Neurology Reviews

The records came in by fax. A patient who’d recently moved here and needed to connect with a local neurologist.

When I had time, I flipped through the records. He needed ongoing treatment for a rare neurological disease that I’d heard of, but wasn’t otherwise familiar with. It didn’t even exist in the textbooks or conferences when I was in residency. I’d never seen a case of it, just read about it here and there in journals.

I looked it up, reviewed current treatment options, monitoring, and other knowledge about it, then stared at the notes for a minute. Finally, after thinking it over, I attached a sticky note for my secretary that, if the person called, to redirect them to one of the local subspecialty neurology centers.

I have nothing against this patient, but realistically he would be better served seeing someone with time to keep up on advancements in esoteric disorders, not a general neurologist like myself.

Isn’t that why we have subspecialty centers?

Some of it is also me. There was a time in my career when keeping up on newly discovered disorders and their treatments was, well, cool. But after 25 years in practice, that changes.

In the daily trenches of general neurology, one can only be on top of so much. You have to prioritize the things you’re most likely to see. It’s important to be at least somewhat aware of new developments (such as in this case) as you may encounter them, and need to know when it’s something you can handle and when to send it elsewhere.

Driving home that afternoon I thought, “I’m an old dog. I don’t want to learn new tricks.” Maybe that’s all it is. There are other neurologists my age and older who thrive on the challenge of learning about and treating new and rare disorders that were unknown when they started out. There’s nothing wrong with that.

But I’ve never pretended to be an academic or sub-sub-specialist. My patients depend on me to stay up to date on the large number of commonly seen neurological disorders, and I do my best to do that.

It ain’t easy being an old dog.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

The records came in by fax. A patient who’d recently moved here and needed to connect with a local neurologist.

When I had time, I flipped through the records. He needed ongoing treatment for a rare neurological disease that I’d heard of, but wasn’t otherwise familiar with. It didn’t even exist in the textbooks or conferences when I was in residency. I’d never seen a case of it, just read about it here and there in journals.

I looked it up, reviewed current treatment options, monitoring, and other knowledge about it, then stared at the notes for a minute. Finally, after thinking it over, I attached a sticky note for my secretary that, if the person called, to redirect them to one of the local subspecialty neurology centers.

I have nothing against this patient, but realistically he would be better served seeing someone with time to keep up on advancements in esoteric disorders, not a general neurologist like myself.

Isn’t that why we have subspecialty centers?

Some of it is also me. There was a time in my career when keeping up on newly discovered disorders and their treatments was, well, cool. But after 25 years in practice, that changes.

In the daily trenches of general neurology, one can only be on top of so much. You have to prioritize the things you’re most likely to see. It’s important to be at least somewhat aware of new developments (such as in this case) as you may encounter them, and need to know when it’s something you can handle and when to send it elsewhere.

Driving home that afternoon I thought, “I’m an old dog. I don’t want to learn new tricks.” Maybe that’s all it is. There are other neurologists my age and older who thrive on the challenge of learning about and treating new and rare disorders that were unknown when they started out. There’s nothing wrong with that.

But I’ve never pretended to be an academic or sub-sub-specialist. My patients depend on me to stay up to date on the large number of commonly seen neurological disorders, and I do my best to do that.

It ain’t easy being an old dog.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

The records came in by fax. A patient who’d recently moved here and needed to connect with a local neurologist.

When I had time, I flipped through the records. He needed ongoing treatment for a rare neurological disease that I’d heard of, but wasn’t otherwise familiar with. It didn’t even exist in the textbooks or conferences when I was in residency. I’d never seen a case of it, just read about it here and there in journals.

I looked it up, reviewed current treatment options, monitoring, and other knowledge about it, then stared at the notes for a minute. Finally, after thinking it over, I attached a sticky note for my secretary that, if the person called, to redirect them to one of the local subspecialty neurology centers.

I have nothing against this patient, but realistically he would be better served seeing someone with time to keep up on advancements in esoteric disorders, not a general neurologist like myself.

Isn’t that why we have subspecialty centers?

Some of it is also me. There was a time in my career when keeping up on newly discovered disorders and their treatments was, well, cool. But after 25 years in practice, that changes.

In the daily trenches of general neurology, one can only be on top of so much. You have to prioritize the things you’re most likely to see. It’s important to be at least somewhat aware of new developments (such as in this case) as you may encounter them, and need to know when it’s something you can handle and when to send it elsewhere.

Driving home that afternoon I thought, “I’m an old dog. I don’t want to learn new tricks.” Maybe that’s all it is. There are other neurologists my age and older who thrive on the challenge of learning about and treating new and rare disorders that were unknown when they started out. There’s nothing wrong with that.

But I’ve never pretended to be an academic or sub-sub-specialist. My patients depend on me to stay up to date on the large number of commonly seen neurological disorders, and I do my best to do that.

It ain’t easy being an old dog.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

TOPLINE:

Inebilizumab-cdon, a monoclonal antibody that depletes B cells, reduces the risk for flares without showing any new safety signals in patients with immunoglobulin G4-related disease (IgG4-RD) who have multiorgan disease and are on glucocorticoid therapy.

METHODOLOGY:

• IgG4-RD is an immune-mediated, fibroinflammatory condition that affects multiple organs, causing irreversible organ damage. MITIGATE is the first multinational, placebo-controlled trial involving patients with IgG4-RD.
• Researchers evaluated the efficacy and safety of inebilizumab in 135 adult patients at risk for flares due to a history of multiorgan disease and active disease requiring treatment with glucocorticoids.
• The patients were randomly assigned to receive 300-mg intravenous inebilizumab or placebo on day 1, day 15, and week 26.
• The primary endpoint was the time to the first treated and adjudicated IgG4-RD flare within 52 weeks.
• The secondary endpoints included the annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission.

TAKEAWAY:

• Compared with the placebo, inebilizumab reduced the risk for IgG4-RD flares by 87% during the 52-week trial period (hazard ratio, 0.13; P < .0001).
• All the secondary endpoints showed improvement following treatment with inebilizumab.
• The most common adverse reactions with inebilizumab, as observed in a previous trial for neuromyelitis optica spectrum disorder, were urinary tract infection and arthralgia.
• There were no new safety signals in the MITIGATE trial.

IN PRACTICE:

“These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD but also key insights into the nature of this condition,” John Stone, MD, MPH, principal investigator, said in a news release.

SOURCE:

Dr. Stone, a professor of medicine at the Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, Boston, led this study.

LIMITATIONS:

This press release did not discuss any limitations of the current study.

DISCLOSURES:

This study was funded by Mitsubishi Tanabe Pharma and Hansoh Pharma and sponsored by Amgen. The author disclosures were not available.

A version of this article appeared on Medscape.com.

TOPLINE:

Inebilizumab-cdon, a monoclonal antibody that depletes B cells, reduces the risk for flares without showing any new safety signals in patients with immunoglobulin G4-related disease (IgG4-RD) who have multiorgan disease and are on glucocorticoid therapy.

METHODOLOGY:

• IgG4-RD is an immune-mediated, fibroinflammatory condition that affects multiple organs, causing irreversible organ damage. MITIGATE is the first multinational, placebo-controlled trial involving patients with IgG4-RD.
• Researchers evaluated the efficacy and safety of inebilizumab in 135 adult patients at risk for flares due to a history of multiorgan disease and active disease requiring treatment with glucocorticoids.
• The patients were randomly assigned to receive 300-mg intravenous inebilizumab or placebo on day 1, day 15, and week 26.
• The primary endpoint was the time to the first treated and adjudicated IgG4-RD flare within 52 weeks.
• The secondary endpoints included the annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission.

TAKEAWAY:

• Compared with the placebo, inebilizumab reduced the risk for IgG4-RD flares by 87% during the 52-week trial period (hazard ratio, 0.13; P < .0001).
• All the secondary endpoints showed improvement following treatment with inebilizumab.
• The most common adverse reactions with inebilizumab, as observed in a previous trial for neuromyelitis optica spectrum disorder, were urinary tract infection and arthralgia.
• There were no new safety signals in the MITIGATE trial.

IN PRACTICE:

“These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD but also key insights into the nature of this condition,” John Stone, MD, MPH, principal investigator, said in a news release.

SOURCE:

Dr. Stone, a professor of medicine at the Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, Boston, led this study.

LIMITATIONS:

This press release did not discuss any limitations of the current study.

DISCLOSURES:

This study was funded by Mitsubishi Tanabe Pharma and Hansoh Pharma and sponsored by Amgen. The author disclosures were not available.

A version of this article appeared on Medscape.com.

TOPLINE:

Inebilizumab-cdon, a monoclonal antibody that depletes B cells, reduces the risk for flares without showing any new safety signals in patients with immunoglobulin G4-related disease (IgG4-RD) who have multiorgan disease and are on glucocorticoid therapy.

METHODOLOGY:

• IgG4-RD is an immune-mediated, fibroinflammatory condition that affects multiple organs, causing irreversible organ damage. MITIGATE is the first multinational, placebo-controlled trial involving patients with IgG4-RD.
• Researchers evaluated the efficacy and safety of inebilizumab in 135 adult patients at risk for flares due to a history of multiorgan disease and active disease requiring treatment with glucocorticoids.
• The patients were randomly assigned to receive 300-mg intravenous inebilizumab or placebo on day 1, day 15, and week 26.
• The primary endpoint was the time to the first treated and adjudicated IgG4-RD flare within 52 weeks.
• The secondary endpoints included the annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission.

TAKEAWAY:

• Compared with the placebo, inebilizumab reduced the risk for IgG4-RD flares by 87% during the 52-week trial period (hazard ratio, 0.13; P < .0001).
• All the secondary endpoints showed improvement following treatment with inebilizumab.
• The most common adverse reactions with inebilizumab, as observed in a previous trial for neuromyelitis optica spectrum disorder, were urinary tract infection and arthralgia.
• There were no new safety signals in the MITIGATE trial.

IN PRACTICE:

“These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD but also key insights into the nature of this condition,” John Stone, MD, MPH, principal investigator, said in a news release.

SOURCE:

Dr. Stone, a professor of medicine at the Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, Boston, led this study.

LIMITATIONS:

This press release did not discuss any limitations of the current study.

DISCLOSURES:

This study was funded by Mitsubishi Tanabe Pharma and Hansoh Pharma and sponsored by Amgen. The author disclosures were not available.

A version of this article appeared on Medscape.com.

Five commonly prescribed drugs may be associated with a lower risk for aneurysmal subarachnoid hemorrhage (aSAH), a drug-wide association study suggested.

The blood pressure drug lisinopril; the cholesterol drug simvastatin; the diabetes drug metformin; and the drug tamsulosin, prescribed for an enlarged prostate, were all associated with decreased aSAH risk, investigators found.

Conversely, four other drugs were associated with an increased risk for this severely morbid, often deadly, condition.

“The motivation for this study was the fact that we can currently prevent bleeding from intracranial aneurysms only by invasive treatment of those aneurysms with inherent complication risks,” said study investigator Ynte Ruigrok, MD, PhD, associate professor of neurology and neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands. “Drugs to reduce or eliminate this risk are not yet available. This study is a first step in identifying such drugs.”

The findings were published online in Neurology.
 

Surprising Results

For the study, the researchers used the Secure Anonymized Information Linkage data bank in Wales to identify 4879 patients with aSAH between January 2000 and December 2019 and 43,911 patients without aSAH matched on age, sex, and year of database entry. Clustering resulted in 2023 unique drugs, of which 205 were commonly prescribed.

After adjusting for other factors such as high blood pressure, alcohol abuse, smoking, and a total number of health conditions, the results yielded two surprises, Dr. Ruigrok observed.

The first was a significant decrease in aSAH risk for current use of lisinopril, compared with nonuse (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.44-0.90), and a nonsignificant decrease with current use of amlodipine (OR, 0.82; 95% CI, 0.65-1.04).

“Hypertension is a major risk factor for occurrence and bleeding from aneurysms. If there is indeed a specific blood pressure–lowering drug that not only has a blood pressure–lowering effect but also has additional protection against aSAH, then perhaps that drug should become the drug of choice in aneurysm patients in the future,” he said.

Notably, recent use of both drugs, defined as between 1 year and 3 months before the index date, was associated with an increased risk for aSAH. This trend was not found for other antihypertensives and was significant for amlodipine but not lisinopril.

The reasons are unclear, but “we trust the findings on lisinopril more,” Dr. Ruigrok said. “The findings on amlodipine may be due to confounding by indication, specifically caused by hypertension. Therefore, it is important to validate our findings in an independent research cohort, and we are in the process of doing so.”

The study’s second surprise was the antidiabetic drug metformin and cholesterol-lowering drug simvastatin were also associated with reduced aSAH risk, Dr. Ruigrok noted.

“We already knew from previous studies that diabetes and high cholesterol are protective factors for aSAH,” he said. “Our results suggest that perhaps not the conditions themselves are protective for aSAH but rather the drugs used to treat these conditions with are.”

The risk for a ruptured brain aneurysm among current users was 42% lower with metformin (OR, 0.58; 95% CI, 0.43-0.78), 22% lower with simvastatin (OR, 0.78; 95% CI, 0.64-0.96), and 45% lower with tamsulosin (OR, 0.55; 95% CI, 0.32-0.93).

An increased risk for aSAH was found only in current users of warfarin (OR, 1.35; 95% CI, 1.02-1.79), venlafaxine (OR, 1.67; 95% CI, 1.01-2.75), prochlorperazine (OR, 2.15; 95% CI, 1.45-3.18), and co-codamol (OR, 1.31; 95% CI, 1.10-1.56).

Other drugs within the classes of vitamin K antagonists, serotonin reuptake inhibitors, conventional antipsychotics, and compound analgesics did not show an association with aSAH.

The study was limited by the use of drug prescriptions, and patients may not take their drugs or use them incorrectly, noted the researchers, led by Jos P. Kanning, MSc, also with University Medical Center Utrecht.

The study was supported by the European Research Council. The authors reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Five commonly prescribed drugs may be associated with a lower risk for aneurysmal subarachnoid hemorrhage (aSAH), a drug-wide association study suggested.

The blood pressure drug lisinopril; the cholesterol drug simvastatin; the diabetes drug metformin; and the drug tamsulosin, prescribed for an enlarged prostate, were all associated with decreased aSAH risk, investigators found.

Conversely, four other drugs were associated with an increased risk for this severely morbid, often deadly, condition.

“The motivation for this study was the fact that we can currently prevent bleeding from intracranial aneurysms only by invasive treatment of those aneurysms with inherent complication risks,” said study investigator Ynte Ruigrok, MD, PhD, associate professor of neurology and neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands. “Drugs to reduce or eliminate this risk are not yet available. This study is a first step in identifying such drugs.”

The findings were published online in Neurology.
 

Surprising Results

For the study, the researchers used the Secure Anonymized Information Linkage data bank in Wales to identify 4879 patients with aSAH between January 2000 and December 2019 and 43,911 patients without aSAH matched on age, sex, and year of database entry. Clustering resulted in 2023 unique drugs, of which 205 were commonly prescribed.

After adjusting for other factors such as high blood pressure, alcohol abuse, smoking, and a total number of health conditions, the results yielded two surprises, Dr. Ruigrok observed.

The first was a significant decrease in aSAH risk for current use of lisinopril, compared with nonuse (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.44-0.90), and a nonsignificant decrease with current use of amlodipine (OR, 0.82; 95% CI, 0.65-1.04).

“Hypertension is a major risk factor for occurrence and bleeding from aneurysms. If there is indeed a specific blood pressure–lowering drug that not only has a blood pressure–lowering effect but also has additional protection against aSAH, then perhaps that drug should become the drug of choice in aneurysm patients in the future,” he said.

Notably, recent use of both drugs, defined as between 1 year and 3 months before the index date, was associated with an increased risk for aSAH. This trend was not found for other antihypertensives and was significant for amlodipine but not lisinopril.

The reasons are unclear, but “we trust the findings on lisinopril more,” Dr. Ruigrok said. “The findings on amlodipine may be due to confounding by indication, specifically caused by hypertension. Therefore, it is important to validate our findings in an independent research cohort, and we are in the process of doing so.”

The study’s second surprise was the antidiabetic drug metformin and cholesterol-lowering drug simvastatin were also associated with reduced aSAH risk, Dr. Ruigrok noted.

“We already knew from previous studies that diabetes and high cholesterol are protective factors for aSAH,” he said. “Our results suggest that perhaps not the conditions themselves are protective for aSAH but rather the drugs used to treat these conditions with are.”

The risk for a ruptured brain aneurysm among current users was 42% lower with metformin (OR, 0.58; 95% CI, 0.43-0.78), 22% lower with simvastatin (OR, 0.78; 95% CI, 0.64-0.96), and 45% lower with tamsulosin (OR, 0.55; 95% CI, 0.32-0.93).

An increased risk for aSAH was found only in current users of warfarin (OR, 1.35; 95% CI, 1.02-1.79), venlafaxine (OR, 1.67; 95% CI, 1.01-2.75), prochlorperazine (OR, 2.15; 95% CI, 1.45-3.18), and co-codamol (OR, 1.31; 95% CI, 1.10-1.56).

Other drugs within the classes of vitamin K antagonists, serotonin reuptake inhibitors, conventional antipsychotics, and compound analgesics did not show an association with aSAH.

The study was limited by the use of drug prescriptions, and patients may not take their drugs or use them incorrectly, noted the researchers, led by Jos P. Kanning, MSc, also with University Medical Center Utrecht.

The study was supported by the European Research Council. The authors reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Five commonly prescribed drugs may be associated with a lower risk for aneurysmal subarachnoid hemorrhage (aSAH), a drug-wide association study suggested.

The blood pressure drug lisinopril; the cholesterol drug simvastatin; the diabetes drug metformin; and the drug tamsulosin, prescribed for an enlarged prostate, were all associated with decreased aSAH risk, investigators found.

Conversely, four other drugs were associated with an increased risk for this severely morbid, often deadly, condition.

“The motivation for this study was the fact that we can currently prevent bleeding from intracranial aneurysms only by invasive treatment of those aneurysms with inherent complication risks,” said study investigator Ynte Ruigrok, MD, PhD, associate professor of neurology and neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands. “Drugs to reduce or eliminate this risk are not yet available. This study is a first step in identifying such drugs.”

The findings were published online in Neurology.
 

Surprising Results

For the study, the researchers used the Secure Anonymized Information Linkage data bank in Wales to identify 4879 patients with aSAH between January 2000 and December 2019 and 43,911 patients without aSAH matched on age, sex, and year of database entry. Clustering resulted in 2023 unique drugs, of which 205 were commonly prescribed.

After adjusting for other factors such as high blood pressure, alcohol abuse, smoking, and a total number of health conditions, the results yielded two surprises, Dr. Ruigrok observed.

The first was a significant decrease in aSAH risk for current use of lisinopril, compared with nonuse (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.44-0.90), and a nonsignificant decrease with current use of amlodipine (OR, 0.82; 95% CI, 0.65-1.04).

“Hypertension is a major risk factor for occurrence and bleeding from aneurysms. If there is indeed a specific blood pressure–lowering drug that not only has a blood pressure–lowering effect but also has additional protection against aSAH, then perhaps that drug should become the drug of choice in aneurysm patients in the future,” he said.

Notably, recent use of both drugs, defined as between 1 year and 3 months before the index date, was associated with an increased risk for aSAH. This trend was not found for other antihypertensives and was significant for amlodipine but not lisinopril.

The reasons are unclear, but “we trust the findings on lisinopril more,” Dr. Ruigrok said. “The findings on amlodipine may be due to confounding by indication, specifically caused by hypertension. Therefore, it is important to validate our findings in an independent research cohort, and we are in the process of doing so.”

The study’s second surprise was the antidiabetic drug metformin and cholesterol-lowering drug simvastatin were also associated with reduced aSAH risk, Dr. Ruigrok noted.

“We already knew from previous studies that diabetes and high cholesterol are protective factors for aSAH,” he said. “Our results suggest that perhaps not the conditions themselves are protective for aSAH but rather the drugs used to treat these conditions with are.”

The risk for a ruptured brain aneurysm among current users was 42% lower with metformin (OR, 0.58; 95% CI, 0.43-0.78), 22% lower with simvastatin (OR, 0.78; 95% CI, 0.64-0.96), and 45% lower with tamsulosin (OR, 0.55; 95% CI, 0.32-0.93).

An increased risk for aSAH was found only in current users of warfarin (OR, 1.35; 95% CI, 1.02-1.79), venlafaxine (OR, 1.67; 95% CI, 1.01-2.75), prochlorperazine (OR, 2.15; 95% CI, 1.45-3.18), and co-codamol (OR, 1.31; 95% CI, 1.10-1.56).

Other drugs within the classes of vitamin K antagonists, serotonin reuptake inhibitors, conventional antipsychotics, and compound analgesics did not show an association with aSAH.

The study was limited by the use of drug prescriptions, and patients may not take their drugs or use them incorrectly, noted the researchers, led by Jos P. Kanning, MSc, also with University Medical Center Utrecht.

The study was supported by the European Research Council. The authors reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

There is a significant association between higher interictal burden, disability, and allodynia in patients who sought medical care for migraine, according to recent research published in the journal Headache.

“[T]he burden and impact of migraine on the individual both during and between attacks were identified through supervised machine learning models to be strongly associated with seeking care,” Sait Ashina, MD, of the department of neurology at Harvard Medical School in Boston, and colleagues wrote in their study.

Dr. Ashina and colleagues performed a cross-sectional study of 61,826 patients from the web-based ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study with migraine who visited a primary care, specialty care, or urgent care, or emergency setting for headache between 2018 and 2020.

The patients recruited for OBSERVE were a mean of 41.7 years old and had experienced migraines for an average of 19.0 years; 59.4% had between 0 and 3 average headache days per month, 74.5% were women, 78.8% were White, and 85.4% had health insurance; and they were demographically representative of the US population.

Researchers used a machine learning model, which consisted of random forest and least absolute shrinkage and selection operator (LASSO) algorithms, to identify the relationship between patients who sought care for migraine and 54 different clinical, sociodemographic, and migraine-associated factors, which included age, years with migraine, symptom scores, pain intensity scores, disability score, comorbidities, vomiting, presence and severity of allodynia, and other factors.

The results showed 31,529 patients (51.0%) had an in-person or e-visit encounter with a primary care, specialty care, or urgent care, or emergency care location within 12 months of the survey, and were mostly White (76.5%) women (73.3%) with health insurance (88.9%). Of the patients who sought care, 52.8% had severe interictal burden measured by Migraine Interictal Burden Scale-4 score, compared with 23.1% of patients who did not seek care. Compared with patients who did not seek care, those who did visit a health care setting for migraine had a higher percentage of severe migraine-related disability as measured by the Migraine Disability Assessment Scale (36.7% vs 14.6%) and severe ictal cutaneous allodynia as measured by the Allodynia Symptom Checklist (21.0% vs 7.4%).

In a multivariable logistic regression model analysis, Dr. Ashina and colleagues said the factors most associated with seeking care included severe interictal burden (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.5-2.8), severe migraine-related disability (OR, 2.2; 95% CI, 2.0-2.3), and severe ictal allodynia (OR, 1.7; 95% CI, 1.6-1.8), compared with less severe factors.

The researchers said their results have “significant implications for public health and advocacy efforts.”

“As seen through three decades of epidemiological research in the United States, rates of care-seeking have not improved dramatically over time despite significant additions to scientific knowledge and the therapeutic armamentarium, leaving a significant unmet need. This is also important from a clinical perspective,” they explained. “Health care professionals in primary care and internal medicine most likely see patients with migraine who do not discuss it during visits. This underscores the importance of maintaining vigilance for migraine, especially among those who may experience greater disability, impact, and interictal burden.”
 

Asking the Right Questions

Asked to comment on the research, Robert P. Cowan, MD, a neurologist and professor in the Stanford University School of Medicine department of neurology and neurological sciences in Palo Alto, California, said in an interview that the value of the paper is in what it does not say about the main reasons patients seek care.

“Most clinicians readily acknowledge that the average number of migraine headache days per month is, at best, a weak predictor of which patients seek care and when,” he said.

Dr. Cowan said that most patients are referred to him by other providers, and when he asks them why they did not seek care for migraine sooner, the answer is usually because the migraine was not severe enough or because over-the-counter medication had previously worked for them. He noted that change in frequency is, in his experience, a primary reason why patients will seek care. “[F]or new (or increasing) headache, it is the concern that the headaches are something more ‘serious,’ and once that is ruled out, the conversation often stops,” he said. “For long-standing migraine sufferers, it is the perception that the headache is a ‘fact of life’ and does not rise to the bar of seeking medical advice.”

The questions a survey or a provider asks matters, Dr. Cowan said. “Often, when we ask a patient how many headache (or migraine) days per month, the answer is in single digits. But if we follow-up with a question about the number of headache-free days [per] month, the answer is ‘never’ or ‘hardly ever,’” he explained. “The point here is that what questions a survey (or a provider) asks introduces a clear bias. The use of machine learning instruments, especially when utilizing supervised learning, only reinforces and amplifies the bias of the designers of the categories.”

Epidemiologic studies are interesting but “often ask the wrong questions,” Dr. Cowan said. “I am less worried about the ... 49% of migraine or possible migraine patients who do not seek care and do [not] progress to more disabling ‘chronic’ migraine than I am with identifying the subpopulations of migraine patients who seek care from providers who do not have adequate tools to match patients to the best treatments.”

The authors reported personal and institutional relationships in the form of advisory board memberships, consultancies, employment, honoraria, research support, speakers bureau positions, stock ownership, and teaching services with AbbVie, Aeon, Alder, Allay Lamp, Allergan, Amgen, Axon, Biohaven Pharmaceuticals, Collegium, CoolTech, Currax, Dr. Reddy’s Laboratories (Promius), electroCore, GlaxoSmithKline, Impel NeuroPharma, Informa, Eli Lilly and Company, Lundbeck, Mainistee, Merck, National Headache Foundation, National Institutes of Health, Novartis, Pfizer, Satsuma, Supernus, Percept, Teva, Theranica, UpsherSmith, the US Food and Drug Administration, Vector, Vedanta Research, and Wolff’s Headache. The study was supported by Eli Lilly. Dr. Cowan reports no relevant conflicts of interest.

There is a significant association between higher interictal burden, disability, and allodynia in patients who sought medical care for migraine, according to recent research published in the journal Headache.

“[T]he burden and impact of migraine on the individual both during and between attacks were identified through supervised machine learning models to be strongly associated with seeking care,” Sait Ashina, MD, of the department of neurology at Harvard Medical School in Boston, and colleagues wrote in their study.

Dr. Ashina and colleagues performed a cross-sectional study of 61,826 patients from the web-based ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study with migraine who visited a primary care, specialty care, or urgent care, or emergency setting for headache between 2018 and 2020.

The patients recruited for OBSERVE were a mean of 41.7 years old and had experienced migraines for an average of 19.0 years; 59.4% had between 0 and 3 average headache days per month, 74.5% were women, 78.8% were White, and 85.4% had health insurance; and they were demographically representative of the US population.

Researchers used a machine learning model, which consisted of random forest and least absolute shrinkage and selection operator (LASSO) algorithms, to identify the relationship between patients who sought care for migraine and 54 different clinical, sociodemographic, and migraine-associated factors, which included age, years with migraine, symptom scores, pain intensity scores, disability score, comorbidities, vomiting, presence and severity of allodynia, and other factors.

The results showed 31,529 patients (51.0%) had an in-person or e-visit encounter with a primary care, specialty care, or urgent care, or emergency care location within 12 months of the survey, and were mostly White (76.5%) women (73.3%) with health insurance (88.9%). Of the patients who sought care, 52.8% had severe interictal burden measured by Migraine Interictal Burden Scale-4 score, compared with 23.1% of patients who did not seek care. Compared with patients who did not seek care, those who did visit a health care setting for migraine had a higher percentage of severe migraine-related disability as measured by the Migraine Disability Assessment Scale (36.7% vs 14.6%) and severe ictal cutaneous allodynia as measured by the Allodynia Symptom Checklist (21.0% vs 7.4%).

In a multivariable logistic regression model analysis, Dr. Ashina and colleagues said the factors most associated with seeking care included severe interictal burden (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.5-2.8), severe migraine-related disability (OR, 2.2; 95% CI, 2.0-2.3), and severe ictal allodynia (OR, 1.7; 95% CI, 1.6-1.8), compared with less severe factors.

The researchers said their results have “significant implications for public health and advocacy efforts.”

“As seen through three decades of epidemiological research in the United States, rates of care-seeking have not improved dramatically over time despite significant additions to scientific knowledge and the therapeutic armamentarium, leaving a significant unmet need. This is also important from a clinical perspective,” they explained. “Health care professionals in primary care and internal medicine most likely see patients with migraine who do not discuss it during visits. This underscores the importance of maintaining vigilance for migraine, especially among those who may experience greater disability, impact, and interictal burden.”
 

Asking the Right Questions

Asked to comment on the research, Robert P. Cowan, MD, a neurologist and professor in the Stanford University School of Medicine department of neurology and neurological sciences in Palo Alto, California, said in an interview that the value of the paper is in what it does not say about the main reasons patients seek care.

“Most clinicians readily acknowledge that the average number of migraine headache days per month is, at best, a weak predictor of which patients seek care and when,” he said.

Dr. Cowan said that most patients are referred to him by other providers, and when he asks them why they did not seek care for migraine sooner, the answer is usually because the migraine was not severe enough or because over-the-counter medication had previously worked for them. He noted that change in frequency is, in his experience, a primary reason why patients will seek care. “[F]or new (or increasing) headache, it is the concern that the headaches are something more ‘serious,’ and once that is ruled out, the conversation often stops,” he said. “For long-standing migraine sufferers, it is the perception that the headache is a ‘fact of life’ and does not rise to the bar of seeking medical advice.”

The questions a survey or a provider asks matters, Dr. Cowan said. “Often, when we ask a patient how many headache (or migraine) days per month, the answer is in single digits. But if we follow-up with a question about the number of headache-free days [per] month, the answer is ‘never’ or ‘hardly ever,’” he explained. “The point here is that what questions a survey (or a provider) asks introduces a clear bias. The use of machine learning instruments, especially when utilizing supervised learning, only reinforces and amplifies the bias of the designers of the categories.”

Epidemiologic studies are interesting but “often ask the wrong questions,” Dr. Cowan said. “I am less worried about the ... 49% of migraine or possible migraine patients who do not seek care and do [not] progress to more disabling ‘chronic’ migraine than I am with identifying the subpopulations of migraine patients who seek care from providers who do not have adequate tools to match patients to the best treatments.”

The authors reported personal and institutional relationships in the form of advisory board memberships, consultancies, employment, honoraria, research support, speakers bureau positions, stock ownership, and teaching services with AbbVie, Aeon, Alder, Allay Lamp, Allergan, Amgen, Axon, Biohaven Pharmaceuticals, Collegium, CoolTech, Currax, Dr. Reddy’s Laboratories (Promius), electroCore, GlaxoSmithKline, Impel NeuroPharma, Informa, Eli Lilly and Company, Lundbeck, Mainistee, Merck, National Headache Foundation, National Institutes of Health, Novartis, Pfizer, Satsuma, Supernus, Percept, Teva, Theranica, UpsherSmith, the US Food and Drug Administration, Vector, Vedanta Research, and Wolff’s Headache. The study was supported by Eli Lilly. Dr. Cowan reports no relevant conflicts of interest.

There is a significant association between higher interictal burden, disability, and allodynia in patients who sought medical care for migraine, according to recent research published in the journal Headache.

“[T]he burden and impact of migraine on the individual both during and between attacks were identified through supervised machine learning models to be strongly associated with seeking care,” Sait Ashina, MD, of the department of neurology at Harvard Medical School in Boston, and colleagues wrote in their study.

Dr. Ashina and colleagues performed a cross-sectional study of 61,826 patients from the web-based ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study with migraine who visited a primary care, specialty care, or urgent care, or emergency setting for headache between 2018 and 2020.

The patients recruited for OBSERVE were a mean of 41.7 years old and had experienced migraines for an average of 19.0 years; 59.4% had between 0 and 3 average headache days per month, 74.5% were women, 78.8% were White, and 85.4% had health insurance; and they were demographically representative of the US population.

Researchers used a machine learning model, which consisted of random forest and least absolute shrinkage and selection operator (LASSO) algorithms, to identify the relationship between patients who sought care for migraine and 54 different clinical, sociodemographic, and migraine-associated factors, which included age, years with migraine, symptom scores, pain intensity scores, disability score, comorbidities, vomiting, presence and severity of allodynia, and other factors.

The results showed 31,529 patients (51.0%) had an in-person or e-visit encounter with a primary care, specialty care, or urgent care, or emergency care location within 12 months of the survey, and were mostly White (76.5%) women (73.3%) with health insurance (88.9%). Of the patients who sought care, 52.8% had severe interictal burden measured by Migraine Interictal Burden Scale-4 score, compared with 23.1% of patients who did not seek care. Compared with patients who did not seek care, those who did visit a health care setting for migraine had a higher percentage of severe migraine-related disability as measured by the Migraine Disability Assessment Scale (36.7% vs 14.6%) and severe ictal cutaneous allodynia as measured by the Allodynia Symptom Checklist (21.0% vs 7.4%).

In a multivariable logistic regression model analysis, Dr. Ashina and colleagues said the factors most associated with seeking care included severe interictal burden (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.5-2.8), severe migraine-related disability (OR, 2.2; 95% CI, 2.0-2.3), and severe ictal allodynia (OR, 1.7; 95% CI, 1.6-1.8), compared with less severe factors.

The researchers said their results have “significant implications for public health and advocacy efforts.”

“As seen through three decades of epidemiological research in the United States, rates of care-seeking have not improved dramatically over time despite significant additions to scientific knowledge and the therapeutic armamentarium, leaving a significant unmet need. This is also important from a clinical perspective,” they explained. “Health care professionals in primary care and internal medicine most likely see patients with migraine who do not discuss it during visits. This underscores the importance of maintaining vigilance for migraine, especially among those who may experience greater disability, impact, and interictal burden.”
 

Asking the Right Questions

Asked to comment on the research, Robert P. Cowan, MD, a neurologist and professor in the Stanford University School of Medicine department of neurology and neurological sciences in Palo Alto, California, said in an interview that the value of the paper is in what it does not say about the main reasons patients seek care.

“Most clinicians readily acknowledge that the average number of migraine headache days per month is, at best, a weak predictor of which patients seek care and when,” he said.

Dr. Cowan said that most patients are referred to him by other providers, and when he asks them why they did not seek care for migraine sooner, the answer is usually because the migraine was not severe enough or because over-the-counter medication had previously worked for them. He noted that change in frequency is, in his experience, a primary reason why patients will seek care. “[F]or new (or increasing) headache, it is the concern that the headaches are something more ‘serious,’ and once that is ruled out, the conversation often stops,” he said. “For long-standing migraine sufferers, it is the perception that the headache is a ‘fact of life’ and does not rise to the bar of seeking medical advice.”

The questions a survey or a provider asks matters, Dr. Cowan said. “Often, when we ask a patient how many headache (or migraine) days per month, the answer is in single digits. But if we follow-up with a question about the number of headache-free days [per] month, the answer is ‘never’ or ‘hardly ever,’” he explained. “The point here is that what questions a survey (or a provider) asks introduces a clear bias. The use of machine learning instruments, especially when utilizing supervised learning, only reinforces and amplifies the bias of the designers of the categories.”

Epidemiologic studies are interesting but “often ask the wrong questions,” Dr. Cowan said. “I am less worried about the ... 49% of migraine or possible migraine patients who do not seek care and do [not] progress to more disabling ‘chronic’ migraine than I am with identifying the subpopulations of migraine patients who seek care from providers who do not have adequate tools to match patients to the best treatments.”

The authors reported personal and institutional relationships in the form of advisory board memberships, consultancies, employment, honoraria, research support, speakers bureau positions, stock ownership, and teaching services with AbbVie, Aeon, Alder, Allay Lamp, Allergan, Amgen, Axon, Biohaven Pharmaceuticals, Collegium, CoolTech, Currax, Dr. Reddy’s Laboratories (Promius), electroCore, GlaxoSmithKline, Impel NeuroPharma, Informa, Eli Lilly and Company, Lundbeck, Mainistee, Merck, National Headache Foundation, National Institutes of Health, Novartis, Pfizer, Satsuma, Supernus, Percept, Teva, Theranica, UpsherSmith, the US Food and Drug Administration, Vector, Vedanta Research, and Wolff’s Headache. The study was supported by Eli Lilly. Dr. Cowan reports no relevant conflicts of interest.

Irisin levels in cerebrospinal fluid (CSF) are significantly lower among patients with Alzheimer’s disease, and levels positively correlate with amyloid beta 1-42 (Abeta42), increasing support for this emerging Alzheimer’s disease biomarker, according to investigators.

Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.

Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.

“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
 

Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease

The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.

Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).

Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).

Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).

Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.

Plasma irisin levels were not significantly correlated with any of the other biomarkers.
 

Clinical Implications

This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.

In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.

“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”

Cleveland Clinic

It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.

“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.

The route of collection could also cause challenges.

“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”

Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”

The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.

Irisin levels in cerebrospinal fluid (CSF) are significantly lower among patients with Alzheimer’s disease, and levels positively correlate with amyloid beta 1-42 (Abeta42), increasing support for this emerging Alzheimer’s disease biomarker, according to investigators.

Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.

Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.

“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
 

Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease

The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.

Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).

Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).

Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).

Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.

Plasma irisin levels were not significantly correlated with any of the other biomarkers.
 

Clinical Implications

This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.

In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.

“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”

Cleveland Clinic

It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.

“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.

The route of collection could also cause challenges.

“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”

Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”

The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.

Irisin levels in cerebrospinal fluid (CSF) are significantly lower among patients with Alzheimer’s disease, and levels positively correlate with amyloid beta 1-42 (Abeta42), increasing support for this emerging Alzheimer’s disease biomarker, according to investigators.

Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.

Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.

“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
 

Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease

The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.

Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).

Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).

Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).

Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.

Plasma irisin levels were not significantly correlated with any of the other biomarkers.
 

Clinical Implications

This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.

In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.

“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”

Cleveland Clinic

It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.

“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.

The route of collection could also cause challenges.

“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”

Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”

The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.

NASHVILLE, TENNESSEE — Multiple sclerosis (MS) is much more commonly diagnosed in women, but men get the diagnosis too and can present some special challenges to disease management and treatment. Disease course, mental health, and social function may be different in male patients.

Among the clinical differences: Men may be diagnosed at an older age, often closer to 30 years of age, and they more often experience memory problems, spinal cord lesions, and motor symptoms. They are at higher risk of progressive-onset disease, but have lower relapse rates. Disability rates are higher in men than in women, but long-term survival is no different. Brain atrophy is also more common among men.

Not all MRI facilities will include brain atrophy assessment, so it is a good idea to put an order in for brain atrophy when there are reasons to be concerned, such as cognitive effects or issues with walking, according to Jeffrey Hernandez, DNP, during a talk at the annual meeting of the Consortium of Multiple Sclerosis Centers. Dr. Hernandez is affiliated with the University of Miami Multiple Sclerosis Center.
 

Addressing Sensitive Topics

Men may be less willing to discuss their symptoms, in part because they may have been raised to be tough and stoic. “Looking for help might make them feel more vulnerable,” said Dr. Hernandez. That’s not a feeling that most men are familiar with, he said. Men “don’t want to be deemed or seem weak or dependent on anyone.” Consequently, men are less likely to complain about any symptom, said Dr. Hernandez.

He advised asking more open-ended questions in an effort to draw men out. “Just ask how they’re doing. See if anything has changed from their usual habits, have their activities of daily living changed, has their work performance changed? That can give you an indication. One of my patients [said he] was demoted from [his] position, that the demotion was related to cognitive impairment and the way that he was working. That gives you an idea as to where you can help intervene and perhaps make an improvement for that patient’s quality of life, or consider switching treatments,” said Dr. Hernandez.

Men are less likely to report symptoms such as tingling, physical complaints, cognitive difficulties, mood changes, and sexual dysfunction. That doesn’t mean they’re not experiencing issues, though, especially when it comes to sexual problems. Dr. Hernandez recalled one patient who just stared out the window when asked about his sex life. “Then I said, the next time I want your wife to be here, and then she spilled the beans on everything. So it’s important sometimes to include other members of the family or their partners in the conversation to give you some insight. And perhaps that day it wasn’t a priority for him, but then the next time it was a priority for his wife,” he said.

He pointed out that erectile dysfunction could be due to a physiological response to MS, or to psychological effects.

Low testosterone levels may also play a role in MS, since it is a natural anti-inflammatory hormone. Hypogonadism has been found to be high among men with MS in some studies. MS in men is associated with more enhancing lesions, greater cognitive decline, and increased risk of disability, while high levels of testosterone are linked to neuroprotective effects and lower risk of developing MS.

Men with MS are more likely than women to report suicidal thoughts when depressed, and mental health can be taboo, as men may try to solve problems on their own before seeking help. “But a lot of the times they can use a little bit of help, whether it be from talk therapy or meds. With the expansion of telemedicine, virtual care has skyrocketed in psychiatry. I advocate strongly for it. Psychologytoday.com is a very common portal that I recommend so they can look up providers with their insurances, and they can see who gives in person versus virtual care. They can do it from the comfort of their car. I’ve had people in their car crying because they don’t want to be in their house when they talk to me,” said Dr. Hernandez.

Physical struggles can lead men to feel they’ve lost their independence, and that they are no longer the protector of the household. Divorce is common, which can lead to social isolation. One patient wanted to see Dr. Hernandez monthly, a request that he had to decline. “Sometimes they want to discuss these things and they just don’t have someone to talk to,” said Dr. Hernandez. Social support programs through the National MS Society, the MS Foundation, or the Multiple Sclerosis Association of America may sponsor local programs that could be beneficial.

Dr. Hernandez has no relevant financial disclosures.

NASHVILLE, TENNESSEE — Multiple sclerosis (MS) is much more commonly diagnosed in women, but men get the diagnosis too and can present some special challenges to disease management and treatment. Disease course, mental health, and social function may be different in male patients.

Among the clinical differences: Men may be diagnosed at an older age, often closer to 30 years of age, and they more often experience memory problems, spinal cord lesions, and motor symptoms. They are at higher risk of progressive-onset disease, but have lower relapse rates. Disability rates are higher in men than in women, but long-term survival is no different. Brain atrophy is also more common among men.

Not all MRI facilities will include brain atrophy assessment, so it is a good idea to put an order in for brain atrophy when there are reasons to be concerned, such as cognitive effects or issues with walking, according to Jeffrey Hernandez, DNP, during a talk at the annual meeting of the Consortium of Multiple Sclerosis Centers. Dr. Hernandez is affiliated with the University of Miami Multiple Sclerosis Center.
 

Addressing Sensitive Topics

Men may be less willing to discuss their symptoms, in part because they may have been raised to be tough and stoic. “Looking for help might make them feel more vulnerable,” said Dr. Hernandez. That’s not a feeling that most men are familiar with, he said. Men “don’t want to be deemed or seem weak or dependent on anyone.” Consequently, men are less likely to complain about any symptom, said Dr. Hernandez.

He advised asking more open-ended questions in an effort to draw men out. “Just ask how they’re doing. See if anything has changed from their usual habits, have their activities of daily living changed, has their work performance changed? That can give you an indication. One of my patients [said he] was demoted from [his] position, that the demotion was related to cognitive impairment and the way that he was working. That gives you an idea as to where you can help intervene and perhaps make an improvement for that patient’s quality of life, or consider switching treatments,” said Dr. Hernandez.

Men are less likely to report symptoms such as tingling, physical complaints, cognitive difficulties, mood changes, and sexual dysfunction. That doesn’t mean they’re not experiencing issues, though, especially when it comes to sexual problems. Dr. Hernandez recalled one patient who just stared out the window when asked about his sex life. “Then I said, the next time I want your wife to be here, and then she spilled the beans on everything. So it’s important sometimes to include other members of the family or their partners in the conversation to give you some insight. And perhaps that day it wasn’t a priority for him, but then the next time it was a priority for his wife,” he said.

He pointed out that erectile dysfunction could be due to a physiological response to MS, or to psychological effects.

Low testosterone levels may also play a role in MS, since it is a natural anti-inflammatory hormone. Hypogonadism has been found to be high among men with MS in some studies. MS in men is associated with more enhancing lesions, greater cognitive decline, and increased risk of disability, while high levels of testosterone are linked to neuroprotective effects and lower risk of developing MS.

Men with MS are more likely than women to report suicidal thoughts when depressed, and mental health can be taboo, as men may try to solve problems on their own before seeking help. “But a lot of the times they can use a little bit of help, whether it be from talk therapy or meds. With the expansion of telemedicine, virtual care has skyrocketed in psychiatry. I advocate strongly for it. Psychologytoday.com is a very common portal that I recommend so they can look up providers with their insurances, and they can see who gives in person versus virtual care. They can do it from the comfort of their car. I’ve had people in their car crying because they don’t want to be in their house when they talk to me,” said Dr. Hernandez.

Physical struggles can lead men to feel they’ve lost their independence, and that they are no longer the protector of the household. Divorce is common, which can lead to social isolation. One patient wanted to see Dr. Hernandez monthly, a request that he had to decline. “Sometimes they want to discuss these things and they just don’t have someone to talk to,” said Dr. Hernandez. Social support programs through the National MS Society, the MS Foundation, or the Multiple Sclerosis Association of America may sponsor local programs that could be beneficial.

Dr. Hernandez has no relevant financial disclosures.

NASHVILLE, TENNESSEE — Multiple sclerosis (MS) is much more commonly diagnosed in women, but men get the diagnosis too and can present some special challenges to disease management and treatment. Disease course, mental health, and social function may be different in male patients.

Among the clinical differences: Men may be diagnosed at an older age, often closer to 30 years of age, and they more often experience memory problems, spinal cord lesions, and motor symptoms. They are at higher risk of progressive-onset disease, but have lower relapse rates. Disability rates are higher in men than in women, but long-term survival is no different. Brain atrophy is also more common among men.

Not all MRI facilities will include brain atrophy assessment, so it is a good idea to put an order in for brain atrophy when there are reasons to be concerned, such as cognitive effects or issues with walking, according to Jeffrey Hernandez, DNP, during a talk at the annual meeting of the Consortium of Multiple Sclerosis Centers. Dr. Hernandez is affiliated with the University of Miami Multiple Sclerosis Center.
 

Addressing Sensitive Topics

Men may be less willing to discuss their symptoms, in part because they may have been raised to be tough and stoic. “Looking for help might make them feel more vulnerable,” said Dr. Hernandez. That’s not a feeling that most men are familiar with, he said. Men “don’t want to be deemed or seem weak or dependent on anyone.” Consequently, men are less likely to complain about any symptom, said Dr. Hernandez.

He advised asking more open-ended questions in an effort to draw men out. “Just ask how they’re doing. See if anything has changed from their usual habits, have their activities of daily living changed, has their work performance changed? That can give you an indication. One of my patients [said he] was demoted from [his] position, that the demotion was related to cognitive impairment and the way that he was working. That gives you an idea as to where you can help intervene and perhaps make an improvement for that patient’s quality of life, or consider switching treatments,” said Dr. Hernandez.

Men are less likely to report symptoms such as tingling, physical complaints, cognitive difficulties, mood changes, and sexual dysfunction. That doesn’t mean they’re not experiencing issues, though, especially when it comes to sexual problems. Dr. Hernandez recalled one patient who just stared out the window when asked about his sex life. “Then I said, the next time I want your wife to be here, and then she spilled the beans on everything. So it’s important sometimes to include other members of the family or their partners in the conversation to give you some insight. And perhaps that day it wasn’t a priority for him, but then the next time it was a priority for his wife,” he said.

He pointed out that erectile dysfunction could be due to a physiological response to MS, or to psychological effects.

Low testosterone levels may also play a role in MS, since it is a natural anti-inflammatory hormone. Hypogonadism has been found to be high among men with MS in some studies. MS in men is associated with more enhancing lesions, greater cognitive decline, and increased risk of disability, while high levels of testosterone are linked to neuroprotective effects and lower risk of developing MS.

Men with MS are more likely than women to report suicidal thoughts when depressed, and mental health can be taboo, as men may try to solve problems on their own before seeking help. “But a lot of the times they can use a little bit of help, whether it be from talk therapy or meds. With the expansion of telemedicine, virtual care has skyrocketed in psychiatry. I advocate strongly for it. Psychologytoday.com is a very common portal that I recommend so they can look up providers with their insurances, and they can see who gives in person versus virtual care. They can do it from the comfort of their car. I’ve had people in their car crying because they don’t want to be in their house when they talk to me,” said Dr. Hernandez.

Physical struggles can lead men to feel they’ve lost their independence, and that they are no longer the protector of the household. Divorce is common, which can lead to social isolation. One patient wanted to see Dr. Hernandez monthly, a request that he had to decline. “Sometimes they want to discuss these things and they just don’t have someone to talk to,” said Dr. Hernandez. Social support programs through the National MS Society, the MS Foundation, or the Multiple Sclerosis Association of America may sponsor local programs that could be beneficial.

Dr. Hernandez has no relevant financial disclosures.

NASHVILLE, TENNESSEE — A second-generation anti-CD40L monoclonal antibody suppresses multiple sclerosis (MS) disease activity on MRI to an uncommonly high degree, new trial data suggested.

Researchers found a near absence of new brain lesions at 48 weeks in patients on the highest dose. At this level of disease suppression, there was no evidence of increased infection risk, which investigators said might relate to its mechanism of action. In addition, there were no thrombotic events, which is what defeated a first-generation drug in this same class.

Among those initially randomly assigned to receive 1200 mg every 4 weeks, 96% were free of new gadolinium-positive (Gd+ T1) lesions at 48 weeks, reported investigator Yang Mao-Draayer, MD, PhD, director of Clinical and Experimental Therapeutics at the Oklahoma Medical Research Foundation’s Multiple Sclerosis Center of Excellence, Oklahoma City. Annual relapse rates were also low.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

No Effect on Lymphocyte Count

As previously reported, 12-week frexalimab results were noteworthy because they provided validation for CD40L as a target in the control of MS. One of the unique features of this therapy relative to many other immunomodulatory therapies is that it has shown little, if any, effect on lymphocyte counts or immunoglobulin levels.

In the double-blind randomized phase 2 trial, 125 patients with MS of all other MS therapy were randomized in a 4:4:4:1 ratio to 1200-mg frexalimab administered intravenously every 4 weeks after a loading dose, to 300-mg frexalimab administered subcutaneously every 2 weeks after a loading dose, or to one of the two matching placebo arms.

For the primary endpoint of new Gd+ T1 lesions at the end of the blinded study, the rates at week 12 were 0.2 and 0.3 in the higher- and lower-dose treatment groups, respectively, and 1.4 in the pooled placebo groups.

At 48 weeks, the results were even better. From 12 weeks, the rate of Gd+ T1 lesions in the high-dose group continued to fall, reaching 0.1 at week 24 and 0.0 at week 48. In the lower-dose group, there was also a stepwise decline over time with a value of 0.2 at week 48. The annual relapse rate at week 48 was 0.4.
 

Reengineered Agent

In the placebo groups, the same type of suppression of disease activity was observed after they were switched to active therapy at the end of 12 weeks.

By 24 weeks, the number of new Gd+ T1 lesions had fallen to 0.3 in placebo patients switched to the higher dose and 1.0 in those switched to the lower dose.

By week 48, the rates were 0.2 in both of the switch arms.

The proportions of patients free of new Gd+ T1 lesions at 48 weeks were 96% in the group started and maintained on the highest dose of frexalimab, 87% in those started and maintained on the lower dose, 90% in those started on placebo and switched to the highest dose of frexalimab, and 92% of placebo patients switched to the lower dose.

“T2 lesion volume from baseline through week 48 was stable in patients who continued receiving frexalimab and decreased in placebo participants after switching to frexalimab at week 12,” Dr. Mao-Draayer reported.

The CD40-CD40L co-stimulatory pathway that regulates both adaptive and innate immune responses has been pursued as a target for MS therapies for decades, Dr. Mao-Draayer said.

A first-generation monoclonal antibody directed at elevated levels of CD40L, which is implicated in the inflammation that drives MS, showed promise but was abandoned after it was associated with an increased risk for thromboembolic events in a phase 1 trial, she said.

However, the second-generation agent was engineered to avoid an interaction with platelets, which played a role in the risk for thrombosis associated with the failure of the earlier drug.

As with the first-generation agent, frexalimab had little or no impact on lymphocyte count or immunoglobulin G and immunoglobulin M levels. Both remained stable during the 12-week controlled trial and through the ongoing open-label extension, Dr. Mao-Draayer said.

This might be a factor in the low level of adverse events. Most importantly, there have been no thromboembolic events associated with frexalimab so far, but the follow-up data also show rates of infection and other events, such as nasopharyngitis, that were comparable with placebo in the 12-week controlled trial and have not increased over longer-term monitoring.

Such adverse events as headache and COVID-19 infection have also occurred at rates similar to placebo.

Two phase 3 trials are underway. FREXALT is being conducted in relapsing-remitting MS. FREVIV has enrolled patients with nonrelapsing secondary progressive MS.
 

Impressively Low New Lesion Count

Commenting on the findings, Jeffrey Cohen, MD, director of the Mellen Center for Multiple Sclerosis, Cleveland Clinic, who was not involved in the research, said that over the course of the extended follow-up, MS activity in the central nervous system as measured with new Gd+ T1 lesions was impressively low. 

He noted that the phase 2 open-label follow-up continues to support the promise of frexalimab. But Dr. Cohen cautioned that this does not obviate the need for phase 3 data.

In particular, he said that an immunomodulatory agent that does not affect the lymphocyte count has a theoretical advantage, but pointed out that the benefit is still presumably mediated by blocking pathways that mediate autoimmune activity.

Even if lymphocyte count is unaffected, the immunomodulatory pathway by which frexalimab does exert its benefit might pose a different set of risks, he said.

“We will not have sufficient data to judge the promise of this agent until the phase 3 trials are completed,” he said.

Dr. Mao-Draayer reported financial relationships with Acorda, Bayer, Biogen, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, Horizon, Janssen, Novartis, Questor, Teva, and Sanofi, which provided funding for the phase 2 frexalimab trial. Dr. Cohen reported financial relationships with Astoria, Convelo, EMD Serono, FiND, INmune, and Sandoz.

A version of this article appeared on Medscape.com.

NASHVILLE, TENNESSEE — A second-generation anti-CD40L monoclonal antibody suppresses multiple sclerosis (MS) disease activity on MRI to an uncommonly high degree, new trial data suggested.

Researchers found a near absence of new brain lesions at 48 weeks in patients on the highest dose. At this level of disease suppression, there was no evidence of increased infection risk, which investigators said might relate to its mechanism of action. In addition, there were no thrombotic events, which is what defeated a first-generation drug in this same class.

Among those initially randomly assigned to receive 1200 mg every 4 weeks, 96% were free of new gadolinium-positive (Gd+ T1) lesions at 48 weeks, reported investigator Yang Mao-Draayer, MD, PhD, director of Clinical and Experimental Therapeutics at the Oklahoma Medical Research Foundation’s Multiple Sclerosis Center of Excellence, Oklahoma City. Annual relapse rates were also low.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

No Effect on Lymphocyte Count

As previously reported, 12-week frexalimab results were noteworthy because they provided validation for CD40L as a target in the control of MS. One of the unique features of this therapy relative to many other immunomodulatory therapies is that it has shown little, if any, effect on lymphocyte counts or immunoglobulin levels.

In the double-blind randomized phase 2 trial, 125 patients with MS of all other MS therapy were randomized in a 4:4:4:1 ratio to 1200-mg frexalimab administered intravenously every 4 weeks after a loading dose, to 300-mg frexalimab administered subcutaneously every 2 weeks after a loading dose, or to one of the two matching placebo arms.

For the primary endpoint of new Gd+ T1 lesions at the end of the blinded study, the rates at week 12 were 0.2 and 0.3 in the higher- and lower-dose treatment groups, respectively, and 1.4 in the pooled placebo groups.

At 48 weeks, the results were even better. From 12 weeks, the rate of Gd+ T1 lesions in the high-dose group continued to fall, reaching 0.1 at week 24 and 0.0 at week 48. In the lower-dose group, there was also a stepwise decline over time with a value of 0.2 at week 48. The annual relapse rate at week 48 was 0.4.
 

Reengineered Agent

In the placebo groups, the same type of suppression of disease activity was observed after they were switched to active therapy at the end of 12 weeks.

By 24 weeks, the number of new Gd+ T1 lesions had fallen to 0.3 in placebo patients switched to the higher dose and 1.0 in those switched to the lower dose.

By week 48, the rates were 0.2 in both of the switch arms.

The proportions of patients free of new Gd+ T1 lesions at 48 weeks were 96% in the group started and maintained on the highest dose of frexalimab, 87% in those started and maintained on the lower dose, 90% in those started on placebo and switched to the highest dose of frexalimab, and 92% of placebo patients switched to the lower dose.

“T2 lesion volume from baseline through week 48 was stable in patients who continued receiving frexalimab and decreased in placebo participants after switching to frexalimab at week 12,” Dr. Mao-Draayer reported.

The CD40-CD40L co-stimulatory pathway that regulates both adaptive and innate immune responses has been pursued as a target for MS therapies for decades, Dr. Mao-Draayer said.

A first-generation monoclonal antibody directed at elevated levels of CD40L, which is implicated in the inflammation that drives MS, showed promise but was abandoned after it was associated with an increased risk for thromboembolic events in a phase 1 trial, she said.

However, the second-generation agent was engineered to avoid an interaction with platelets, which played a role in the risk for thrombosis associated with the failure of the earlier drug.

As with the first-generation agent, frexalimab had little or no impact on lymphocyte count or immunoglobulin G and immunoglobulin M levels. Both remained stable during the 12-week controlled trial and through the ongoing open-label extension, Dr. Mao-Draayer said.

This might be a factor in the low level of adverse events. Most importantly, there have been no thromboembolic events associated with frexalimab so far, but the follow-up data also show rates of infection and other events, such as nasopharyngitis, that were comparable with placebo in the 12-week controlled trial and have not increased over longer-term monitoring.

Such adverse events as headache and COVID-19 infection have also occurred at rates similar to placebo.

Two phase 3 trials are underway. FREXALT is being conducted in relapsing-remitting MS. FREVIV has enrolled patients with nonrelapsing secondary progressive MS.
 

Impressively Low New Lesion Count

Commenting on the findings, Jeffrey Cohen, MD, director of the Mellen Center for Multiple Sclerosis, Cleveland Clinic, who was not involved in the research, said that over the course of the extended follow-up, MS activity in the central nervous system as measured with new Gd+ T1 lesions was impressively low. 

He noted that the phase 2 open-label follow-up continues to support the promise of frexalimab. But Dr. Cohen cautioned that this does not obviate the need for phase 3 data.

In particular, he said that an immunomodulatory agent that does not affect the lymphocyte count has a theoretical advantage, but pointed out that the benefit is still presumably mediated by blocking pathways that mediate autoimmune activity.

Even if lymphocyte count is unaffected, the immunomodulatory pathway by which frexalimab does exert its benefit might pose a different set of risks, he said.

“We will not have sufficient data to judge the promise of this agent until the phase 3 trials are completed,” he said.

Dr. Mao-Draayer reported financial relationships with Acorda, Bayer, Biogen, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, Horizon, Janssen, Novartis, Questor, Teva, and Sanofi, which provided funding for the phase 2 frexalimab trial. Dr. Cohen reported financial relationships with Astoria, Convelo, EMD Serono, FiND, INmune, and Sandoz.

A version of this article appeared on Medscape.com.

NASHVILLE, TENNESSEE — A second-generation anti-CD40L monoclonal antibody suppresses multiple sclerosis (MS) disease activity on MRI to an uncommonly high degree, new trial data suggested.

Researchers found a near absence of new brain lesions at 48 weeks in patients on the highest dose. At this level of disease suppression, there was no evidence of increased infection risk, which investigators said might relate to its mechanism of action. In addition, there were no thrombotic events, which is what defeated a first-generation drug in this same class.

Among those initially randomly assigned to receive 1200 mg every 4 weeks, 96% were free of new gadolinium-positive (Gd+ T1) lesions at 48 weeks, reported investigator Yang Mao-Draayer, MD, PhD, director of Clinical and Experimental Therapeutics at the Oklahoma Medical Research Foundation’s Multiple Sclerosis Center of Excellence, Oklahoma City. Annual relapse rates were also low.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

No Effect on Lymphocyte Count

As previously reported, 12-week frexalimab results were noteworthy because they provided validation for CD40L as a target in the control of MS. One of the unique features of this therapy relative to many other immunomodulatory therapies is that it has shown little, if any, effect on lymphocyte counts or immunoglobulin levels.

In the double-blind randomized phase 2 trial, 125 patients with MS of all other MS therapy were randomized in a 4:4:4:1 ratio to 1200-mg frexalimab administered intravenously every 4 weeks after a loading dose, to 300-mg frexalimab administered subcutaneously every 2 weeks after a loading dose, or to one of the two matching placebo arms.

For the primary endpoint of new Gd+ T1 lesions at the end of the blinded study, the rates at week 12 were 0.2 and 0.3 in the higher- and lower-dose treatment groups, respectively, and 1.4 in the pooled placebo groups.

At 48 weeks, the results were even better. From 12 weeks, the rate of Gd+ T1 lesions in the high-dose group continued to fall, reaching 0.1 at week 24 and 0.0 at week 48. In the lower-dose group, there was also a stepwise decline over time with a value of 0.2 at week 48. The annual relapse rate at week 48 was 0.4.
 

Reengineered Agent

In the placebo groups, the same type of suppression of disease activity was observed after they were switched to active therapy at the end of 12 weeks.

By 24 weeks, the number of new Gd+ T1 lesions had fallen to 0.3 in placebo patients switched to the higher dose and 1.0 in those switched to the lower dose.

By week 48, the rates were 0.2 in both of the switch arms.

The proportions of patients free of new Gd+ T1 lesions at 48 weeks were 96% in the group started and maintained on the highest dose of frexalimab, 87% in those started and maintained on the lower dose, 90% in those started on placebo and switched to the highest dose of frexalimab, and 92% of placebo patients switched to the lower dose.

“T2 lesion volume from baseline through week 48 was stable in patients who continued receiving frexalimab and decreased in placebo participants after switching to frexalimab at week 12,” Dr. Mao-Draayer reported.

The CD40-CD40L co-stimulatory pathway that regulates both adaptive and innate immune responses has been pursued as a target for MS therapies for decades, Dr. Mao-Draayer said.

A first-generation monoclonal antibody directed at elevated levels of CD40L, which is implicated in the inflammation that drives MS, showed promise but was abandoned after it was associated with an increased risk for thromboembolic events in a phase 1 trial, she said.

However, the second-generation agent was engineered to avoid an interaction with platelets, which played a role in the risk for thrombosis associated with the failure of the earlier drug.

As with the first-generation agent, frexalimab had little or no impact on lymphocyte count or immunoglobulin G and immunoglobulin M levels. Both remained stable during the 12-week controlled trial and through the ongoing open-label extension, Dr. Mao-Draayer said.

This might be a factor in the low level of adverse events. Most importantly, there have been no thromboembolic events associated with frexalimab so far, but the follow-up data also show rates of infection and other events, such as nasopharyngitis, that were comparable with placebo in the 12-week controlled trial and have not increased over longer-term monitoring.

Such adverse events as headache and COVID-19 infection have also occurred at rates similar to placebo.

Two phase 3 trials are underway. FREXALT is being conducted in relapsing-remitting MS. FREVIV has enrolled patients with nonrelapsing secondary progressive MS.
 

Impressively Low New Lesion Count

Commenting on the findings, Jeffrey Cohen, MD, director of the Mellen Center for Multiple Sclerosis, Cleveland Clinic, who was not involved in the research, said that over the course of the extended follow-up, MS activity in the central nervous system as measured with new Gd+ T1 lesions was impressively low. 

He noted that the phase 2 open-label follow-up continues to support the promise of frexalimab. But Dr. Cohen cautioned that this does not obviate the need for phase 3 data.

In particular, he said that an immunomodulatory agent that does not affect the lymphocyte count has a theoretical advantage, but pointed out that the benefit is still presumably mediated by blocking pathways that mediate autoimmune activity.

Even if lymphocyte count is unaffected, the immunomodulatory pathway by which frexalimab does exert its benefit might pose a different set of risks, he said.

“We will not have sufficient data to judge the promise of this agent until the phase 3 trials are completed,” he said.

Dr. Mao-Draayer reported financial relationships with Acorda, Bayer, Biogen, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, Horizon, Janssen, Novartis, Questor, Teva, and Sanofi, which provided funding for the phase 2 frexalimab trial. Dr. Cohen reported financial relationships with Astoria, Convelo, EMD Serono, FiND, INmune, and Sandoz.

A version of this article appeared on Medscape.com.

NASHVILLE, TENNESSEE — Fatigue and sleep problems are common among patients with multiple sclerosis (MS), but there are ways to help them manage these difficulties through personalized care.

Fatigue related to MS is complex, but it often follows a pattern. “Oftentimes when I meet with patients for the first time, they’re not always sure [what their own pattern is]. They know that the fatigue is present, and it’s limiting their activities. It’s important for us to break down and see that pattern for [the patient] specifically, and what are some ways that we can intervene to perhaps make that pattern something that improves quality of life and day-to-day living,” said Grace Tworek, PsyD, during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

A cycle may start on a day that a patient has lots of energy. They are ambitious that day and get a lot done on their “to do” list while they have the energy. Unfortunately, they commonly overdo it, leading to fatigue the next day. Over ensuing days, the patient might feel unable to engage in everyday tasks and begin to feel they are falling behind. This in turn can affect mood, resulting in increased symptoms of depression and anxiety. That leads to days of inactivity and rest, which leads to recovery. Then comes a day with better mood and increased energy, where the cycle can begin again.

It’s an addressable problem. “What we really want to do is break this cycle, get out of those peaks and valleys of high energy days and very low energy days to try to create more sustainable patterns” said Dr. Tworek, who is a staff health psychologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis, Cleveland, Ohio.
 

Fatigue

When addressing fatigue in MS patients, Dr. Tworek and her colleagues begin with a fatigue diary that includes typical activities engaged in throughout the day. It also distinguishes between activities the patient feels are important and activities that give them satisfaction.

“If we can find ways to include these [satisfying] activities, and not focus only on those important activities. This is where that quality of life really comes into play. But I always say to folks, we are not striving for perfection at first. I want you to write down what’s actually happening so we can use this data to later inform how we are going to make changes,” said Dr. Tworek.

It’s also important to encourage patients to seek help. Activities that are neither important nor satisfying may not need doing at all, and they encourage patients to seek help in other tasks. As for tasks that are important in their day-to-day lives, “How can we break those down? We break those down by pacing activities,” said Dr. Tworek.

A simple way to pace yourself is to use “The rule of two.” It asks: How long can I do a task before I experience a two-point increase on a 1-10 fatigue scale. “At that time, is when we want to start inserting breaks. We want to find activities we can do that will reduce [fatigue] or get us back to baseline. Or if that’s not realistic, keep us where we are at rather than increasing fatigue,” said Dr. Tworek.

Another way to think about it is spoon theory, sometimes referred to as coin theory. The idea is that you wake up each morning with ten spoons. Each task on a given day will cost a certain number of spoons. “You might start your day, you go downstairs, you have breakfast, and you’re already down to seven points, the next day, you might still be at 10. So it’s really about monitoring where you’re at in terms of how many coins or spoons you’re spending so that we can then reflect on how many coins or spoons do I have left?” said Dr. Tworek.

The strategy can aid communication with partners or family members who may have difficulty understanding MS fatigue. “Sometimes putting a number to it can really open up the doors to having these difficult conversations with friends and family,” said Dr. Tworek.
 

Sleep

Fatigue and sleep are naturally intertwined, and sleep problems are also common in MS, with 30%-56% reporting problems, depending on the estimate.

One concept to think about is sleep drive. “From the moment we wake up, we are building sleep pressure, just like from the moment you stop eating, your body starts building pressure to eat again,” said Dr. Tworek.

Naps can interfere with that drive, much like a snack can rob you of a meal-time appetite. “A nap is going to curb that appetite for sleep, making it more difficult potentially to fall asleep,” said Dr. Tworek. If a nap is absolutely necessary, it’s better to do it earlier in the day to allow time to build sleep pressure again.

As with fatigue, Dr. Tworek has patients fill out a sleep diary that documents difficulty falling or staying asleep, timing and length of awakenings, quality of sleep, length and timing of any naps, and other factors. It sometimes reveals patterns, like difficulty falling asleep on specific days of the week. Such rhythms may be attributable to regular stressors, like anticipating some event the next morning. Then it might be possible to tie in other techniques like stress management to reduce accompanying anxiety.

Sleep hygiene is an important factor, employing strategies like staying off screens or social media while in bed. “About 1 hour before bedtime, we want to try to create some relaxation time,” said Dr. Tworek.

Her clinic also emphasizes consistent wake time. “If we are waking every day in about the same half hour period, we are able to build that sleep pressure consistently. [Then] your body is going to let you know when it is time for bed. You’re going to feel sleepiness,” said Dr. Tworek.

Dr. Tworek did not report any disclosures or conflicts of interest.

NASHVILLE, TENNESSEE — Fatigue and sleep problems are common among patients with multiple sclerosis (MS), but there are ways to help them manage these difficulties through personalized care.

Fatigue related to MS is complex, but it often follows a pattern. “Oftentimes when I meet with patients for the first time, they’re not always sure [what their own pattern is]. They know that the fatigue is present, and it’s limiting their activities. It’s important for us to break down and see that pattern for [the patient] specifically, and what are some ways that we can intervene to perhaps make that pattern something that improves quality of life and day-to-day living,” said Grace Tworek, PsyD, during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

A cycle may start on a day that a patient has lots of energy. They are ambitious that day and get a lot done on their “to do” list while they have the energy. Unfortunately, they commonly overdo it, leading to fatigue the next day. Over ensuing days, the patient might feel unable to engage in everyday tasks and begin to feel they are falling behind. This in turn can affect mood, resulting in increased symptoms of depression and anxiety. That leads to days of inactivity and rest, which leads to recovery. Then comes a day with better mood and increased energy, where the cycle can begin again.

It’s an addressable problem. “What we really want to do is break this cycle, get out of those peaks and valleys of high energy days and very low energy days to try to create more sustainable patterns” said Dr. Tworek, who is a staff health psychologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis, Cleveland, Ohio.
 

Fatigue

When addressing fatigue in MS patients, Dr. Tworek and her colleagues begin with a fatigue diary that includes typical activities engaged in throughout the day. It also distinguishes between activities the patient feels are important and activities that give them satisfaction.

“If we can find ways to include these [satisfying] activities, and not focus only on those important activities. This is where that quality of life really comes into play. But I always say to folks, we are not striving for perfection at first. I want you to write down what’s actually happening so we can use this data to later inform how we are going to make changes,” said Dr. Tworek.

It’s also important to encourage patients to seek help. Activities that are neither important nor satisfying may not need doing at all, and they encourage patients to seek help in other tasks. As for tasks that are important in their day-to-day lives, “How can we break those down? We break those down by pacing activities,” said Dr. Tworek.

A simple way to pace yourself is to use “The rule of two.” It asks: How long can I do a task before I experience a two-point increase on a 1-10 fatigue scale. “At that time, is when we want to start inserting breaks. We want to find activities we can do that will reduce [fatigue] or get us back to baseline. Or if that’s not realistic, keep us where we are at rather than increasing fatigue,” said Dr. Tworek.

Another way to think about it is spoon theory, sometimes referred to as coin theory. The idea is that you wake up each morning with ten spoons. Each task on a given day will cost a certain number of spoons. “You might start your day, you go downstairs, you have breakfast, and you’re already down to seven points, the next day, you might still be at 10. So it’s really about monitoring where you’re at in terms of how many coins or spoons you’re spending so that we can then reflect on how many coins or spoons do I have left?” said Dr. Tworek.

The strategy can aid communication with partners or family members who may have difficulty understanding MS fatigue. “Sometimes putting a number to it can really open up the doors to having these difficult conversations with friends and family,” said Dr. Tworek.
 

Sleep

Fatigue and sleep are naturally intertwined, and sleep problems are also common in MS, with 30%-56% reporting problems, depending on the estimate.

One concept to think about is sleep drive. “From the moment we wake up, we are building sleep pressure, just like from the moment you stop eating, your body starts building pressure to eat again,” said Dr. Tworek.

Naps can interfere with that drive, much like a snack can rob you of a meal-time appetite. “A nap is going to curb that appetite for sleep, making it more difficult potentially to fall asleep,” said Dr. Tworek. If a nap is absolutely necessary, it’s better to do it earlier in the day to allow time to build sleep pressure again.

As with fatigue, Dr. Tworek has patients fill out a sleep diary that documents difficulty falling or staying asleep, timing and length of awakenings, quality of sleep, length and timing of any naps, and other factors. It sometimes reveals patterns, like difficulty falling asleep on specific days of the week. Such rhythms may be attributable to regular stressors, like anticipating some event the next morning. Then it might be possible to tie in other techniques like stress management to reduce accompanying anxiety.

Sleep hygiene is an important factor, employing strategies like staying off screens or social media while in bed. “About 1 hour before bedtime, we want to try to create some relaxation time,” said Dr. Tworek.

Her clinic also emphasizes consistent wake time. “If we are waking every day in about the same half hour period, we are able to build that sleep pressure consistently. [Then] your body is going to let you know when it is time for bed. You’re going to feel sleepiness,” said Dr. Tworek.

Dr. Tworek did not report any disclosures or conflicts of interest.

NASHVILLE, TENNESSEE — Fatigue and sleep problems are common among patients with multiple sclerosis (MS), but there are ways to help them manage these difficulties through personalized care.

Fatigue related to MS is complex, but it often follows a pattern. “Oftentimes when I meet with patients for the first time, they’re not always sure [what their own pattern is]. They know that the fatigue is present, and it’s limiting their activities. It’s important for us to break down and see that pattern for [the patient] specifically, and what are some ways that we can intervene to perhaps make that pattern something that improves quality of life and day-to-day living,” said Grace Tworek, PsyD, during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

A cycle may start on a day that a patient has lots of energy. They are ambitious that day and get a lot done on their “to do” list while they have the energy. Unfortunately, they commonly overdo it, leading to fatigue the next day. Over ensuing days, the patient might feel unable to engage in everyday tasks and begin to feel they are falling behind. This in turn can affect mood, resulting in increased symptoms of depression and anxiety. That leads to days of inactivity and rest, which leads to recovery. Then comes a day with better mood and increased energy, where the cycle can begin again.

It’s an addressable problem. “What we really want to do is break this cycle, get out of those peaks and valleys of high energy days and very low energy days to try to create more sustainable patterns” said Dr. Tworek, who is a staff health psychologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis, Cleveland, Ohio.
 

Fatigue

When addressing fatigue in MS patients, Dr. Tworek and her colleagues begin with a fatigue diary that includes typical activities engaged in throughout the day. It also distinguishes between activities the patient feels are important and activities that give them satisfaction.

“If we can find ways to include these [satisfying] activities, and not focus only on those important activities. This is where that quality of life really comes into play. But I always say to folks, we are not striving for perfection at first. I want you to write down what’s actually happening so we can use this data to later inform how we are going to make changes,” said Dr. Tworek.

It’s also important to encourage patients to seek help. Activities that are neither important nor satisfying may not need doing at all, and they encourage patients to seek help in other tasks. As for tasks that are important in their day-to-day lives, “How can we break those down? We break those down by pacing activities,” said Dr. Tworek.

A simple way to pace yourself is to use “The rule of two.” It asks: How long can I do a task before I experience a two-point increase on a 1-10 fatigue scale. “At that time, is when we want to start inserting breaks. We want to find activities we can do that will reduce [fatigue] or get us back to baseline. Or if that’s not realistic, keep us where we are at rather than increasing fatigue,” said Dr. Tworek.

Another way to think about it is spoon theory, sometimes referred to as coin theory. The idea is that you wake up each morning with ten spoons. Each task on a given day will cost a certain number of spoons. “You might start your day, you go downstairs, you have breakfast, and you’re already down to seven points, the next day, you might still be at 10. So it’s really about monitoring where you’re at in terms of how many coins or spoons you’re spending so that we can then reflect on how many coins or spoons do I have left?” said Dr. Tworek.

The strategy can aid communication with partners or family members who may have difficulty understanding MS fatigue. “Sometimes putting a number to it can really open up the doors to having these difficult conversations with friends and family,” said Dr. Tworek.
 

Sleep

Fatigue and sleep are naturally intertwined, and sleep problems are also common in MS, with 30%-56% reporting problems, depending on the estimate.

One concept to think about is sleep drive. “From the moment we wake up, we are building sleep pressure, just like from the moment you stop eating, your body starts building pressure to eat again,” said Dr. Tworek.

Naps can interfere with that drive, much like a snack can rob you of a meal-time appetite. “A nap is going to curb that appetite for sleep, making it more difficult potentially to fall asleep,” said Dr. Tworek. If a nap is absolutely necessary, it’s better to do it earlier in the day to allow time to build sleep pressure again.

As with fatigue, Dr. Tworek has patients fill out a sleep diary that documents difficulty falling or staying asleep, timing and length of awakenings, quality of sleep, length and timing of any naps, and other factors. It sometimes reveals patterns, like difficulty falling asleep on specific days of the week. Such rhythms may be attributable to regular stressors, like anticipating some event the next morning. Then it might be possible to tie in other techniques like stress management to reduce accompanying anxiety.

Sleep hygiene is an important factor, employing strategies like staying off screens or social media while in bed. “About 1 hour before bedtime, we want to try to create some relaxation time,” said Dr. Tworek.

Her clinic also emphasizes consistent wake time. “If we are waking every day in about the same half hour period, we are able to build that sleep pressure consistently. [Then] your body is going to let you know when it is time for bed. You’re going to feel sleepiness,” said Dr. Tworek.

Dr. Tworek did not report any disclosures or conflicts of interest.

Recently, “low field” MRIs have been in the news, with the promise that they’ll be safer and easier. People can go in them with their cell phones, car keys in pockets, no ear plugs needed for the noise, etc. They’re cheaper to build and can be plugged into a standard outlet.

That’s all well and good, but what about accuracy and image quality?

That’s a big question. Even proponents of the technology say it’s not as good as what we see with 3T MRI, so they’re trying to compensate by using AI and other software protocols to enhance the pictures. Allegedly it looks good, but so far only healthy volunteers have been scanned. How will it do with a small low-grade glioma or other subtle (but important) findings? We don’t know yet.

Personally, I think having to give up your iPhone and car keys for an hour, and put in foam ear plugs, are small trade-offs to get an accurate diagnosis.

Of course, I’m also approaching this as someone who deals with brain imaging. Maybe for other structures, like a knee, that kind of detail isn’t as necessary (or maybe it is. I’m definitely not in that field).

So, as with so many things that make it into the popular press, they likely have potential, but are still not ready for prime time.

This sort of stuff always gets my office phones ringing. Patients see a blurb about it on the news or Facebook and assume it’s available now, so they want one. They seem to think the new MRI is like Bones McCoy’s tricorder. I take the scanner off my belt, wave it over them, and the answer comes up on the screen. The fact that the unit still weighs over a ton is hidden at the bottom of the blurb, if it’s even mentioned at all.

There’s also the likelihood that this sort of thing is going to be taken to the public, in the same way carotid Dopplers have been. Marketed to the worried well with celebrity endorsements and taglines like “see what your doctor won’t look for.” Of course, MRIs are chock full of things like nonspecific white matter changes, disc bulges, tiny meningiomas, and a host of other incidental findings that cause panic in cyberchondriacs. Who then call us.

But that’s another story.

I understand that for some parts of the world a comparatively inexpensive, transportable, MRI that requires less shielding and power is a HUGE deal. Its availability can make the difference between life and death.

I’m not knocking the technology. I’m sure it will be useful. But, like so much in medicine, it’s not here yet.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Recently, “low field” MRIs have been in the news, with the promise that they’ll be safer and easier. People can go in them with their cell phones, car keys in pockets, no ear plugs needed for the noise, etc. They’re cheaper to build and can be plugged into a standard outlet.

That’s all well and good, but what about accuracy and image quality?

That’s a big question. Even proponents of the technology say it’s not as good as what we see with 3T MRI, so they’re trying to compensate by using AI and other software protocols to enhance the pictures. Allegedly it looks good, but so far only healthy volunteers have been scanned. How will it do with a small low-grade glioma or other subtle (but important) findings? We don’t know yet.

Personally, I think having to give up your iPhone and car keys for an hour, and put in foam ear plugs, are small trade-offs to get an accurate diagnosis.

Of course, I’m also approaching this as someone who deals with brain imaging. Maybe for other structures, like a knee, that kind of detail isn’t as necessary (or maybe it is. I’m definitely not in that field).

So, as with so many things that make it into the popular press, they likely have potential, but are still not ready for prime time.

This sort of stuff always gets my office phones ringing. Patients see a blurb about it on the news or Facebook and assume it’s available now, so they want one. They seem to think the new MRI is like Bones McCoy’s tricorder. I take the scanner off my belt, wave it over them, and the answer comes up on the screen. The fact that the unit still weighs over a ton is hidden at the bottom of the blurb, if it’s even mentioned at all.

There’s also the likelihood that this sort of thing is going to be taken to the public, in the same way carotid Dopplers have been. Marketed to the worried well with celebrity endorsements and taglines like “see what your doctor won’t look for.” Of course, MRIs are chock full of things like nonspecific white matter changes, disc bulges, tiny meningiomas, and a host of other incidental findings that cause panic in cyberchondriacs. Who then call us.

But that’s another story.

I understand that for some parts of the world a comparatively inexpensive, transportable, MRI that requires less shielding and power is a HUGE deal. Its availability can make the difference between life and death.

I’m not knocking the technology. I’m sure it will be useful. But, like so much in medicine, it’s not here yet.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Recently, “low field” MRIs have been in the news, with the promise that they’ll be safer and easier. People can go in them with their cell phones, car keys in pockets, no ear plugs needed for the noise, etc. They’re cheaper to build and can be plugged into a standard outlet.

That’s all well and good, but what about accuracy and image quality?

That’s a big question. Even proponents of the technology say it’s not as good as what we see with 3T MRI, so they’re trying to compensate by using AI and other software protocols to enhance the pictures. Allegedly it looks good, but so far only healthy volunteers have been scanned. How will it do with a small low-grade glioma or other subtle (but important) findings? We don’t know yet.

Personally, I think having to give up your iPhone and car keys for an hour, and put in foam ear plugs, are small trade-offs to get an accurate diagnosis.

Of course, I’m also approaching this as someone who deals with brain imaging. Maybe for other structures, like a knee, that kind of detail isn’t as necessary (or maybe it is. I’m definitely not in that field).

So, as with so many things that make it into the popular press, they likely have potential, but are still not ready for prime time.

This sort of stuff always gets my office phones ringing. Patients see a blurb about it on the news or Facebook and assume it’s available now, so they want one. They seem to think the new MRI is like Bones McCoy’s tricorder. I take the scanner off my belt, wave it over them, and the answer comes up on the screen. The fact that the unit still weighs over a ton is hidden at the bottom of the blurb, if it’s even mentioned at all.

There’s also the likelihood that this sort of thing is going to be taken to the public, in the same way carotid Dopplers have been. Marketed to the worried well with celebrity endorsements and taglines like “see what your doctor won’t look for.” Of course, MRIs are chock full of things like nonspecific white matter changes, disc bulges, tiny meningiomas, and a host of other incidental findings that cause panic in cyberchondriacs. Who then call us.

But that’s another story.

I understand that for some parts of the world a comparatively inexpensive, transportable, MRI that requires less shielding and power is a HUGE deal. Its availability can make the difference between life and death.

I’m not knocking the technology. I’m sure it will be useful. But, like so much in medicine, it’s not here yet.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

As the availability of potential biomarkers for Parkinson’s disease drives the debate around diagnosing prodromal Parkinson’s disease (pPD) from theory to practice, said authors of a recent study, clinicians should weigh each patient’s preferences, circumstances, and goals against the potential benefits and harms of disclosure. The study and an accompanying editorial appeared online in Neurology.

Because markers such as SNCA, LRRK2, and GBA mutations impact small subgroups of patients at risk of developing monogenic forms of Parkinson’s disease, wrote Richard N. Rees, MBChB, MD, from the Department of Clinical and Movement Neurosciences at University College London Queen Square Institute of Neurology, and colleagues, researchers are working to identify people at risk of idiopathic Parkinson’s disease using models based on known risk and protective factors. The recent development of highly accurate cerebrospinal fluid (and potentially serum) alpha-synuclein seed amplification assays, which may show Parkinson’s disease’s signature before overt symptoms appear, will reinforce these efforts, authors added.
 

‘Tap the Brakes’

However, sources interviewed by Neurology Reviews counseled caution with potential prodromal Parkinson’s disease biomarkers. “As the science advances in Parkinson’s disease and related disorders,” said Michael S. Okun, MD, “our ability to predict who will and will not be diagnosed will improve. We should, however, tap the brakes and consider the consequences of making a diagnosis in someone at risk — especially someone without symptoms.” Dr. Okun is National Medical Advisor to the Parkinson’s Foundation and director of the Norman Fixel Institute for Neurological Diseases at University of Florida Health in Gainesville, Florida. He was not involved with the study.

Neurologists should ask themselves why they are testing for Parkinson’s disease biomarkers, said Dr. Okun, and what counseling and shared decision-making they provided beforehand. “This already complex scenario becomes even more complicated when we consider that many people with GBA gene mutations and some with LRRK2 mutations may never actually manifest Parkinson’s disease.”

A Holistic Approach to Shared Decision-Making

To avoid needlessly scaring patients, Dr. Hoy suggested broaching the topic of Parkinson’s disease biomarkers during advance care planning. “In the same conversation that you might talk about establishing surrogate decision-makers or potential do-not-resuscitate/intubate orders, you can talk about the potential of predictive testing, which is becoming more prevalent across domains of clinical practice.”

Understanding each patient’s values, preferences, and priorities requires a holistic approach, he said. “In the context of prodromal Parkinson’s disease, the benefits of enrolling in a new clinical trial or implementing lifestyle changes might vary depending on the person. Do you think this person would be likely to enroll in a clinical trial or implement those lifestyle changes?” Additionally, he recommended considering how a patient might react to a false diagnosis.

Whereas a diagnosis of mild cognitive impairment might not lead to Alzheimer’s disease or dementia, wrote Dr. Rees and colleagues, growing evidence including a review published in Neurology in 2022 supports the accuracy of alpha-synuclein seed amplification assays in detecting both established and prodromal Parkinson’s disease. For people thusly diagnosed, Dr. Rees and colleagues wrote, the psychosocial burden of inevitable progression could create feelings of helplessness, possibly undermining benefits of early knowledge.

Beyond patients’ reactions, said Dr. Hoy, a diagnosis of prodromal Parkinson’s disease could result in social stigma, changes to interpersonal relationships, or discrimination. “Understanding the implications and uncertainties of potential disclosure, relative to what a person would want to know or might be able to do about it, will be the key for deciding when is the right time,” he said.
 

Supporting Primary Care

As the shared decision-making burden likely will fall to primary care providers, Dr. Hoy added, neurologists should prioritize increasing these providers’ capacity to advise and refer patients appropriately. Although it is too soon to develop clinical guidelines, he said, neurologists could help educate such providers about pPD and the growing availability of promising biomarkers.

“Parkinson’s is thought of as a movement disorder first and foremost,” said Dr. Hoy. However, various non-motor symptoms including sleep problems, depression, anxiety, apathy, constipation, and gastrointestinal issues often appear before movement-related symptoms during the prodromal phase.

As potentially the first line of defense against prodromal Parkinson’s disease, primary care providers also should know the distinction between early and timely diagnosis, added Dr. Hoy. Introduced by Dr. Rees and colleagues in a 2018 review published in F1000Research, timely diagnosis balances patient preferences, the availability and efficacy of DMT, and health systems’ ability to support and manage individuals at every stage of disease.

The current study was funded by a Parkinson’s UK grant (which paid Dr. Rees’s salary). The editorial was supported by a National Institute of Mental Health Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative award, a grant from the National Institute on Aging, and a Wellcome Discovery Award. Dr. Hoy reported no relevant disclosures.

As the availability of potential biomarkers for Parkinson’s disease drives the debate around diagnosing prodromal Parkinson’s disease (pPD) from theory to practice, said authors of a recent study, clinicians should weigh each patient’s preferences, circumstances, and goals against the potential benefits and harms of disclosure. The study and an accompanying editorial appeared online in Neurology.

Because markers such as SNCA, LRRK2, and GBA mutations impact small subgroups of patients at risk of developing monogenic forms of Parkinson’s disease, wrote Richard N. Rees, MBChB, MD, from the Department of Clinical and Movement Neurosciences at University College London Queen Square Institute of Neurology, and colleagues, researchers are working to identify people at risk of idiopathic Parkinson’s disease using models based on known risk and protective factors. The recent development of highly accurate cerebrospinal fluid (and potentially serum) alpha-synuclein seed amplification assays, which may show Parkinson’s disease’s signature before overt symptoms appear, will reinforce these efforts, authors added.
 

‘Tap the Brakes’

However, sources interviewed by Neurology Reviews counseled caution with potential prodromal Parkinson’s disease biomarkers. “As the science advances in Parkinson’s disease and related disorders,” said Michael S. Okun, MD, “our ability to predict who will and will not be diagnosed will improve. We should, however, tap the brakes and consider the consequences of making a diagnosis in someone at risk — especially someone without symptoms.” Dr. Okun is National Medical Advisor to the Parkinson’s Foundation and director of the Norman Fixel Institute for Neurological Diseases at University of Florida Health in Gainesville, Florida. He was not involved with the study.

Neurologists should ask themselves why they are testing for Parkinson’s disease biomarkers, said Dr. Okun, and what counseling and shared decision-making they provided beforehand. “This already complex scenario becomes even more complicated when we consider that many people with GBA gene mutations and some with LRRK2 mutations may never actually manifest Parkinson’s disease.”

A Holistic Approach to Shared Decision-Making

To avoid needlessly scaring patients, Dr. Hoy suggested broaching the topic of Parkinson’s disease biomarkers during advance care planning. “In the same conversation that you might talk about establishing surrogate decision-makers or potential do-not-resuscitate/intubate orders, you can talk about the potential of predictive testing, which is becoming more prevalent across domains of clinical practice.”

Understanding each patient’s values, preferences, and priorities requires a holistic approach, he said. “In the context of prodromal Parkinson’s disease, the benefits of enrolling in a new clinical trial or implementing lifestyle changes might vary depending on the person. Do you think this person would be likely to enroll in a clinical trial or implement those lifestyle changes?” Additionally, he recommended considering how a patient might react to a false diagnosis.

Whereas a diagnosis of mild cognitive impairment might not lead to Alzheimer’s disease or dementia, wrote Dr. Rees and colleagues, growing evidence including a review published in Neurology in 2022 supports the accuracy of alpha-synuclein seed amplification assays in detecting both established and prodromal Parkinson’s disease. For people thusly diagnosed, Dr. Rees and colleagues wrote, the psychosocial burden of inevitable progression could create feelings of helplessness, possibly undermining benefits of early knowledge.

Beyond patients’ reactions, said Dr. Hoy, a diagnosis of prodromal Parkinson’s disease could result in social stigma, changes to interpersonal relationships, or discrimination. “Understanding the implications and uncertainties of potential disclosure, relative to what a person would want to know or might be able to do about it, will be the key for deciding when is the right time,” he said.
 

Supporting Primary Care

As the shared decision-making burden likely will fall to primary care providers, Dr. Hoy added, neurologists should prioritize increasing these providers’ capacity to advise and refer patients appropriately. Although it is too soon to develop clinical guidelines, he said, neurologists could help educate such providers about pPD and the growing availability of promising biomarkers.

“Parkinson’s is thought of as a movement disorder first and foremost,” said Dr. Hoy. However, various non-motor symptoms including sleep problems, depression, anxiety, apathy, constipation, and gastrointestinal issues often appear before movement-related symptoms during the prodromal phase.

As potentially the first line of defense against prodromal Parkinson’s disease, primary care providers also should know the distinction between early and timely diagnosis, added Dr. Hoy. Introduced by Dr. Rees and colleagues in a 2018 review published in F1000Research, timely diagnosis balances patient preferences, the availability and efficacy of DMT, and health systems’ ability to support and manage individuals at every stage of disease.

The current study was funded by a Parkinson’s UK grant (which paid Dr. Rees’s salary). The editorial was supported by a National Institute of Mental Health Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative award, a grant from the National Institute on Aging, and a Wellcome Discovery Award. Dr. Hoy reported no relevant disclosures.

As the availability of potential biomarkers for Parkinson’s disease drives the debate around diagnosing prodromal Parkinson’s disease (pPD) from theory to practice, said authors of a recent study, clinicians should weigh each patient’s preferences, circumstances, and goals against the potential benefits and harms of disclosure. The study and an accompanying editorial appeared online in Neurology.

Because markers such as SNCA, LRRK2, and GBA mutations impact small subgroups of patients at risk of developing monogenic forms of Parkinson’s disease, wrote Richard N. Rees, MBChB, MD, from the Department of Clinical and Movement Neurosciences at University College London Queen Square Institute of Neurology, and colleagues, researchers are working to identify people at risk of idiopathic Parkinson’s disease using models based on known risk and protective factors. The recent development of highly accurate cerebrospinal fluid (and potentially serum) alpha-synuclein seed amplification assays, which may show Parkinson’s disease’s signature before overt symptoms appear, will reinforce these efforts, authors added.
 

‘Tap the Brakes’

However, sources interviewed by Neurology Reviews counseled caution with potential prodromal Parkinson’s disease biomarkers. “As the science advances in Parkinson’s disease and related disorders,” said Michael S. Okun, MD, “our ability to predict who will and will not be diagnosed will improve. We should, however, tap the brakes and consider the consequences of making a diagnosis in someone at risk — especially someone without symptoms.” Dr. Okun is National Medical Advisor to the Parkinson’s Foundation and director of the Norman Fixel Institute for Neurological Diseases at University of Florida Health in Gainesville, Florida. He was not involved with the study.

Neurologists should ask themselves why they are testing for Parkinson’s disease biomarkers, said Dr. Okun, and what counseling and shared decision-making they provided beforehand. “This already complex scenario becomes even more complicated when we consider that many people with GBA gene mutations and some with LRRK2 mutations may never actually manifest Parkinson’s disease.”

A Holistic Approach to Shared Decision-Making

To avoid needlessly scaring patients, Dr. Hoy suggested broaching the topic of Parkinson’s disease biomarkers during advance care planning. “In the same conversation that you might talk about establishing surrogate decision-makers or potential do-not-resuscitate/intubate orders, you can talk about the potential of predictive testing, which is becoming more prevalent across domains of clinical practice.”

Understanding each patient’s values, preferences, and priorities requires a holistic approach, he said. “In the context of prodromal Parkinson’s disease, the benefits of enrolling in a new clinical trial or implementing lifestyle changes might vary depending on the person. Do you think this person would be likely to enroll in a clinical trial or implement those lifestyle changes?” Additionally, he recommended considering how a patient might react to a false diagnosis.

Whereas a diagnosis of mild cognitive impairment might not lead to Alzheimer’s disease or dementia, wrote Dr. Rees and colleagues, growing evidence including a review published in Neurology in 2022 supports the accuracy of alpha-synuclein seed amplification assays in detecting both established and prodromal Parkinson’s disease. For people thusly diagnosed, Dr. Rees and colleagues wrote, the psychosocial burden of inevitable progression could create feelings of helplessness, possibly undermining benefits of early knowledge.

Beyond patients’ reactions, said Dr. Hoy, a diagnosis of prodromal Parkinson’s disease could result in social stigma, changes to interpersonal relationships, or discrimination. “Understanding the implications and uncertainties of potential disclosure, relative to what a person would want to know or might be able to do about it, will be the key for deciding when is the right time,” he said.
 

Supporting Primary Care

As the shared decision-making burden likely will fall to primary care providers, Dr. Hoy added, neurologists should prioritize increasing these providers’ capacity to advise and refer patients appropriately. Although it is too soon to develop clinical guidelines, he said, neurologists could help educate such providers about pPD and the growing availability of promising biomarkers.

“Parkinson’s is thought of as a movement disorder first and foremost,” said Dr. Hoy. However, various non-motor symptoms including sleep problems, depression, anxiety, apathy, constipation, and gastrointestinal issues often appear before movement-related symptoms during the prodromal phase.

As potentially the first line of defense against prodromal Parkinson’s disease, primary care providers also should know the distinction between early and timely diagnosis, added Dr. Hoy. Introduced by Dr. Rees and colleagues in a 2018 review published in F1000Research, timely diagnosis balances patient preferences, the availability and efficacy of DMT, and health systems’ ability to support and manage individuals at every stage of disease.

The current study was funded by a Parkinson’s UK grant (which paid Dr. Rees’s salary). The editorial was supported by a National Institute of Mental Health Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative award, a grant from the National Institute on Aging, and a Wellcome Discovery Award. Dr. Hoy reported no relevant disclosures.