So, would blocking CGRP function in one area affect its function in another? So far, I have to say the answer is no. Neither the literature nor my observations say otherwise. 

Trials vs the real world

Finding an answer to this question takes more than reading clinical trials data. Participants in these trials do not necessarily represent the real world – no complicated morbidities, no pregnant or lactating women. And trial lengths are generally short.

Thus, it is important to assess the safety of these medications in the real world.  

In the trials of the subcutaneous mAbs, local injection site reactions were the most common adverse event. More specifically, erenumab showed increased incidence of constipation, and  post-marketing surveillance has revealed some risk of hypertension; pooled analysis from 4 trial phases showed that across treatment groups, 20 people out of 2443 began treatment for hypertension. Some patients enrolled in trials for atogepant, an oral small molecule CGRP receptor agonist, also reported constipation and nausea, suggesting that receptor blockade may result in a higher incidence of GI disturbance. In addition, these medicines on occasion have caused alopecia, fatigue, or achiness. 

Eptinezumab is administered intravenously, every 3 months, and thus does not have injection site reactions as a safety concern. In clinical trials, the most common adverse event was nasopharyngitis and hypersensitivity; Datta et al have provided a summary of safety and efficacy.

Raynaud’s and cluster headaches

A retrospective chart review study from the Mayo Clinic looking at individuals with Raynaud’s disease who were treated with CGRP antagonists showed that 5.3% of 169 patients had microvascular complications such as gangrene or autoimmune necrosis. There was no significant difference in demographic characteristics or rheumatologic history among those with Raynaud's who did or did not experience complications. In addition, microvascular complications of migraine therapies have preceded the use of CGRP modulators, as this has been documented in the past with other vasoactive substances such as ergots, triptans, and beta blockers. 

In a tolerability and safety study of galcanezumab in patients with chronic cluster headache, with up to 15 months of treatment, the most common treatment emergent adverse events were nasopharyngitis and injection site pain. In this population with 11% to 12% of individuals having baseline hypertension and nearly 63% currently using tobacco, less than 2.5% had any abnormalities on ECG.  

Vascular complications including pulmonary embolism, TIA, myocardial infarction, and atrial fibrillation have been reported but with no apparent relation between galcanezumab dosing and onset, with onset following the second to up to the eleventh monthly dose. 

Antidrug antibodies can also occur as a complication of exposure to therapeutic antibodies of this class and have been detected in up to 12% of individuals treated. This might lead to therapeutic failure but would not likely be a safety issue.

Anaphylaxis or serious hypersensitivity reactions are uncommon, and in general are the only contraindication to the use of these agents. 

Pregnancy registry information is just starting to become available. The number of reports on adverse drug reactions remains limited, and thus it is wise to avoid pregnancy and breastfeeding exposures as best as possible.

FAERS

The FDA adverse event reporting system (FAERS) database does contain reports on adverse events of approved medications. However, even the FDA website warns that the information provided regarding individual cases is unverified and wouldn’t establish causation, considering the confounding variables involved, and this information can be duplicated as well as incomplete. In addition, rates of occurrence cannot be established with reports, as the denominator of exposure is uncertain.  

With those caveats established, the most common reports in FAERS concern injection site reactions, more frequent migraine or headache, or drug ineffectiveness. While constipation has been the second most common AE for erenumab, it did not make the top 10 for fremanezumab or galcanezumab, and cardiovascular events have not ranked in the top 10 for any product. Reasons for discontinuing treatment included withdrawal by the patient (147 of 1,890 [8%]) and lack of efficacy (77 of 1,890 [4%]). 

As the reader can ascertain, different studies point out different reasons for discontinuing CGRP therapies. Other studies note that the most frequent reasons for discontinuation are lack of efficacy, constipation, and lack of insurance .

Conclusions

These medications have been well received; I believe. Fremanezumab, manufactured by Teva Pharmaceuticals, was approved in September 2018. According to Teva’s 2021 annual report, Ajovy, fremanezumab’s brand name, reached 21% market share in the US and 21% in Europe.

Aimovig, or erenumab, has been prescribed 620,000 times since its approval, according to the Novartis 2021 annual report. Galcanezumab, or Emgality, was approved in 2019, and had 65,300 prescriptions written in the since then. . Adherence to treatment has generally been very high in clinical practice, with the most common reason for a patient to switch being lack of effectiveness, rather than adverse events.

Of note, adverse events of other migraine therapeutics are not insignificant, and considering the pain that people with migraine endure, side effects must be hard to contend with for individuals to stop taking them. Case in point: A year before erenumab was approved, a study was published that looked at medical records for medication persistence in 8,700 chronic migraine patients, who all had been prescribed beta blockers, anti-seizure medications, or antidepressants. By 6 months, only 1 out of 4 patients were still taking the prescribed medicines. By 12 months, that  was down to 14%. And about one-third of patients who stopped treatment stayed untreated for at least a year. 

The presumed reasons these patients stopped their medications: side effects and-or lack of efficacy. 

Migraine is a disabling disorder, for which the mAb class of medications has been highly beneficial for large numbers of patients, with far greater tolerability than prior oral preventives. While no treatments have absolute safety, the overall safety of this class of medications has been very high, leading to much improved clinical outcomes.

Dr. Obeidat is an Assistant Professor in the Department of Neurology, 

Neuroimmunology and Multiple Sclerosis and is the Founding Director of the Neuroimmunology and MS Fellowship Program at The Medical College of Wisconsin in Milwaukee, WI.

Dr. Obeidat reports having consulted with/spoken for/conducted clinical trials for AbbVie, Alexion, Atara Biotherapeutics, Biogen, Bristol-Myers Squibb, Central, Celgene, EMD Serono, GW Pharmaceuticals, Genentech, Horizon, Jazz Pharma, Novartis, Sanofi/Genzyme, TG Therapeutics, and Viela Bio. Dr. Obeidat serves on the editorial board of the International Journal of MS Care, the advisory board of Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS®), and the Board of Governors of the Consortium of Multiple Sclerosis Centers.

“Could multiple sclerosis be the direct result of a yet-to-be identified infection?” asked John Kurtzke, MD, of his audience during his Grand Rounds entitled “Epidemiology and the Cause of Multiple Sclerosis” at the National Institute of Health (NIH) in 2015.¹ As a pioneer of neuroepidemiology, Dr Kurtzke had long considered that infection was a key step in the development of multiple sclerosis (MS), the most disabling nontraumatic neurologic disease in young adults. He and others, from the 1970s onwards, described disease outbreaks and patterns of disease distribution in various countries during periods of immigration and even wartime.^1,2 

A half century later and Dr Kurtzke’s question has a possible answer: The Epstein-Barr virus (EBV), a gamma herpes virus responsible for mononucleosis that has been long suspected as a link to the development of MS,³ is now more than a virus of interest. A longitudinal study pinpointed the virus’ almost universal presence in patients with MS.⁴ Not everyone who develops mononucleosis from EBV develops MS, but most people become infected with EBV at some point in their lives. EBV is highly prevalent in the general population, with some studies suggesting that more than 90% of people worldwide are infected with EBV.⁵ While the discovery raises many questions about MS etiology and disease progression, it also allows discussion on more therapeutic possibilities.

MS Numbers

With nearly 1 million people in the United States living with MS, and over 2.5 million people worldwide, MS has been the subject of numerous investigations.² Its complexity and heterogeneity have gained significant interest from the scientific community, including from Dr. Kurtzke, who passed away the same year as his NIH presentation.1

Several investigators over the years have attempted to link viral infections to MS,³ especially EBV. In February 2022, a longitudinal study spanning 20 years shed additional light on this longstanding, controversial, heavily researched potential association.⁴ The collaborative group of investigators used a database of serial blood samples from more than 10 million active US military personnel to investigate the association between EBV and MS and to learn whether EBV infection preceded the development of MS. 

Out of 801 persons with a documented diagnosis of MS in this study, only 1 case occurred in a person who tested negative for EBV infection.⁴ At baseline, 35 people with MS tested negative for EBV infection, but after receiving their MS diagnosis, they tested positive for the virus,  suggesting a causal relationship between EBV and MS. The study also showed that the levels of serum neurofilament light (sNfL), a nonspecific biomarker indicative of neuroaxonal injury or degeneration, increased post-EBV infection in the sera of initially EBV-negative patients with MS.⁴ This raises the question again: Why do only a small subset of people with EBV develop MS?

Facts and Questions

MS is a complex, heterogeneous disease whose development would require more than a human gamma herpesvirus to directly trigger its life-long, unrelenting immune dysregulation in select people. The complexity, which has been reviewed in detail, 6 suggests a role for interaction between host genetics, vitamin D levels, vitamin D receptors, and a specific protein of EBV, called Epstein-Barr nuclear antigen 1 (EBNA1).6 A recent publication described the potential for molecular mimicry (also known as cross-reactivity) between (EBNA1)⁶ and a specific cell adhesion molecule expressed in glial cells of the central nervous system (GlialCAM).⁷ 

But this molecular mimicry is not sufficient to explain the EBV/MS relationship. Even in monozygotic twins, the concordance rate is around 25%, leaving three-fourths of the risk of MS to the environment and genetics-environment interaction.⁸ The chances for monozygotic twins to both be infected with EBV are estimated at much more than 25%, given the epidemiology of EBV. Thus, EBV infection combined with specific genetic susceptibility remains insufficient to explain the observed epidemiology of MS. 

More Factors

Several investigators have reported on the association between low vitamin D levels and MS. Low vitamin D is thought to affect both disease development and inflammatory activity.⁹ So, does MS result from the interaction between EBV, genetics, and low vitamin D? This interaction is plausible and is supported by several lines of evidence^.6 However, even the interaction between these 3 factors remains insufficient to explain the complexity of MS pathogenesis. 

An Unknown Mechanism

The triggering mechanism from EBV into MS remains an open question, and further research is needed. Nevertheless, if infection by EBV is a necessary, yet insufficient, step for MS to occur, can we prevent MS simply by preventing the primary EBV infection via vaccination? If so, what considerations must we make? For example, if EBV infection triggers MS via the transformation of infected memory B cells, thereby triggering an autoreactive immune response, then a vaccine capable of preventing the primary EBV infection could reduce the number of new MS cases, or ambitiously eradicate the disease itself. On the other hand, if molecular mimicry is the leading mechanism by which EBV infection triggers MS, then an EBV vaccine may have detrimental effects and theoretically trigger MS in susceptible individuals. Thus, it is of utmost importance to clearly understand how EBV infection contributes to MS pathogenesis to evaluate potential EBV vaccine candidates. 

Treatment Possibilities

What are some possible clinical implications for the EBV-MS story for people living with MS? An important consideration is whether latent EBV infection contributes to the disease process over time, or if the infection is just an initial step that triggers numerous events that then operate independently from the virus. Suppose latent EBV infection contributes to the ongoing inflammatory and neurodegenerative changes in MS. In that case, some may consider using antiviral therapies as possible therapeutics for MS (possibly as an add-on, in combination with existing or future classes of disease-modifying therapies). Other interventions targeted at infected, transformed, or autoreactive B cells may bring us closer to precision medicine in MS. On the other hand, if the role of EBV is mainly to kick off MS, then further interventions targeted at the virus may not prove to be clinically effective.

Finally, the recent evidence of possible molecular mimicry to support causality between EBV infection and MS needs further investigation to elucidate how a common, ubiquitous infection kicks off MS in selected individuals. Additionally, the complex interactions between EBV, the human immune system, and genetics, as well as with other factors such as emotional stress,¹⁰  low sun exposure,11 and other, yet-to-be-identified environmental factors, may add more pieces to the complex etiology puzzle of MS and perhaps allow for effective interventions to help reduce the incidence of MS and even modulate disease progression.

Dr. Obeidat is an Assistant Professor in the Department of Neurology, 

Neuroimmunology and Multiple Sclerosis and is the Founding Director of the Neuroimmunology and MS Fellowship Program at The Medical College of Wisconsin in Milwaukee, WI.

Dr. Obeidat reports having consulted with/spoken for/conducted clinical trials for AbbVie, Alexion, Atara Biotherapeutics, Biogen, Bristol-Myers Squibb, Central, Celgene, EMD Serono, GW Pharmaceuticals, Genentech, Horizon, Jazz Pharma, Novartis, Sanofi/Genzyme, TG Therapeutics, and Viela Bio. Dr. Obeidat serves on the editorial board of the International Journal of MS Care, the advisory board of Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS®), and the Board of Governors of the Consortium of Multiple Sclerosis Centers.

“Could multiple sclerosis be the direct result of a yet-to-be identified infection?” asked John Kurtzke, MD, of his audience during his Grand Rounds entitled “Epidemiology and the Cause of Multiple Sclerosis” at the National Institute of Health (NIH) in 2015.¹ As a pioneer of neuroepidemiology, Dr Kurtzke had long considered that infection was a key step in the development of multiple sclerosis (MS), the most disabling nontraumatic neurologic disease in young adults. He and others, from the 1970s onwards, described disease outbreaks and patterns of disease distribution in various countries during periods of immigration and even wartime.^1,2 

A half century later and Dr Kurtzke’s question has a possible answer: The Epstein-Barr virus (EBV), a gamma herpes virus responsible for mononucleosis that has been long suspected as a link to the development of MS,³ is now more than a virus of interest. A longitudinal study pinpointed the virus’ almost universal presence in patients with MS.⁴ Not everyone who develops mononucleosis from EBV develops MS, but most people become infected with EBV at some point in their lives. EBV is highly prevalent in the general population, with some studies suggesting that more than 90% of people worldwide are infected with EBV.⁵ While the discovery raises many questions about MS etiology and disease progression, it also allows discussion on more therapeutic possibilities.

MS Numbers

With nearly 1 million people in the United States living with MS, and over 2.5 million people worldwide, MS has been the subject of numerous investigations.² Its complexity and heterogeneity have gained significant interest from the scientific community, including from Dr. Kurtzke, who passed away the same year as his NIH presentation.1

Several investigators over the years have attempted to link viral infections to MS,³ especially EBV. In February 2022, a longitudinal study spanning 20 years shed additional light on this longstanding, controversial, heavily researched potential association.⁴ The collaborative group of investigators used a database of serial blood samples from more than 10 million active US military personnel to investigate the association between EBV and MS and to learn whether EBV infection preceded the development of MS. 

Out of 801 persons with a documented diagnosis of MS in this study, only 1 case occurred in a person who tested negative for EBV infection.⁴ At baseline, 35 people with MS tested negative for EBV infection, but after receiving their MS diagnosis, they tested positive for the virus,  suggesting a causal relationship between EBV and MS. The study also showed that the levels of serum neurofilament light (sNfL), a nonspecific biomarker indicative of neuroaxonal injury or degeneration, increased post-EBV infection in the sera of initially EBV-negative patients with MS.⁴ This raises the question again: Why do only a small subset of people with EBV develop MS?

Facts and Questions

MS is a complex, heterogeneous disease whose development would require more than a human gamma herpesvirus to directly trigger its life-long, unrelenting immune dysregulation in select people. The complexity, which has been reviewed in detail, 6 suggests a role for interaction between host genetics, vitamin D levels, vitamin D receptors, and a specific protein of EBV, called Epstein-Barr nuclear antigen 1 (EBNA1).6 A recent publication described the potential for molecular mimicry (also known as cross-reactivity) between (EBNA1)⁶ and a specific cell adhesion molecule expressed in glial cells of the central nervous system (GlialCAM).⁷ 

But this molecular mimicry is not sufficient to explain the EBV/MS relationship. Even in monozygotic twins, the concordance rate is around 25%, leaving three-fourths of the risk of MS to the environment and genetics-environment interaction.⁸ The chances for monozygotic twins to both be infected with EBV are estimated at much more than 25%, given the epidemiology of EBV. Thus, EBV infection combined with specific genetic susceptibility remains insufficient to explain the observed epidemiology of MS. 

More Factors

Several investigators have reported on the association between low vitamin D levels and MS. Low vitamin D is thought to affect both disease development and inflammatory activity.⁹ So, does MS result from the interaction between EBV, genetics, and low vitamin D? This interaction is plausible and is supported by several lines of evidence^.6 However, even the interaction between these 3 factors remains insufficient to explain the complexity of MS pathogenesis. 

An Unknown Mechanism

The triggering mechanism from EBV into MS remains an open question, and further research is needed. Nevertheless, if infection by EBV is a necessary, yet insufficient, step for MS to occur, can we prevent MS simply by preventing the primary EBV infection via vaccination? If so, what considerations must we make? For example, if EBV infection triggers MS via the transformation of infected memory B cells, thereby triggering an autoreactive immune response, then a vaccine capable of preventing the primary EBV infection could reduce the number of new MS cases, or ambitiously eradicate the disease itself. On the other hand, if molecular mimicry is the leading mechanism by which EBV infection triggers MS, then an EBV vaccine may have detrimental effects and theoretically trigger MS in susceptible individuals. Thus, it is of utmost importance to clearly understand how EBV infection contributes to MS pathogenesis to evaluate potential EBV vaccine candidates. 

Treatment Possibilities

What are some possible clinical implications for the EBV-MS story for people living with MS? An important consideration is whether latent EBV infection contributes to the disease process over time, or if the infection is just an initial step that triggers numerous events that then operate independently from the virus. Suppose latent EBV infection contributes to the ongoing inflammatory and neurodegenerative changes in MS. In that case, some may consider using antiviral therapies as possible therapeutics for MS (possibly as an add-on, in combination with existing or future classes of disease-modifying therapies). Other interventions targeted at infected, transformed, or autoreactive B cells may bring us closer to precision medicine in MS. On the other hand, if the role of EBV is mainly to kick off MS, then further interventions targeted at the virus may not prove to be clinically effective.

Finally, the recent evidence of possible molecular mimicry to support causality between EBV infection and MS needs further investigation to elucidate how a common, ubiquitous infection kicks off MS in selected individuals. Additionally, the complex interactions between EBV, the human immune system, and genetics, as well as with other factors such as emotional stress,¹⁰  low sun exposure,11 and other, yet-to-be-identified environmental factors, may add more pieces to the complex etiology puzzle of MS and perhaps allow for effective interventions to help reduce the incidence of MS and even modulate disease progression.

Dr. Obeidat is an Assistant Professor in the Department of Neurology, 

Neuroimmunology and Multiple Sclerosis and is the Founding Director of the Neuroimmunology and MS Fellowship Program at The Medical College of Wisconsin in Milwaukee, WI.

Dr. Obeidat reports having consulted with/spoken for/conducted clinical trials for AbbVie, Alexion, Atara Biotherapeutics, Biogen, Bristol-Myers Squibb, Central, Celgene, EMD Serono, GW Pharmaceuticals, Genentech, Horizon, Jazz Pharma, Novartis, Sanofi/Genzyme, TG Therapeutics, and Viela Bio. Dr. Obeidat serves on the editorial board of the International Journal of MS Care, the advisory board of Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS®), and the Board of Governors of the Consortium of Multiple Sclerosis Centers.

“Could multiple sclerosis be the direct result of a yet-to-be identified infection?” asked John Kurtzke, MD, of his audience during his Grand Rounds entitled “Epidemiology and the Cause of Multiple Sclerosis” at the National Institute of Health (NIH) in 2015.¹ As a pioneer of neuroepidemiology, Dr Kurtzke had long considered that infection was a key step in the development of multiple sclerosis (MS), the most disabling nontraumatic neurologic disease in young adults. He and others, from the 1970s onwards, described disease outbreaks and patterns of disease distribution in various countries during periods of immigration and even wartime.^1,2 

A half century later and Dr Kurtzke’s question has a possible answer: The Epstein-Barr virus (EBV), a gamma herpes virus responsible for mononucleosis that has been long suspected as a link to the development of MS,³ is now more than a virus of interest. A longitudinal study pinpointed the virus’ almost universal presence in patients with MS.⁴ Not everyone who develops mononucleosis from EBV develops MS, but most people become infected with EBV at some point in their lives. EBV is highly prevalent in the general population, with some studies suggesting that more than 90% of people worldwide are infected with EBV.⁵ While the discovery raises many questions about MS etiology and disease progression, it also allows discussion on more therapeutic possibilities.

MS Numbers

With nearly 1 million people in the United States living with MS, and over 2.5 million people worldwide, MS has been the subject of numerous investigations.² Its complexity and heterogeneity have gained significant interest from the scientific community, including from Dr. Kurtzke, who passed away the same year as his NIH presentation.1

Several investigators over the years have attempted to link viral infections to MS,³ especially EBV. In February 2022, a longitudinal study spanning 20 years shed additional light on this longstanding, controversial, heavily researched potential association.⁴ The collaborative group of investigators used a database of serial blood samples from more than 10 million active US military personnel to investigate the association between EBV and MS and to learn whether EBV infection preceded the development of MS. 

Out of 801 persons with a documented diagnosis of MS in this study, only 1 case occurred in a person who tested negative for EBV infection.⁴ At baseline, 35 people with MS tested negative for EBV infection, but after receiving their MS diagnosis, they tested positive for the virus,  suggesting a causal relationship between EBV and MS. The study also showed that the levels of serum neurofilament light (sNfL), a nonspecific biomarker indicative of neuroaxonal injury or degeneration, increased post-EBV infection in the sera of initially EBV-negative patients with MS.⁴ This raises the question again: Why do only a small subset of people with EBV develop MS?

Facts and Questions

MS is a complex, heterogeneous disease whose development would require more than a human gamma herpesvirus to directly trigger its life-long, unrelenting immune dysregulation in select people. The complexity, which has been reviewed in detail, 6 suggests a role for interaction between host genetics, vitamin D levels, vitamin D receptors, and a specific protein of EBV, called Epstein-Barr nuclear antigen 1 (EBNA1).6 A recent publication described the potential for molecular mimicry (also known as cross-reactivity) between (EBNA1)⁶ and a specific cell adhesion molecule expressed in glial cells of the central nervous system (GlialCAM).⁷ 

But this molecular mimicry is not sufficient to explain the EBV/MS relationship. Even in monozygotic twins, the concordance rate is around 25%, leaving three-fourths of the risk of MS to the environment and genetics-environment interaction.⁸ The chances for monozygotic twins to both be infected with EBV are estimated at much more than 25%, given the epidemiology of EBV. Thus, EBV infection combined with specific genetic susceptibility remains insufficient to explain the observed epidemiology of MS. 

More Factors

Several investigators have reported on the association between low vitamin D levels and MS. Low vitamin D is thought to affect both disease development and inflammatory activity.⁹ So, does MS result from the interaction between EBV, genetics, and low vitamin D? This interaction is plausible and is supported by several lines of evidence^.6 However, even the interaction between these 3 factors remains insufficient to explain the complexity of MS pathogenesis. 

An Unknown Mechanism

The triggering mechanism from EBV into MS remains an open question, and further research is needed. Nevertheless, if infection by EBV is a necessary, yet insufficient, step for MS to occur, can we prevent MS simply by preventing the primary EBV infection via vaccination? If so, what considerations must we make? For example, if EBV infection triggers MS via the transformation of infected memory B cells, thereby triggering an autoreactive immune response, then a vaccine capable of preventing the primary EBV infection could reduce the number of new MS cases, or ambitiously eradicate the disease itself. On the other hand, if molecular mimicry is the leading mechanism by which EBV infection triggers MS, then an EBV vaccine may have detrimental effects and theoretically trigger MS in susceptible individuals. Thus, it is of utmost importance to clearly understand how EBV infection contributes to MS pathogenesis to evaluate potential EBV vaccine candidates. 

Treatment Possibilities

What are some possible clinical implications for the EBV-MS story for people living with MS? An important consideration is whether latent EBV infection contributes to the disease process over time, or if the infection is just an initial step that triggers numerous events that then operate independently from the virus. Suppose latent EBV infection contributes to the ongoing inflammatory and neurodegenerative changes in MS. In that case, some may consider using antiviral therapies as possible therapeutics for MS (possibly as an add-on, in combination with existing or future classes of disease-modifying therapies). Other interventions targeted at infected, transformed, or autoreactive B cells may bring us closer to precision medicine in MS. On the other hand, if the role of EBV is mainly to kick off MS, then further interventions targeted at the virus may not prove to be clinically effective.

Finally, the recent evidence of possible molecular mimicry to support causality between EBV infection and MS needs further investigation to elucidate how a common, ubiquitous infection kicks off MS in selected individuals. Additionally, the complex interactions between EBV, the human immune system, and genetics, as well as with other factors such as emotional stress,¹⁰  low sun exposure,11 and other, yet-to-be-identified environmental factors, may add more pieces to the complex etiology puzzle of MS and perhaps allow for effective interventions to help reduce the incidence of MS and even modulate disease progression.

In February, citing the need for more data, Pfizer and BioNTech announced that they were delaying the application for their COVID-19 vaccine for children under the age of 5. Earlier evidence suggests that two doses may not provide adequate protection in the 2- to 4-year old age group. With the larger number of infections and illness in the younger age group from the Omicron variant, Pfizer and BioNTech felt they needed more data on the effectiveness of a third dose.

This delay came as a disappointment to parents of children under 5 who have been eager to have them receive the vaccination. However, Peter Marks, MD, director of the Center for Biologics Evaluation and Research at the Food and Drug Administration, told parents that this delay should be reassuring – that the companies were doing important due diligence before releasing a product that is both safe and effective. The American Academy of Pediatrics wisely released a similar statement of reassurance and support.

It is difficult to know how many parents will eventually immunize their young children once the vaccine is approved. Any survey done more than a few weeks ago must be viewed cautiously as “the COVID numbers” around the country continue to improve and parental attitudes are likely to change.

There will always remain subgroups of parents on either extreme of the bell-shaped curve. Some will reject the under-5 vaccine simply because it is a vaccine. Some parents are so anxious to vaccinate that they will want to be first in line even if waiting is the more prudent approach. In a recent opinion piece appearing in the New York Times, a statistician writes that he is so eager to have his young children immunized that he is encouraging the FDA to replace its traditional reliance on “statistical significance” with a less rigid and binary method such as one based on Bayesian theory (Aubrey Carlton, “I’m a parent and a statistician. There’s a smarter way to think about the under-5 vaccine.” The New York Times. 2022 Mar 1.). However, what this statistician misses in his haste to vaccinate his own children is that we are dealing with an entire population with varying levels of scientific sophistication and appetite for risk. While “statistical significance” may no longer be cutting edge to some statisticians, most of the rest of the country finds the term reassuring.

It will be interesting to see what happens if and when the vaccine is approved. Will the American Academy of Pediatrics come out with a strong recommendation? I hope they are careful and provide a sufficient number of caveats, otherwise we in the trenches will again be left to provide more nuanced advice to families who are both anxious and hesitant.

Despite the recent surge in cases among young children, apparently as a result of the Omicron variant, the disease continues to cause less and milder disease among young children than it does in adults. And the degree to which illness in the pediatric population contributes to the health of the general population appears to still be a matter of debate. This may be yet another instance of when the crafty COVID-19 has moved with a pace that will make an under–age-5 vaccine of relatively little value.

First, we must be careful to assure ourselves that any side effects the vaccine might generate are well within an even more restricted acceptable range. Second, we must be careful not to squander our persuasive currency by promoting a vaccine that in retrospect may turn out to be of relatively little value.

Although there is ample evidence that education often fails to convince the committed anti-vaxxers, pediatricians continue to be held in high regard by most parents, many of whom are understandably confused by the tsunami of health information of mixed quality generated by the pandemic. We must be cautious not to cast ourselves as a group whose knee-jerk reaction is to recommend every vaccine with equal vigor. All vaccines are not created equal. We must be patient and prepared to adjust the level of our enthusiasm. We must continue to tailor our advice based on the hard data. Otherwise, parents will stop asking for our advice because they will believe that they already know what we’re going to say.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In February, citing the need for more data, Pfizer and BioNTech announced that they were delaying the application for their COVID-19 vaccine for children under the age of 5. Earlier evidence suggests that two doses may not provide adequate protection in the 2- to 4-year old age group. With the larger number of infections and illness in the younger age group from the Omicron variant, Pfizer and BioNTech felt they needed more data on the effectiveness of a third dose.

This delay came as a disappointment to parents of children under 5 who have been eager to have them receive the vaccination. However, Peter Marks, MD, director of the Center for Biologics Evaluation and Research at the Food and Drug Administration, told parents that this delay should be reassuring – that the companies were doing important due diligence before releasing a product that is both safe and effective. The American Academy of Pediatrics wisely released a similar statement of reassurance and support.

It is difficult to know how many parents will eventually immunize their young children once the vaccine is approved. Any survey done more than a few weeks ago must be viewed cautiously as “the COVID numbers” around the country continue to improve and parental attitudes are likely to change.

There will always remain subgroups of parents on either extreme of the bell-shaped curve. Some will reject the under-5 vaccine simply because it is a vaccine. Some parents are so anxious to vaccinate that they will want to be first in line even if waiting is the more prudent approach. In a recent opinion piece appearing in the New York Times, a statistician writes that he is so eager to have his young children immunized that he is encouraging the FDA to replace its traditional reliance on “statistical significance” with a less rigid and binary method such as one based on Bayesian theory (Aubrey Carlton, “I’m a parent and a statistician. There’s a smarter way to think about the under-5 vaccine.” The New York Times. 2022 Mar 1.). However, what this statistician misses in his haste to vaccinate his own children is that we are dealing with an entire population with varying levels of scientific sophistication and appetite for risk. While “statistical significance” may no longer be cutting edge to some statisticians, most of the rest of the country finds the term reassuring.

It will be interesting to see what happens if and when the vaccine is approved. Will the American Academy of Pediatrics come out with a strong recommendation? I hope they are careful and provide a sufficient number of caveats, otherwise we in the trenches will again be left to provide more nuanced advice to families who are both anxious and hesitant.

Despite the recent surge in cases among young children, apparently as a result of the Omicron variant, the disease continues to cause less and milder disease among young children than it does in adults. And the degree to which illness in the pediatric population contributes to the health of the general population appears to still be a matter of debate. This may be yet another instance of when the crafty COVID-19 has moved with a pace that will make an under–age-5 vaccine of relatively little value.

First, we must be careful to assure ourselves that any side effects the vaccine might generate are well within an even more restricted acceptable range. Second, we must be careful not to squander our persuasive currency by promoting a vaccine that in retrospect may turn out to be of relatively little value.

Although there is ample evidence that education often fails to convince the committed anti-vaxxers, pediatricians continue to be held in high regard by most parents, many of whom are understandably confused by the tsunami of health information of mixed quality generated by the pandemic. We must be cautious not to cast ourselves as a group whose knee-jerk reaction is to recommend every vaccine with equal vigor. All vaccines are not created equal. We must be patient and prepared to adjust the level of our enthusiasm. We must continue to tailor our advice based on the hard data. Otherwise, parents will stop asking for our advice because they will believe that they already know what we’re going to say.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In February, citing the need for more data, Pfizer and BioNTech announced that they were delaying the application for their COVID-19 vaccine for children under the age of 5. Earlier evidence suggests that two doses may not provide adequate protection in the 2- to 4-year old age group. With the larger number of infections and illness in the younger age group from the Omicron variant, Pfizer and BioNTech felt they needed more data on the effectiveness of a third dose.

This delay came as a disappointment to parents of children under 5 who have been eager to have them receive the vaccination. However, Peter Marks, MD, director of the Center for Biologics Evaluation and Research at the Food and Drug Administration, told parents that this delay should be reassuring – that the companies were doing important due diligence before releasing a product that is both safe and effective. The American Academy of Pediatrics wisely released a similar statement of reassurance and support.

It is difficult to know how many parents will eventually immunize their young children once the vaccine is approved. Any survey done more than a few weeks ago must be viewed cautiously as “the COVID numbers” around the country continue to improve and parental attitudes are likely to change.

There will always remain subgroups of parents on either extreme of the bell-shaped curve. Some will reject the under-5 vaccine simply because it is a vaccine. Some parents are so anxious to vaccinate that they will want to be first in line even if waiting is the more prudent approach. In a recent opinion piece appearing in the New York Times, a statistician writes that he is so eager to have his young children immunized that he is encouraging the FDA to replace its traditional reliance on “statistical significance” with a less rigid and binary method such as one based on Bayesian theory (Aubrey Carlton, “I’m a parent and a statistician. There’s a smarter way to think about the under-5 vaccine.” The New York Times. 2022 Mar 1.). However, what this statistician misses in his haste to vaccinate his own children is that we are dealing with an entire population with varying levels of scientific sophistication and appetite for risk. While “statistical significance” may no longer be cutting edge to some statisticians, most of the rest of the country finds the term reassuring.

It will be interesting to see what happens if and when the vaccine is approved. Will the American Academy of Pediatrics come out with a strong recommendation? I hope they are careful and provide a sufficient number of caveats, otherwise we in the trenches will again be left to provide more nuanced advice to families who are both anxious and hesitant.

Despite the recent surge in cases among young children, apparently as a result of the Omicron variant, the disease continues to cause less and milder disease among young children than it does in adults. And the degree to which illness in the pediatric population contributes to the health of the general population appears to still be a matter of debate. This may be yet another instance of when the crafty COVID-19 has moved with a pace that will make an under–age-5 vaccine of relatively little value.

First, we must be careful to assure ourselves that any side effects the vaccine might generate are well within an even more restricted acceptable range. Second, we must be careful not to squander our persuasive currency by promoting a vaccine that in retrospect may turn out to be of relatively little value.

Although there is ample evidence that education often fails to convince the committed anti-vaxxers, pediatricians continue to be held in high regard by most parents, many of whom are understandably confused by the tsunami of health information of mixed quality generated by the pandemic. We must be cautious not to cast ourselves as a group whose knee-jerk reaction is to recommend every vaccine with equal vigor. All vaccines are not created equal. We must be patient and prepared to adjust the level of our enthusiasm. We must continue to tailor our advice based on the hard data. Otherwise, parents will stop asking for our advice because they will believe that they already know what we’re going to say.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].