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Neurology Reviews covers innovative and emerging news in neurology and neuroscience every month, with a focus on practical approaches to treating Parkinson's disease, epilepsy, headache, stroke, multiple sclerosis, Alzheimer's disease, and other neurologic disorders.
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Progressive multifocal leukoencephalopathy
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Patient Navigators for Serious Illnesses Can Now Bill Under New Medicare Codes
In a move that acknowledges the gauntlet the US health system poses for people facing serious and fatal illnesses, Medicare will pay for a new class of workers to help patients manage treatments for conditions like cancer and heart failure.
The 2024 Medicare physician fee schedule includes new billing codes, including G0023, to pay for 60 minutes a month of care coordination by certified or trained auxiliary personnel working under the direction of a clinician.
A diagnosis of cancer or another serious illness takes a toll beyond the physical effects of the disease. Patients often scramble to make adjustments in family and work schedules to manage treatment, said Samyukta Mullangi, MD, MBA, medical director of oncology at Thyme Care, a Nashville, Tennessee–based firm that provides navigation and coordination services to oncology practices and insurers.
“It just really does create a bit of a pressure cooker for patients,” Dr. Mullangi told this news organization.
Medicare has for many years paid for medical professionals to help patients cope with the complexities of disease, such as chronic care management (CCM) provided by physicians, nurses, and physician assistants.
The new principal illness navigation (PIN) payments are intended to pay for work that to date typically has been done by people without medical degrees, including those involved in peer support networks and community health programs. The US Centers for Medicare and Medicaid Services(CMS) expects these navigators will undergo training and work under the supervision of clinicians.
The new navigators may coordinate care transitions between medical settings, follow up with patients after emergency department (ED) visits, or communicate with skilled nursing facilities regarding the psychosocial needs and functional deficits of a patient, among other functions.
CMS expects the new navigators may:
- Conduct assessments to understand a patient’s life story, strengths, needs, goals, preferences, and desired outcomes, including understanding cultural and linguistic factors.
- Provide support to accomplish the clinician’s treatment plan.
- Coordinate the receipt of needed services from healthcare facilities, home- and community-based service providers, and caregivers.
Peers as Navigators
The new navigators can be former patients who have undergone similar treatments for serious diseases, CMS said. This approach sets the new program apart from other care management services Medicare already covers, program officials wrote in the 2024 physician fee schedule.
“For some conditions, patients are best able to engage with the healthcare system and access care if they have assistance from a single, dedicated individual who has ‘lived experience,’ ” according to the rule.
The agency has taken a broad initial approach in defining what kinds of illnesses a patient may have to qualify for services. Patients must have a serious condition that is expected to last at least 3 months, such as cancer, heart failure, or substance use disorder.
But those without a definitive diagnosis may also qualify to receive navigator services.
In the rule, CMS cited a case in which a CT scan identified a suspicious mass in a patient’s colon. A clinician might decide this person would benefit from navigation services due to the potential risks for an undiagnosed illness.
“Regardless of the definitive diagnosis of the mass, presence of a colonic mass for that patient may be a serious high-risk condition that could, for example, cause obstruction and lead the patient to present to the emergency department, as well as be potentially indicative of an underlying life-threatening illness such as colon cancer,” CMS wrote in the rule.
Navigators often start their work when cancer patients are screened and guide them through initial diagnosis, potential surgery, radiation, or chemotherapy, said Sharon Gentry, MSN, RN, a former nurse navigator who is now the editor in chief of the Journal of the Academy of Oncology Nurse & Patient Navigators.
The navigators are meant to be a trusted and continual presence for patients, who otherwise might be left to start anew in finding help at each phase of care.
The navigators “see the whole picture. They see the whole journey the patient takes, from pre-diagnosis all the way through diagnosis care out through survival,” Ms. Gentry said.
Gaining a special Medicare payment for these kinds of services will elevate this work, she said.
Many newer drugs can target specific mechanisms and proteins of cancer. Often, oncology treatment involves testing to find out if mutations are allowing the cancer cells to evade a patient’s immune system.
Checking these biomarkers takes time, however. Patients sometimes become frustrated because they are anxious to begin treatment. Patients may receive inaccurate information from friends or family who went through treatment previously. Navigators can provide knowledge on the current state of care for a patient’s disease, helping them better manage anxieties.
“You have to explain to them that things have changed since the guy you drink coffee with was diagnosed with cancer, and there may be a drug that could target that,” Ms. Gentry said.
Potential Challenges
Initial uptake of the new PIN codes may be slow going, however, as clinicians and health systems may already use well-established codes. These include CCM and principal care management services, which may pay higher rates, Mullangi said.
“There might be sensitivity around not wanting to cannibalize existing programs with a new program,” Dr. Mullangi said.
In addition, many patients will have a copay for the services of principal illness navigators, Dr. Mullangi said.
While many patients have additional insurance that would cover the service, not all do. People with traditional Medicare coverage can sometimes pay 20% of the cost of some medical services.
“I think that may give patients pause, particularly if they’re already feeling the financial burden of a cancer treatment journey,” Dr. Mullangi said.
Pay rates for PIN services involve calculations of regional price differences, which are posted publicly by CMS, and potential added fees for services provided by hospital-affiliated organizations.
Consider payments for code G0023, covering 60 minutes of principal navigation services provided in a single month.
A set reimbursement for patients cared for in independent medical practices exists, with variation for local costs. Medicare’s non-facility price for G0023 would be $102.41 in some parts of Silicon Valley in California, including San Jose. In Arkansas, where costs are lower, reimbursement would be $73.14 for this same service.
Patients who get services covered by code G0023 in independent medical practices would have monthly copays of about $15-$20, depending on where they live.
The tab for patients tends to be higher for these same services if delivered through a medical practice owned by a hospital, as this would trigger the addition of facility fees to the payments made to cover the services. Facility fees are difficult for the public to ascertain before getting a treatment or service.
Dr. Mullangi and Ms. Gentry reported no relevant financial disclosures outside of their employers.
A version of this article first appeared on Medscape.com.
In a move that acknowledges the gauntlet the US health system poses for people facing serious and fatal illnesses, Medicare will pay for a new class of workers to help patients manage treatments for conditions like cancer and heart failure.
The 2024 Medicare physician fee schedule includes new billing codes, including G0023, to pay for 60 minutes a month of care coordination by certified or trained auxiliary personnel working under the direction of a clinician.
A diagnosis of cancer or another serious illness takes a toll beyond the physical effects of the disease. Patients often scramble to make adjustments in family and work schedules to manage treatment, said Samyukta Mullangi, MD, MBA, medical director of oncology at Thyme Care, a Nashville, Tennessee–based firm that provides navigation and coordination services to oncology practices and insurers.
“It just really does create a bit of a pressure cooker for patients,” Dr. Mullangi told this news organization.
Medicare has for many years paid for medical professionals to help patients cope with the complexities of disease, such as chronic care management (CCM) provided by physicians, nurses, and physician assistants.
The new principal illness navigation (PIN) payments are intended to pay for work that to date typically has been done by people without medical degrees, including those involved in peer support networks and community health programs. The US Centers for Medicare and Medicaid Services(CMS) expects these navigators will undergo training and work under the supervision of clinicians.
The new navigators may coordinate care transitions between medical settings, follow up with patients after emergency department (ED) visits, or communicate with skilled nursing facilities regarding the psychosocial needs and functional deficits of a patient, among other functions.
CMS expects the new navigators may:
- Conduct assessments to understand a patient’s life story, strengths, needs, goals, preferences, and desired outcomes, including understanding cultural and linguistic factors.
- Provide support to accomplish the clinician’s treatment plan.
- Coordinate the receipt of needed services from healthcare facilities, home- and community-based service providers, and caregivers.
Peers as Navigators
The new navigators can be former patients who have undergone similar treatments for serious diseases, CMS said. This approach sets the new program apart from other care management services Medicare already covers, program officials wrote in the 2024 physician fee schedule.
“For some conditions, patients are best able to engage with the healthcare system and access care if they have assistance from a single, dedicated individual who has ‘lived experience,’ ” according to the rule.
The agency has taken a broad initial approach in defining what kinds of illnesses a patient may have to qualify for services. Patients must have a serious condition that is expected to last at least 3 months, such as cancer, heart failure, or substance use disorder.
But those without a definitive diagnosis may also qualify to receive navigator services.
In the rule, CMS cited a case in which a CT scan identified a suspicious mass in a patient’s colon. A clinician might decide this person would benefit from navigation services due to the potential risks for an undiagnosed illness.
“Regardless of the definitive diagnosis of the mass, presence of a colonic mass for that patient may be a serious high-risk condition that could, for example, cause obstruction and lead the patient to present to the emergency department, as well as be potentially indicative of an underlying life-threatening illness such as colon cancer,” CMS wrote in the rule.
Navigators often start their work when cancer patients are screened and guide them through initial diagnosis, potential surgery, radiation, or chemotherapy, said Sharon Gentry, MSN, RN, a former nurse navigator who is now the editor in chief of the Journal of the Academy of Oncology Nurse & Patient Navigators.
The navigators are meant to be a trusted and continual presence for patients, who otherwise might be left to start anew in finding help at each phase of care.
The navigators “see the whole picture. They see the whole journey the patient takes, from pre-diagnosis all the way through diagnosis care out through survival,” Ms. Gentry said.
Gaining a special Medicare payment for these kinds of services will elevate this work, she said.
Many newer drugs can target specific mechanisms and proteins of cancer. Often, oncology treatment involves testing to find out if mutations are allowing the cancer cells to evade a patient’s immune system.
Checking these biomarkers takes time, however. Patients sometimes become frustrated because they are anxious to begin treatment. Patients may receive inaccurate information from friends or family who went through treatment previously. Navigators can provide knowledge on the current state of care for a patient’s disease, helping them better manage anxieties.
“You have to explain to them that things have changed since the guy you drink coffee with was diagnosed with cancer, and there may be a drug that could target that,” Ms. Gentry said.
Potential Challenges
Initial uptake of the new PIN codes may be slow going, however, as clinicians and health systems may already use well-established codes. These include CCM and principal care management services, which may pay higher rates, Mullangi said.
“There might be sensitivity around not wanting to cannibalize existing programs with a new program,” Dr. Mullangi said.
In addition, many patients will have a copay for the services of principal illness navigators, Dr. Mullangi said.
While many patients have additional insurance that would cover the service, not all do. People with traditional Medicare coverage can sometimes pay 20% of the cost of some medical services.
“I think that may give patients pause, particularly if they’re already feeling the financial burden of a cancer treatment journey,” Dr. Mullangi said.
Pay rates for PIN services involve calculations of regional price differences, which are posted publicly by CMS, and potential added fees for services provided by hospital-affiliated organizations.
Consider payments for code G0023, covering 60 minutes of principal navigation services provided in a single month.
A set reimbursement for patients cared for in independent medical practices exists, with variation for local costs. Medicare’s non-facility price for G0023 would be $102.41 in some parts of Silicon Valley in California, including San Jose. In Arkansas, where costs are lower, reimbursement would be $73.14 for this same service.
Patients who get services covered by code G0023 in independent medical practices would have monthly copays of about $15-$20, depending on where they live.
The tab for patients tends to be higher for these same services if delivered through a medical practice owned by a hospital, as this would trigger the addition of facility fees to the payments made to cover the services. Facility fees are difficult for the public to ascertain before getting a treatment or service.
Dr. Mullangi and Ms. Gentry reported no relevant financial disclosures outside of their employers.
A version of this article first appeared on Medscape.com.
In a move that acknowledges the gauntlet the US health system poses for people facing serious and fatal illnesses, Medicare will pay for a new class of workers to help patients manage treatments for conditions like cancer and heart failure.
The 2024 Medicare physician fee schedule includes new billing codes, including G0023, to pay for 60 minutes a month of care coordination by certified or trained auxiliary personnel working under the direction of a clinician.
A diagnosis of cancer or another serious illness takes a toll beyond the physical effects of the disease. Patients often scramble to make adjustments in family and work schedules to manage treatment, said Samyukta Mullangi, MD, MBA, medical director of oncology at Thyme Care, a Nashville, Tennessee–based firm that provides navigation and coordination services to oncology practices and insurers.
“It just really does create a bit of a pressure cooker for patients,” Dr. Mullangi told this news organization.
Medicare has for many years paid for medical professionals to help patients cope with the complexities of disease, such as chronic care management (CCM) provided by physicians, nurses, and physician assistants.
The new principal illness navigation (PIN) payments are intended to pay for work that to date typically has been done by people without medical degrees, including those involved in peer support networks and community health programs. The US Centers for Medicare and Medicaid Services(CMS) expects these navigators will undergo training and work under the supervision of clinicians.
The new navigators may coordinate care transitions between medical settings, follow up with patients after emergency department (ED) visits, or communicate with skilled nursing facilities regarding the psychosocial needs and functional deficits of a patient, among other functions.
CMS expects the new navigators may:
- Conduct assessments to understand a patient’s life story, strengths, needs, goals, preferences, and desired outcomes, including understanding cultural and linguistic factors.
- Provide support to accomplish the clinician’s treatment plan.
- Coordinate the receipt of needed services from healthcare facilities, home- and community-based service providers, and caregivers.
Peers as Navigators
The new navigators can be former patients who have undergone similar treatments for serious diseases, CMS said. This approach sets the new program apart from other care management services Medicare already covers, program officials wrote in the 2024 physician fee schedule.
“For some conditions, patients are best able to engage with the healthcare system and access care if they have assistance from a single, dedicated individual who has ‘lived experience,’ ” according to the rule.
The agency has taken a broad initial approach in defining what kinds of illnesses a patient may have to qualify for services. Patients must have a serious condition that is expected to last at least 3 months, such as cancer, heart failure, or substance use disorder.
But those without a definitive diagnosis may also qualify to receive navigator services.
In the rule, CMS cited a case in which a CT scan identified a suspicious mass in a patient’s colon. A clinician might decide this person would benefit from navigation services due to the potential risks for an undiagnosed illness.
“Regardless of the definitive diagnosis of the mass, presence of a colonic mass for that patient may be a serious high-risk condition that could, for example, cause obstruction and lead the patient to present to the emergency department, as well as be potentially indicative of an underlying life-threatening illness such as colon cancer,” CMS wrote in the rule.
Navigators often start their work when cancer patients are screened and guide them through initial diagnosis, potential surgery, radiation, or chemotherapy, said Sharon Gentry, MSN, RN, a former nurse navigator who is now the editor in chief of the Journal of the Academy of Oncology Nurse & Patient Navigators.
The navigators are meant to be a trusted and continual presence for patients, who otherwise might be left to start anew in finding help at each phase of care.
The navigators “see the whole picture. They see the whole journey the patient takes, from pre-diagnosis all the way through diagnosis care out through survival,” Ms. Gentry said.
Gaining a special Medicare payment for these kinds of services will elevate this work, she said.
Many newer drugs can target specific mechanisms and proteins of cancer. Often, oncology treatment involves testing to find out if mutations are allowing the cancer cells to evade a patient’s immune system.
Checking these biomarkers takes time, however. Patients sometimes become frustrated because they are anxious to begin treatment. Patients may receive inaccurate information from friends or family who went through treatment previously. Navigators can provide knowledge on the current state of care for a patient’s disease, helping them better manage anxieties.
“You have to explain to them that things have changed since the guy you drink coffee with was diagnosed with cancer, and there may be a drug that could target that,” Ms. Gentry said.
Potential Challenges
Initial uptake of the new PIN codes may be slow going, however, as clinicians and health systems may already use well-established codes. These include CCM and principal care management services, which may pay higher rates, Mullangi said.
“There might be sensitivity around not wanting to cannibalize existing programs with a new program,” Dr. Mullangi said.
In addition, many patients will have a copay for the services of principal illness navigators, Dr. Mullangi said.
While many patients have additional insurance that would cover the service, not all do. People with traditional Medicare coverage can sometimes pay 20% of the cost of some medical services.
“I think that may give patients pause, particularly if they’re already feeling the financial burden of a cancer treatment journey,” Dr. Mullangi said.
Pay rates for PIN services involve calculations of regional price differences, which are posted publicly by CMS, and potential added fees for services provided by hospital-affiliated organizations.
Consider payments for code G0023, covering 60 minutes of principal navigation services provided in a single month.
A set reimbursement for patients cared for in independent medical practices exists, with variation for local costs. Medicare’s non-facility price for G0023 would be $102.41 in some parts of Silicon Valley in California, including San Jose. In Arkansas, where costs are lower, reimbursement would be $73.14 for this same service.
Patients who get services covered by code G0023 in independent medical practices would have monthly copays of about $15-$20, depending on where they live.
The tab for patients tends to be higher for these same services if delivered through a medical practice owned by a hospital, as this would trigger the addition of facility fees to the payments made to cover the services. Facility fees are difficult for the public to ascertain before getting a treatment or service.
Dr. Mullangi and Ms. Gentry reported no relevant financial disclosures outside of their employers.
A version of this article first appeared on Medscape.com.
From Fish Tanks to Cartoons
There was a recent Sermo post bemoaning the demise of fish tanks, and the calming they bring, in medical waiting rooms.
Aquariums, I agree, have a soporific effect on humans. I’m not immune myself on the rare occasions I encounter one. There’s something relaxing about watching the fish slowly glide back and forth while you admire their different colors, sizes, and patterns. This is why they persisted in a lot of places, such as videotapes (remember “Video Fish Tank”?), screen savers, and a key plot point in Finding Nemo.
Personally, When I get the occasional offer for a free waiting room TV that will play some customized feed about my practice and “ask your doctor” treatments, I send it off to be recycled into kitchen towels.
I think the real reason fish tanks are gone is that eternal bugaboo of medicine: money.
Margins in most practices, including mine, are thin, and a real fish tank (I’m not talking about a guppy in a bowl) aren’t cheap. They take, well, fish, and the most colorful ones are saltwater. Then they take a pump, heater, chemicals, food, plants, and decorations. Then you have to throw in the cost of a service with expertise in maintaining them (let’s face it, none of us have time to do that ourselves) ...
You want to add that to your overhead? Me neither.
My waiting room, as a result, is pretty bland. A handful of magazines, some books of classic Far Side, Calvin & Hobbes, and Doonesbury cartoons. The magazines are older, but relatively timeless ones, like issues of the Smithsonian or National Geographic. I don’t put out news magazines of any kind. If I’m not going to read the news, my patients shouldn’t have to either. My lobby should be relaxing.
We also live in an era where patients bring their own entertainment, on phones or iPads, to read while waiting. There are often days when I straighten up the waiting room while closing and the magazines haven’t been touched.
Yes, I miss fish tanks. But, like so many other things, they’ve become a casualty of modern medicine. They simply don’t make financial sense.
I’d rather cut corners in the waiting room than with patient care.
Block has a solo neurology practice in Scottsdale, Arizona.
There was a recent Sermo post bemoaning the demise of fish tanks, and the calming they bring, in medical waiting rooms.
Aquariums, I agree, have a soporific effect on humans. I’m not immune myself on the rare occasions I encounter one. There’s something relaxing about watching the fish slowly glide back and forth while you admire their different colors, sizes, and patterns. This is why they persisted in a lot of places, such as videotapes (remember “Video Fish Tank”?), screen savers, and a key plot point in Finding Nemo.
Personally, When I get the occasional offer for a free waiting room TV that will play some customized feed about my practice and “ask your doctor” treatments, I send it off to be recycled into kitchen towels.
I think the real reason fish tanks are gone is that eternal bugaboo of medicine: money.
Margins in most practices, including mine, are thin, and a real fish tank (I’m not talking about a guppy in a bowl) aren’t cheap. They take, well, fish, and the most colorful ones are saltwater. Then they take a pump, heater, chemicals, food, plants, and decorations. Then you have to throw in the cost of a service with expertise in maintaining them (let’s face it, none of us have time to do that ourselves) ...
You want to add that to your overhead? Me neither.
My waiting room, as a result, is pretty bland. A handful of magazines, some books of classic Far Side, Calvin & Hobbes, and Doonesbury cartoons. The magazines are older, but relatively timeless ones, like issues of the Smithsonian or National Geographic. I don’t put out news magazines of any kind. If I’m not going to read the news, my patients shouldn’t have to either. My lobby should be relaxing.
We also live in an era where patients bring their own entertainment, on phones or iPads, to read while waiting. There are often days when I straighten up the waiting room while closing and the magazines haven’t been touched.
Yes, I miss fish tanks. But, like so many other things, they’ve become a casualty of modern medicine. They simply don’t make financial sense.
I’d rather cut corners in the waiting room than with patient care.
Block has a solo neurology practice in Scottsdale, Arizona.
There was a recent Sermo post bemoaning the demise of fish tanks, and the calming they bring, in medical waiting rooms.
Aquariums, I agree, have a soporific effect on humans. I’m not immune myself on the rare occasions I encounter one. There’s something relaxing about watching the fish slowly glide back and forth while you admire their different colors, sizes, and patterns. This is why they persisted in a lot of places, such as videotapes (remember “Video Fish Tank”?), screen savers, and a key plot point in Finding Nemo.
Personally, When I get the occasional offer for a free waiting room TV that will play some customized feed about my practice and “ask your doctor” treatments, I send it off to be recycled into kitchen towels.
I think the real reason fish tanks are gone is that eternal bugaboo of medicine: money.
Margins in most practices, including mine, are thin, and a real fish tank (I’m not talking about a guppy in a bowl) aren’t cheap. They take, well, fish, and the most colorful ones are saltwater. Then they take a pump, heater, chemicals, food, plants, and decorations. Then you have to throw in the cost of a service with expertise in maintaining them (let’s face it, none of us have time to do that ourselves) ...
You want to add that to your overhead? Me neither.
My waiting room, as a result, is pretty bland. A handful of magazines, some books of classic Far Side, Calvin & Hobbes, and Doonesbury cartoons. The magazines are older, but relatively timeless ones, like issues of the Smithsonian or National Geographic. I don’t put out news magazines of any kind. If I’m not going to read the news, my patients shouldn’t have to either. My lobby should be relaxing.
We also live in an era where patients bring their own entertainment, on phones or iPads, to read while waiting. There are often days when I straighten up the waiting room while closing and the magazines haven’t been touched.
Yes, I miss fish tanks. But, like so many other things, they’ve become a casualty of modern medicine. They simply don’t make financial sense.
I’d rather cut corners in the waiting room than with patient care.
Block has a solo neurology practice in Scottsdale, Arizona.
Trump Nominations for US Health Agencies Spark Controversy, Criticism, Praise
President-elect Donald Trump’s vision for the nation’s top health agencies is coming into focus with three nominations announced Nov. 22 that drew both criticism and praise:
- Surgeon and health researcher Martin A. Makary, MD, MPH, to lead the US Food and Drug Administration (FDA).
- Former Republican congressman and physician David J. Weldon, MD, for director of the US Centers for Disease Control and Prevention (CDC).
- Fox News contributor Janette Nesheiwat, MD, for surgeon general.
Earlier in November, Trump nominated vaccine skeptic and former presidential candidate Robert F. Kennedy Jr. to lead the US Department of Health and Human Services (HHS).
Here’s what to know about the latest nominees, who, like Kennedy, must be confirmed by the US Senate.
Martin A. Makary
Currently a professor at the Johns Hopkins School of Medicine and chief of islet transplant surgery at Johns Hopkins Hospital, Makary co-invented in 2006 a surgery checklist that became a widely-used patient safety tool.
As a US FDA commissioner, Makary would preside over a $6.5 billion agency with more than 18,000 employees. The agency, part of HHS, oversees human and animal drugs and vaccines, medical devices, food, tobacco and other products. Some of Makary’s views align closely with those of HHS nominee Kennedy.
Makary is also chief medical officer of telehealth platform Sesame.
Makary was primarily known as a health researcher and author of books about price transparency and the cost of health care until the COVID-19 pandemic, when he became an outspoken critic of the federal response, lambasting restrictions and mandates advocated by the CDC and other public health officials.
In 2023, Makary told the House Select Subcommittee on the COVID Pandemic that federal officials had ignored what he called “natural immunity.” Studies have shown that natural immunity is “at least as effective as vaccinated immunity, and probably better,” testified Makary.
Makary called for an overhaul of the US FDA in a 2021 Fox News opinion, saying that its culture was “defined by counterproductive rigidity and a refusal to adapt.”
Blind Spots, his most recent book, takes on what he calls “medical dogma” and challenges conventional views on subjects ranging from the microbiome to marijuana to cancer prevention, hormone replacement therapy, antibiotics and peanut allergies.
In an interview he posted to X, Makary blames inappropriate use of antibiotics for a variety of childhood illnesses. He cites increases in obesity, learning disabilities, attention deficit disorder, asthma, celiac disease, ulcerative colitis and Crohn’s disease as all potentially causally related to antibiotics given in childhood.
Makary is an advisor to two conservative think tanks, the Foundation for Research on Equal Opportunity, and to Paragon Health Institute, begun in 2021 by two former top officials in the previous Trump administration.
Makary would “cut the bureaucratic red tape at the agency to make sure Americans get the medical cures and treatments they deserve,” Trump said on his social media platform, Truth Social, and in a press release.
While Los Angeles Times owner and physician-entrepreneur Patrick Soon-Shiong, MBBCh, MSc, praised the nomination of Makary (and the two other nominees) as “inspired,” other physicians criticized Makary for his anti-COVID mandate views and “fear-mongering” over COVID vaccine side effects.
Janette Nesheiwat
As surgeon general, Nesheiwat would serve as the top “health communicator in chief” and oversee the 6000 member US Public Health Service Commissioned Corps.
She is a frequent medical contributor to Fox News and serves as a medical director for a group of urgent care clinics in New York. She received her medical degree from the American University of the Caribbean School of Medicine and completed a family medicine residency at the University of Arkansas for Medical Sciences. She is board-certified in family medicine.
Nesheiwat sells vitamin supplements on her website and in December will publish a book on “miracles in medicine” and her Christian faith.
Trump said in a statement that Nesheiwat “is a fierce advocate and strong communicator for preventive medicine and public health. She is committed to ensuring that Americans have access to affordable, quality healthcare, and believes in empowering individuals to take charge of their health to live longer, healthier lives.”
While Nesheiwat was critical of COVID mandates, she voiced more support for COVID vaccines and mask-wearing during the pandemic than her fellow nominees, leading some Trump supporters to criticize her nomination.
“A good appointment, happy about this: I got to know @DoctorJanette during the pandemic, exchanging information. She is very smart, thoughtful, interested in learning, and a compassionate doctor, and…a truly nice person,” noted vaccine researcher Peter Hotez, MD, PhD, said on X.
David J. Weldon
If confirmed, former congressman Weldon would oversee the sprawling CDC, an agency with a roughly $17 billion budget, 15,000 employees or contractors, and numerous centers covering everything from health statistics to vaccines to epidemiology.
After earning his medical degree from the University at Buffalo School of Medicine, Weldon served in the US Army and US Army reserve. The Republican later served for 14 years in Congress representing Florida’s 15th district, which covers the Tampa region.
He now practices as an internist in Brevard County, Florida.
In Congress, Weldon raised concerns about the safety of some vaccines and promoted the false narrative that a former vaccine ingredient, thimerosal, caused autism, the Washington Post reported. Thimerosal has not been used in child vaccines for more than two decades. He also introduced a bill to move vaccine safety oversight from the CDC to an independent agency within HHS.
Trump said in a statement that Weldon “will proudly restore the CDC to its true purpose, and will work to end the Chronic Disease Epidemic.”
But some physicians criticized Weldon for what they called his anti-vaccine views.
A version of this article first appeared on Medscape.com.
President-elect Donald Trump’s vision for the nation’s top health agencies is coming into focus with three nominations announced Nov. 22 that drew both criticism and praise:
- Surgeon and health researcher Martin A. Makary, MD, MPH, to lead the US Food and Drug Administration (FDA).
- Former Republican congressman and physician David J. Weldon, MD, for director of the US Centers for Disease Control and Prevention (CDC).
- Fox News contributor Janette Nesheiwat, MD, for surgeon general.
Earlier in November, Trump nominated vaccine skeptic and former presidential candidate Robert F. Kennedy Jr. to lead the US Department of Health and Human Services (HHS).
Here’s what to know about the latest nominees, who, like Kennedy, must be confirmed by the US Senate.
Martin A. Makary
Currently a professor at the Johns Hopkins School of Medicine and chief of islet transplant surgery at Johns Hopkins Hospital, Makary co-invented in 2006 a surgery checklist that became a widely-used patient safety tool.
As a US FDA commissioner, Makary would preside over a $6.5 billion agency with more than 18,000 employees. The agency, part of HHS, oversees human and animal drugs and vaccines, medical devices, food, tobacco and other products. Some of Makary’s views align closely with those of HHS nominee Kennedy.
Makary is also chief medical officer of telehealth platform Sesame.
Makary was primarily known as a health researcher and author of books about price transparency and the cost of health care until the COVID-19 pandemic, when he became an outspoken critic of the federal response, lambasting restrictions and mandates advocated by the CDC and other public health officials.
In 2023, Makary told the House Select Subcommittee on the COVID Pandemic that federal officials had ignored what he called “natural immunity.” Studies have shown that natural immunity is “at least as effective as vaccinated immunity, and probably better,” testified Makary.
Makary called for an overhaul of the US FDA in a 2021 Fox News opinion, saying that its culture was “defined by counterproductive rigidity and a refusal to adapt.”
Blind Spots, his most recent book, takes on what he calls “medical dogma” and challenges conventional views on subjects ranging from the microbiome to marijuana to cancer prevention, hormone replacement therapy, antibiotics and peanut allergies.
In an interview he posted to X, Makary blames inappropriate use of antibiotics for a variety of childhood illnesses. He cites increases in obesity, learning disabilities, attention deficit disorder, asthma, celiac disease, ulcerative colitis and Crohn’s disease as all potentially causally related to antibiotics given in childhood.
Makary is an advisor to two conservative think tanks, the Foundation for Research on Equal Opportunity, and to Paragon Health Institute, begun in 2021 by two former top officials in the previous Trump administration.
Makary would “cut the bureaucratic red tape at the agency to make sure Americans get the medical cures and treatments they deserve,” Trump said on his social media platform, Truth Social, and in a press release.
While Los Angeles Times owner and physician-entrepreneur Patrick Soon-Shiong, MBBCh, MSc, praised the nomination of Makary (and the two other nominees) as “inspired,” other physicians criticized Makary for his anti-COVID mandate views and “fear-mongering” over COVID vaccine side effects.
Janette Nesheiwat
As surgeon general, Nesheiwat would serve as the top “health communicator in chief” and oversee the 6000 member US Public Health Service Commissioned Corps.
She is a frequent medical contributor to Fox News and serves as a medical director for a group of urgent care clinics in New York. She received her medical degree from the American University of the Caribbean School of Medicine and completed a family medicine residency at the University of Arkansas for Medical Sciences. She is board-certified in family medicine.
Nesheiwat sells vitamin supplements on her website and in December will publish a book on “miracles in medicine” and her Christian faith.
Trump said in a statement that Nesheiwat “is a fierce advocate and strong communicator for preventive medicine and public health. She is committed to ensuring that Americans have access to affordable, quality healthcare, and believes in empowering individuals to take charge of their health to live longer, healthier lives.”
While Nesheiwat was critical of COVID mandates, she voiced more support for COVID vaccines and mask-wearing during the pandemic than her fellow nominees, leading some Trump supporters to criticize her nomination.
“A good appointment, happy about this: I got to know @DoctorJanette during the pandemic, exchanging information. She is very smart, thoughtful, interested in learning, and a compassionate doctor, and…a truly nice person,” noted vaccine researcher Peter Hotez, MD, PhD, said on X.
David J. Weldon
If confirmed, former congressman Weldon would oversee the sprawling CDC, an agency with a roughly $17 billion budget, 15,000 employees or contractors, and numerous centers covering everything from health statistics to vaccines to epidemiology.
After earning his medical degree from the University at Buffalo School of Medicine, Weldon served in the US Army and US Army reserve. The Republican later served for 14 years in Congress representing Florida’s 15th district, which covers the Tampa region.
He now practices as an internist in Brevard County, Florida.
In Congress, Weldon raised concerns about the safety of some vaccines and promoted the false narrative that a former vaccine ingredient, thimerosal, caused autism, the Washington Post reported. Thimerosal has not been used in child vaccines for more than two decades. He also introduced a bill to move vaccine safety oversight from the CDC to an independent agency within HHS.
Trump said in a statement that Weldon “will proudly restore the CDC to its true purpose, and will work to end the Chronic Disease Epidemic.”
But some physicians criticized Weldon for what they called his anti-vaccine views.
A version of this article first appeared on Medscape.com.
President-elect Donald Trump’s vision for the nation’s top health agencies is coming into focus with three nominations announced Nov. 22 that drew both criticism and praise:
- Surgeon and health researcher Martin A. Makary, MD, MPH, to lead the US Food and Drug Administration (FDA).
- Former Republican congressman and physician David J. Weldon, MD, for director of the US Centers for Disease Control and Prevention (CDC).
- Fox News contributor Janette Nesheiwat, MD, for surgeon general.
Earlier in November, Trump nominated vaccine skeptic and former presidential candidate Robert F. Kennedy Jr. to lead the US Department of Health and Human Services (HHS).
Here’s what to know about the latest nominees, who, like Kennedy, must be confirmed by the US Senate.
Martin A. Makary
Currently a professor at the Johns Hopkins School of Medicine and chief of islet transplant surgery at Johns Hopkins Hospital, Makary co-invented in 2006 a surgery checklist that became a widely-used patient safety tool.
As a US FDA commissioner, Makary would preside over a $6.5 billion agency with more than 18,000 employees. The agency, part of HHS, oversees human and animal drugs and vaccines, medical devices, food, tobacco and other products. Some of Makary’s views align closely with those of HHS nominee Kennedy.
Makary is also chief medical officer of telehealth platform Sesame.
Makary was primarily known as a health researcher and author of books about price transparency and the cost of health care until the COVID-19 pandemic, when he became an outspoken critic of the federal response, lambasting restrictions and mandates advocated by the CDC and other public health officials.
In 2023, Makary told the House Select Subcommittee on the COVID Pandemic that federal officials had ignored what he called “natural immunity.” Studies have shown that natural immunity is “at least as effective as vaccinated immunity, and probably better,” testified Makary.
Makary called for an overhaul of the US FDA in a 2021 Fox News opinion, saying that its culture was “defined by counterproductive rigidity and a refusal to adapt.”
Blind Spots, his most recent book, takes on what he calls “medical dogma” and challenges conventional views on subjects ranging from the microbiome to marijuana to cancer prevention, hormone replacement therapy, antibiotics and peanut allergies.
In an interview he posted to X, Makary blames inappropriate use of antibiotics for a variety of childhood illnesses. He cites increases in obesity, learning disabilities, attention deficit disorder, asthma, celiac disease, ulcerative colitis and Crohn’s disease as all potentially causally related to antibiotics given in childhood.
Makary is an advisor to two conservative think tanks, the Foundation for Research on Equal Opportunity, and to Paragon Health Institute, begun in 2021 by two former top officials in the previous Trump administration.
Makary would “cut the bureaucratic red tape at the agency to make sure Americans get the medical cures and treatments they deserve,” Trump said on his social media platform, Truth Social, and in a press release.
While Los Angeles Times owner and physician-entrepreneur Patrick Soon-Shiong, MBBCh, MSc, praised the nomination of Makary (and the two other nominees) as “inspired,” other physicians criticized Makary for his anti-COVID mandate views and “fear-mongering” over COVID vaccine side effects.
Janette Nesheiwat
As surgeon general, Nesheiwat would serve as the top “health communicator in chief” and oversee the 6000 member US Public Health Service Commissioned Corps.
She is a frequent medical contributor to Fox News and serves as a medical director for a group of urgent care clinics in New York. She received her medical degree from the American University of the Caribbean School of Medicine and completed a family medicine residency at the University of Arkansas for Medical Sciences. She is board-certified in family medicine.
Nesheiwat sells vitamin supplements on her website and in December will publish a book on “miracles in medicine” and her Christian faith.
Trump said in a statement that Nesheiwat “is a fierce advocate and strong communicator for preventive medicine and public health. She is committed to ensuring that Americans have access to affordable, quality healthcare, and believes in empowering individuals to take charge of their health to live longer, healthier lives.”
While Nesheiwat was critical of COVID mandates, she voiced more support for COVID vaccines and mask-wearing during the pandemic than her fellow nominees, leading some Trump supporters to criticize her nomination.
“A good appointment, happy about this: I got to know @DoctorJanette during the pandemic, exchanging information. She is very smart, thoughtful, interested in learning, and a compassionate doctor, and…a truly nice person,” noted vaccine researcher Peter Hotez, MD, PhD, said on X.
David J. Weldon
If confirmed, former congressman Weldon would oversee the sprawling CDC, an agency with a roughly $17 billion budget, 15,000 employees or contractors, and numerous centers covering everything from health statistics to vaccines to epidemiology.
After earning his medical degree from the University at Buffalo School of Medicine, Weldon served in the US Army and US Army reserve. The Republican later served for 14 years in Congress representing Florida’s 15th district, which covers the Tampa region.
He now practices as an internist in Brevard County, Florida.
In Congress, Weldon raised concerns about the safety of some vaccines and promoted the false narrative that a former vaccine ingredient, thimerosal, caused autism, the Washington Post reported. Thimerosal has not been used in child vaccines for more than two decades. He also introduced a bill to move vaccine safety oversight from the CDC to an independent agency within HHS.
Trump said in a statement that Weldon “will proudly restore the CDC to its true purpose, and will work to end the Chronic Disease Epidemic.”
But some physicians criticized Weldon for what they called his anti-vaccine views.
A version of this article first appeared on Medscape.com.
Spinal Cord Stimulation Promising for Chronic Back, Leg Pain
TOPLINE:
Spinal cord stimulation (SCS) therapies for chronic back and/or leg pain is superior to conventional medical management (CMM) for reduced pain intensity and functional disability, new research suggests.
METHODOLOGY:
- Researchers performed a systematic review and network meta-analysis of 13 randomized clinical trials that compared conventional and novel SCS therapies with CMM.
- More than 1500 adults with chronic back and/or leg pain and no past history of receiving SCS therapies were included.
- Novel therapies included high frequency, burst, differential target multiplexed, and closed-loop SCS; conventional therapies included tonic SCS wave forms.
- Study outcomes included pain intensity in the back and in the leg, proportion of patients achieving at least 50% pain reduction in the back and in the leg, quality of life as measured by the EuroQol-5 Dimensions (EQ-5D) index, and functional disability on the Oswestry Disability Index.
- The analysis included data from multiple follow-up points at 3, 6, 12, and 24 months, with 6-month data being those from the longest mutually reported timepoint across all outcomes.
TAKEAWAY:
- Both conventional and novel SCS therapies demonstrated superior efficacy vs CMM in pain reduction, but the novel SCS therapies were more likely to provide ≥ 50% reduction in back pain (odds ratio, 8.76; 95% credible interval [CrI], 3.84-22.31).
- Both SCS therapies showed a significant reduction in pain intensity, with novel SCS providing the greatest mean difference (MD) for back pain (–2.34; 95% CrI, –2.96 to –1.73) and lower leg pain (MD, –4.01; 95% CrI, –5.31 to –2.75).
- Quality of life improved with both types of SCS therapies, with novel SCS therapies yielding the highest MD (0.17; 95% CrI, 0.13-0.21) in EQ-5D index score.
- Conventional SCS showed greater improvement in functionality vs CMM, yielding the lowest MD (–7.10; 95% CrI, –10.91 to –3.36) in Oswestry Disability Index score.
IN PRACTICE:
“We found that SCS was associated with improved pain and QOL [quality of life] and reduced disability, compared with CMM, after 6 months of follow-up. These findings highlight the potential of SCS therapies as an effective and valuable option in chronic pain management,” the investigators wrote.
SOURCE:
The study was led by Frank J.P.M. Huygen, PhD, MD, Erasmus Medical Center, Rotterdam, the Netherlands. It was published online in JAMA Network Open.
LIMITATIONS:
The lack of randomized clinical trials with long-term follow-up data restricted the inclusion of extended outcome assessments. Most included studies showed a high risk for bias. Safety estimates could not be evaluated as adverse events were only reported as procedure-related outcomes, which are not applicable for CMM. Additionally, the network meta-analytical approach, which combined evidence from studies with varying patient eligibility criteria, may have introduced bias because of between-study heterogeneity.
DISCLOSURES:
This study was funded by Medtronic. Huygen reported receiving personal fees from Abbott, Saluda, and Grunenthal outside the submitted work. The four other authors reported receiving funding from Medtronic.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Spinal cord stimulation (SCS) therapies for chronic back and/or leg pain is superior to conventional medical management (CMM) for reduced pain intensity and functional disability, new research suggests.
METHODOLOGY:
- Researchers performed a systematic review and network meta-analysis of 13 randomized clinical trials that compared conventional and novel SCS therapies with CMM.
- More than 1500 adults with chronic back and/or leg pain and no past history of receiving SCS therapies were included.
- Novel therapies included high frequency, burst, differential target multiplexed, and closed-loop SCS; conventional therapies included tonic SCS wave forms.
- Study outcomes included pain intensity in the back and in the leg, proportion of patients achieving at least 50% pain reduction in the back and in the leg, quality of life as measured by the EuroQol-5 Dimensions (EQ-5D) index, and functional disability on the Oswestry Disability Index.
- The analysis included data from multiple follow-up points at 3, 6, 12, and 24 months, with 6-month data being those from the longest mutually reported timepoint across all outcomes.
TAKEAWAY:
- Both conventional and novel SCS therapies demonstrated superior efficacy vs CMM in pain reduction, but the novel SCS therapies were more likely to provide ≥ 50% reduction in back pain (odds ratio, 8.76; 95% credible interval [CrI], 3.84-22.31).
- Both SCS therapies showed a significant reduction in pain intensity, with novel SCS providing the greatest mean difference (MD) for back pain (–2.34; 95% CrI, –2.96 to –1.73) and lower leg pain (MD, –4.01; 95% CrI, –5.31 to –2.75).
- Quality of life improved with both types of SCS therapies, with novel SCS therapies yielding the highest MD (0.17; 95% CrI, 0.13-0.21) in EQ-5D index score.
- Conventional SCS showed greater improvement in functionality vs CMM, yielding the lowest MD (–7.10; 95% CrI, –10.91 to –3.36) in Oswestry Disability Index score.
IN PRACTICE:
“We found that SCS was associated with improved pain and QOL [quality of life] and reduced disability, compared with CMM, after 6 months of follow-up. These findings highlight the potential of SCS therapies as an effective and valuable option in chronic pain management,” the investigators wrote.
SOURCE:
The study was led by Frank J.P.M. Huygen, PhD, MD, Erasmus Medical Center, Rotterdam, the Netherlands. It was published online in JAMA Network Open.
LIMITATIONS:
The lack of randomized clinical trials with long-term follow-up data restricted the inclusion of extended outcome assessments. Most included studies showed a high risk for bias. Safety estimates could not be evaluated as adverse events were only reported as procedure-related outcomes, which are not applicable for CMM. Additionally, the network meta-analytical approach, which combined evidence from studies with varying patient eligibility criteria, may have introduced bias because of between-study heterogeneity.
DISCLOSURES:
This study was funded by Medtronic. Huygen reported receiving personal fees from Abbott, Saluda, and Grunenthal outside the submitted work. The four other authors reported receiving funding from Medtronic.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Spinal cord stimulation (SCS) therapies for chronic back and/or leg pain is superior to conventional medical management (CMM) for reduced pain intensity and functional disability, new research suggests.
METHODOLOGY:
- Researchers performed a systematic review and network meta-analysis of 13 randomized clinical trials that compared conventional and novel SCS therapies with CMM.
- More than 1500 adults with chronic back and/or leg pain and no past history of receiving SCS therapies were included.
- Novel therapies included high frequency, burst, differential target multiplexed, and closed-loop SCS; conventional therapies included tonic SCS wave forms.
- Study outcomes included pain intensity in the back and in the leg, proportion of patients achieving at least 50% pain reduction in the back and in the leg, quality of life as measured by the EuroQol-5 Dimensions (EQ-5D) index, and functional disability on the Oswestry Disability Index.
- The analysis included data from multiple follow-up points at 3, 6, 12, and 24 months, with 6-month data being those from the longest mutually reported timepoint across all outcomes.
TAKEAWAY:
- Both conventional and novel SCS therapies demonstrated superior efficacy vs CMM in pain reduction, but the novel SCS therapies were more likely to provide ≥ 50% reduction in back pain (odds ratio, 8.76; 95% credible interval [CrI], 3.84-22.31).
- Both SCS therapies showed a significant reduction in pain intensity, with novel SCS providing the greatest mean difference (MD) for back pain (–2.34; 95% CrI, –2.96 to –1.73) and lower leg pain (MD, –4.01; 95% CrI, –5.31 to –2.75).
- Quality of life improved with both types of SCS therapies, with novel SCS therapies yielding the highest MD (0.17; 95% CrI, 0.13-0.21) in EQ-5D index score.
- Conventional SCS showed greater improvement in functionality vs CMM, yielding the lowest MD (–7.10; 95% CrI, –10.91 to –3.36) in Oswestry Disability Index score.
IN PRACTICE:
“We found that SCS was associated with improved pain and QOL [quality of life] and reduced disability, compared with CMM, after 6 months of follow-up. These findings highlight the potential of SCS therapies as an effective and valuable option in chronic pain management,” the investigators wrote.
SOURCE:
The study was led by Frank J.P.M. Huygen, PhD, MD, Erasmus Medical Center, Rotterdam, the Netherlands. It was published online in JAMA Network Open.
LIMITATIONS:
The lack of randomized clinical trials with long-term follow-up data restricted the inclusion of extended outcome assessments. Most included studies showed a high risk for bias. Safety estimates could not be evaluated as adverse events were only reported as procedure-related outcomes, which are not applicable for CMM. Additionally, the network meta-analytical approach, which combined evidence from studies with varying patient eligibility criteria, may have introduced bias because of between-study heterogeneity.
DISCLOSURES:
This study was funded by Medtronic. Huygen reported receiving personal fees from Abbott, Saluda, and Grunenthal outside the submitted work. The four other authors reported receiving funding from Medtronic.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Three Vascular Risk Factors May Up Severe Stroke Risk
TOPLINE:
, a global study shows.
METHODOLOGY:
- The INTERSTROKE case-control study included nearly 27,000 participants, half of whom had a first acute stroke (ischemic or hemorrhagic) and the other half acting as age- and sex-matched controls.
- Participants (mean age, 62 years; 40% women) were recruited across 142 centers in 32 countries between 2007 and 2015. Baseline demographics and lifestyle risk factors for stroke were gathered using standardized questionnaires
- Modified Rankin Scale (mRS) scores measured within 72 hours of hospital admission were used to classify stroke severity (0-3, nonsevere stroke; 4-6, severe stroke).
TAKEAWAY:
- Among the participants with acute stroke, 64% had nonsevere stroke and 36% had severe stroke, based on the mRS.
- Hypertension, atrial fibrillation, and smoking showed a significantly stronger association with severe stroke than with nonsevere stroke (odds ratios [ORs], 3.21 vs 2.87, 4.70 vs 3.61, and 1.87 vs 1.65, respectively; all P < .001).
- A high waist-to-hip ratio showed a stronger association with nonsevere stroke than with severe stroke (OR, 1.37 vs 1.11, respectively; P < .001).
- Diabetes, poor diet, physical inactivity, and stress were linked to increased odds of both severe and nonsevere stroke, whereas alcohol consumption and high apolipoprotein B levels were linked to higher odds of only nonsevere stroke. No significant differences in odds were observed between stroke severities in matched individuals.
IN PRACTICE:
“Our findings emphasize the importance of controlling high blood pressure, which is the most important modifiable risk factor for stroke globally,” lead author Catriona Reddin, MB BCh, BAO, MSc, School of Medicine, University of Galway, in Ireland, said in a press release.
SOURCE:
The study was published online in Neurology.
LIMITATIONS:
The study limitations included potential unmeasured confounders; reliance on the mRS score, which may have underestimated stroke severity; and challenges with recruiting patients with severe stroke in a case-control study. Smoking-related comorbidities and regional or sex-related variations in alcohol intake may also have influenced the results.
DISCLOSURES:
The study was funded by various organizations, including health research councils and foundations from Canada, Sweden, and Scotland, and pharmaceutical companies such as AstraZeneca, Boehringer Ingelheim, Pfizer, and MSD. One investigator reported receiving funding from the Irish Clinical Academic Training Programme, the Wellcome Trust and the Health Research Board, the Health Service Executive, National Doctors Training and Planning, and the Health and Social Care, Research and Development Division in Northern Ireland. No other conflicts of interest were reported.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
, a global study shows.
METHODOLOGY:
- The INTERSTROKE case-control study included nearly 27,000 participants, half of whom had a first acute stroke (ischemic or hemorrhagic) and the other half acting as age- and sex-matched controls.
- Participants (mean age, 62 years; 40% women) were recruited across 142 centers in 32 countries between 2007 and 2015. Baseline demographics and lifestyle risk factors for stroke were gathered using standardized questionnaires
- Modified Rankin Scale (mRS) scores measured within 72 hours of hospital admission were used to classify stroke severity (0-3, nonsevere stroke; 4-6, severe stroke).
TAKEAWAY:
- Among the participants with acute stroke, 64% had nonsevere stroke and 36% had severe stroke, based on the mRS.
- Hypertension, atrial fibrillation, and smoking showed a significantly stronger association with severe stroke than with nonsevere stroke (odds ratios [ORs], 3.21 vs 2.87, 4.70 vs 3.61, and 1.87 vs 1.65, respectively; all P < .001).
- A high waist-to-hip ratio showed a stronger association with nonsevere stroke than with severe stroke (OR, 1.37 vs 1.11, respectively; P < .001).
- Diabetes, poor diet, physical inactivity, and stress were linked to increased odds of both severe and nonsevere stroke, whereas alcohol consumption and high apolipoprotein B levels were linked to higher odds of only nonsevere stroke. No significant differences in odds were observed between stroke severities in matched individuals.
IN PRACTICE:
“Our findings emphasize the importance of controlling high blood pressure, which is the most important modifiable risk factor for stroke globally,” lead author Catriona Reddin, MB BCh, BAO, MSc, School of Medicine, University of Galway, in Ireland, said in a press release.
SOURCE:
The study was published online in Neurology.
LIMITATIONS:
The study limitations included potential unmeasured confounders; reliance on the mRS score, which may have underestimated stroke severity; and challenges with recruiting patients with severe stroke in a case-control study. Smoking-related comorbidities and regional or sex-related variations in alcohol intake may also have influenced the results.
DISCLOSURES:
The study was funded by various organizations, including health research councils and foundations from Canada, Sweden, and Scotland, and pharmaceutical companies such as AstraZeneca, Boehringer Ingelheim, Pfizer, and MSD. One investigator reported receiving funding from the Irish Clinical Academic Training Programme, the Wellcome Trust and the Health Research Board, the Health Service Executive, National Doctors Training and Planning, and the Health and Social Care, Research and Development Division in Northern Ireland. No other conflicts of interest were reported.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
, a global study shows.
METHODOLOGY:
- The INTERSTROKE case-control study included nearly 27,000 participants, half of whom had a first acute stroke (ischemic or hemorrhagic) and the other half acting as age- and sex-matched controls.
- Participants (mean age, 62 years; 40% women) were recruited across 142 centers in 32 countries between 2007 and 2015. Baseline demographics and lifestyle risk factors for stroke were gathered using standardized questionnaires
- Modified Rankin Scale (mRS) scores measured within 72 hours of hospital admission were used to classify stroke severity (0-3, nonsevere stroke; 4-6, severe stroke).
TAKEAWAY:
- Among the participants with acute stroke, 64% had nonsevere stroke and 36% had severe stroke, based on the mRS.
- Hypertension, atrial fibrillation, and smoking showed a significantly stronger association with severe stroke than with nonsevere stroke (odds ratios [ORs], 3.21 vs 2.87, 4.70 vs 3.61, and 1.87 vs 1.65, respectively; all P < .001).
- A high waist-to-hip ratio showed a stronger association with nonsevere stroke than with severe stroke (OR, 1.37 vs 1.11, respectively; P < .001).
- Diabetes, poor diet, physical inactivity, and stress were linked to increased odds of both severe and nonsevere stroke, whereas alcohol consumption and high apolipoprotein B levels were linked to higher odds of only nonsevere stroke. No significant differences in odds were observed between stroke severities in matched individuals.
IN PRACTICE:
“Our findings emphasize the importance of controlling high blood pressure, which is the most important modifiable risk factor for stroke globally,” lead author Catriona Reddin, MB BCh, BAO, MSc, School of Medicine, University of Galway, in Ireland, said in a press release.
SOURCE:
The study was published online in Neurology.
LIMITATIONS:
The study limitations included potential unmeasured confounders; reliance on the mRS score, which may have underestimated stroke severity; and challenges with recruiting patients with severe stroke in a case-control study. Smoking-related comorbidities and regional or sex-related variations in alcohol intake may also have influenced the results.
DISCLOSURES:
The study was funded by various organizations, including health research councils and foundations from Canada, Sweden, and Scotland, and pharmaceutical companies such as AstraZeneca, Boehringer Ingelheim, Pfizer, and MSD. One investigator reported receiving funding from the Irish Clinical Academic Training Programme, the Wellcome Trust and the Health Research Board, the Health Service Executive, National Doctors Training and Planning, and the Health and Social Care, Research and Development Division in Northern Ireland. No other conflicts of interest were reported.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Food as Medicine: Diet’s Role in Parkinson’s Disease
For 15 years, John Duda, MD, national director of the VA Parkinson’s Disease Research, Education and Clinical Centers, has urged his patients to “keep waiting” for effective treatments to manage both motor and nonmotor symptoms of Parkinson’s disease.
However, Duda, who also serves as director of the Brain Wellness Clinic at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania, recognized the persistent lack of effective drugs to address these symptoms. This prompted him to consider what other evidence-based strategies he could use to support his patients.
“I recognized that nutritional approaches within a broader program that includes medication review, stress management, social connections, adequate sleep, and physical exercise could make a real difference,” he said.
Observational studies have shown an inverse association between dietary patterns and Parkinson’s disease risk, age of onset, symptom severity, and mortality rates — particularly with the Mediterranean diet (MeDi) and the MIND diet, which combines elements of MeDi and the Dietary Approaches to Stop Hypertension (DASH) diet. Although randomized controlled trials are still limited, the epidemiologic evidence supporting dietary interventions is “compelling,” said Duda.
For example, a cross-sectional study comparing 167 participants with Parkinson’s disease vs 119 controls showed that later age of Parkinson’s disease onset correlated with adherence to the MIND diet in women, with a difference of up to 17.4 years (P < .001) between low and high dietary tertiles.
The MeDi was correlated with later onset in men, with differences of up to 8.4 years (P = .002). As previously reported, a healthy diet emphasizing vegetables, fruits, nuts, and grains was inversely associated with prodromal features of Parkinson’s disease, including constipation, excessive daytime sleepiness, and depression. In addition, lower rates of Parkinson’s disease have been shown in populations following vegetarian and vegan dietary patterns.
Does Parkinson’s disease Start in the Gut?
Parkinson’s disease is characterized by decreased short-chain fatty acid–producing bacteria and increased pro-inflammatory species linked to intestinal inflammation and alpha-synuclein aggregation. “There are reasons to believe that a-synuclein accumulation may start in the gut,” Duda noted.
Numerous studies implicate gut microbiome dysbiosis as a pathogenic mechanism in Parkinson’s disease, with gastrointestinal symptoms often predating motor symptoms. Dysbiosis might result in a pro-inflammatory state potentially linked to the recurrent gastrointestinal symptoms. Fecal microbiota transplant may restore a healthier gut environment and beneficially affect Parkinson’s disease symptoms, he said.
Some of the benefits conferred by the MeDi and other healthy diets may be mediated by improving the gut microbiome. Duda cited a study that showed that a 14-day ovo-lacto vegetarian diet intervention and a daily fecal enema for 8 days improved not only the microbiome but also Movement Disorder Society Unified Parkinson’s Disease Rating Scale—part III scores.
Duda also reviewed the role of dietary interventions in addressing common Parkinson’s disease symptoms, such as orthostatic hypotension. He recommended that Parkinson’s disease patients with this condition should avoid eating large meals, increase dietary salt intake, increase fluid intake, and decrease alcohol intake.
Malnutrition affects close to 25% of those with Parkinson’s disease, which is partially attributable to diminished olfaction. Because the experience of taste is largely driven by a sense of smell, patients may be less interested in eating. Duda recommended increasing herbs, spices, and other flavors in food. High caloric–density foods, including nuts, nut butters, and seeds, can boost weight, he said. However, he added, any patient with significant weight loss should consult a nutritionist.
Constipation is one of the most debilitating symptoms of Parkinson’s disease, affecting up to 66% of patients. Duda advised increasing fluid intake, exercise, and dietary fiber and use of stool softeners and laxatives. The MeDi may reduce symptoms of constipation and have a beneficial effect on gut microbiota.
Coffee may be helpful for sleepiness in Parkinson’s disease and may also confer neuroprotective, motor, and cognitive benefits. As an adjuvant treatment, caffeine may alter levodopa pharmacokinetics, reduce dyskinesia, improve gait in patients with freezing and may even reduce the risk of developing Parkinson’s disease, with a maximum benefit reached at approximately three cups of coffee daily.
Problematic Foods
There is also a growing body of evidence regarding the deleterious effects of ultraprocessed foods (UPFs), Duda said. He noted that a recent systematic review and meta-analysis of 28 studies showed that higher UPF intake was significantly associated with an enhanced risk for Parkinson’s disease (relative risk, 1.56; 95% CI, 1.21-2.02). As previously reported, UPFs have been tied to a host of adverse neurologic outcomes, including cognitive decline and stroke.
Although protein is a necessary nutrient, incorporating it into the diet of Parkinson’s disease patients taking levodopa is complicated. Levodopa, a large neutral amino acid (LNAA), competes with other LNAAs for transport to the brain from the small intestine, Duda explained.
“Some people notice that carbidopa-levodopa doesn’t work as well if taken with a high-protein meal.” He recommended taking carbidopa-levodopa 30 minutes before or 60 minutes after meals.
Rebecca Gilbert, MD, PhD, chief mission officer of the American Parkinson’s Disease Association, said that patients with Parkinson’s disease might want to avoid eating protein during the day, concentrating instead on carbohydrates and vegetables and saving the protein for the evening, which is closer to bedtime. Some evidence also supports the use of protein redistribution diets to enhance the clinical response to levodopa and reduce motor fluctuations.
What About Supplements?
It’s “hard to prove that one specific supplement can be protective against Parkinson’s disease because diet consists of many different components and the whole diet may be worth more than the sum of its parts,” Gilbert said. The evidence for individual supplements “isn’t robust enough to say they prevent or treat Parkinson’s disease.”
Research on the role of specific nutrients in Parkinson’s disease is conflicting, with no clear evidence supporting or refuting their benefits. For example, a study that followed participants for about 30 years showed no link between reduced Parkinson’s disease risk and vitamin B or folate intake.
On the other hand, there is research suggesting that certain vitamins may help reduce Parkinson’s disease risk, although these nutrients do not operate in isolation. For instance, one recent study showed a connection between vitamins C and E and reduced Parkinson’s disease risk, but factors such as body mass index and coffee consumption appeared to influence the strength of this association.
Consuming polyunsaturated fatty acids along with reducing saturated fatty acid intake has been tied to a reduced risk for Parkinson’s disease.
Additionally, certain foods may offer protective effects, including green and black tea, with consumption of three or more cups per day associated with a delay in motor symptom onset by 7.7 years. Foods high in nicotine content, such as those from the Solanaceae family — including peppers, tomatoes, tomato juice, and potatoes — have also been linked to potential protective benefits.
Diets rich in antioxidants, including carotenoids, lutein, and vitamins E and C, have been robustly linked to a reduced risk for parkinsonism and progression of parkinsonian symptoms in older adults.
Increasing the intake of dietary flavonoids, particularly tea, berry fruits, apples, red wine, and oranges or orange juice, can reduce Parkinson’s disease risk. One study showed that male participants in the highest quintile of total flavonoid consumption had a 40% lower Parkinson’s disease risk compared with those in the lowest quintile. Another study showed that flavonoid-rich foods were also associated with a lower risk for death in patients with Parkinson’s disease.
Food as Medicine
Although recent research shows that the drug development pipeline for Parkinson’s disease is robust, with a wide variety of approaches being developed and evaluated in phase 1 and 2, investigators note that only a limited number of disease-modifying treatments are transitioning to phase 3.
Duda noted that phytochemicals incorporated into the diet might target some of the same mechanisms that are targets of these drugs in development.
“Flavonoids have been shown to stabilize alpha-synuclein in vitro,” he said. “Caffeine, curcumin, resveratrol, and eliminating meat and dairy inhibit mTOR [mammalian target of rapamycin], and mTOR inhibition results in increased autophagy that may help clear alpha-synuclein. Genestein, an isoflavone in soybeans, protects dopaminergic neurons by inhibiting microglia activation. Flavonoids inhibit inflammation by inhibiting release of NO [nitric oxide] and pro-inflammatory cytokines,” he noted.
Ongoing studies of dietary interventions for Parkinson’s disease are exploring various areas, including the potential role of the ketogenic diet in protecting the gut microbiome, optimizing protein intake for muscle preservation and sleep, the effects of psyllium and wheat bran on weight and constipation, and the impact of a gluten-free diet.
Practical Tips for Healthy Eating
Gilbert emphasized that there are no medications or interventions currently available that can delay a Parkinson’s disease diagnosis by up to 17 years, as some dietary patterns have been shown to do, and she noted that it’s not possible to replicate the MeDi diet in a pill. However, she recommended a practical approach to eating that includes a diet low in ultraprocessed foods and high in beneficial nutrients. She encouraged people to shop for “real food” and enjoy a variety of colorful fruits and vegetables.
Duda acknowledged that motivating patients to follow a healthy diet can be difficult. As a result, the focus often shifts to making small adjustments and modifications. For example, he suggested that instead of pairing meat with French fries, people could opt for vegetables or add greens to their meals. Similarly, instead of having eggs and bacon for breakfast, they might choose oatmeal.
Preparing whole-food, plant-based meals may take more time than patients are accustomed to, so Duda suggests that, if possible, patients involve loved ones in both the meal preparation and the meal itself. He explained that a healthy meal can become an opportunity for bonding and that the key is educating them about new meal-related concepts.
Duda reported no relevant financial relationships with the pharmaceutical or food industries. He has received compensation from the Physicians Committee for Responsible Medicine for his lecture delivered at the conference and research grant support from the VA, the National Institutes of Health, the Michael J. Fox Foundation, and the Department of Defense unrelated to this topic. Gilbert reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
For 15 years, John Duda, MD, national director of the VA Parkinson’s Disease Research, Education and Clinical Centers, has urged his patients to “keep waiting” for effective treatments to manage both motor and nonmotor symptoms of Parkinson’s disease.
However, Duda, who also serves as director of the Brain Wellness Clinic at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania, recognized the persistent lack of effective drugs to address these symptoms. This prompted him to consider what other evidence-based strategies he could use to support his patients.
“I recognized that nutritional approaches within a broader program that includes medication review, stress management, social connections, adequate sleep, and physical exercise could make a real difference,” he said.
Observational studies have shown an inverse association between dietary patterns and Parkinson’s disease risk, age of onset, symptom severity, and mortality rates — particularly with the Mediterranean diet (MeDi) and the MIND diet, which combines elements of MeDi and the Dietary Approaches to Stop Hypertension (DASH) diet. Although randomized controlled trials are still limited, the epidemiologic evidence supporting dietary interventions is “compelling,” said Duda.
For example, a cross-sectional study comparing 167 participants with Parkinson’s disease vs 119 controls showed that later age of Parkinson’s disease onset correlated with adherence to the MIND diet in women, with a difference of up to 17.4 years (P < .001) between low and high dietary tertiles.
The MeDi was correlated with later onset in men, with differences of up to 8.4 years (P = .002). As previously reported, a healthy diet emphasizing vegetables, fruits, nuts, and grains was inversely associated with prodromal features of Parkinson’s disease, including constipation, excessive daytime sleepiness, and depression. In addition, lower rates of Parkinson’s disease have been shown in populations following vegetarian and vegan dietary patterns.
Does Parkinson’s disease Start in the Gut?
Parkinson’s disease is characterized by decreased short-chain fatty acid–producing bacteria and increased pro-inflammatory species linked to intestinal inflammation and alpha-synuclein aggregation. “There are reasons to believe that a-synuclein accumulation may start in the gut,” Duda noted.
Numerous studies implicate gut microbiome dysbiosis as a pathogenic mechanism in Parkinson’s disease, with gastrointestinal symptoms often predating motor symptoms. Dysbiosis might result in a pro-inflammatory state potentially linked to the recurrent gastrointestinal symptoms. Fecal microbiota transplant may restore a healthier gut environment and beneficially affect Parkinson’s disease symptoms, he said.
Some of the benefits conferred by the MeDi and other healthy diets may be mediated by improving the gut microbiome. Duda cited a study that showed that a 14-day ovo-lacto vegetarian diet intervention and a daily fecal enema for 8 days improved not only the microbiome but also Movement Disorder Society Unified Parkinson’s Disease Rating Scale—part III scores.
Duda also reviewed the role of dietary interventions in addressing common Parkinson’s disease symptoms, such as orthostatic hypotension. He recommended that Parkinson’s disease patients with this condition should avoid eating large meals, increase dietary salt intake, increase fluid intake, and decrease alcohol intake.
Malnutrition affects close to 25% of those with Parkinson’s disease, which is partially attributable to diminished olfaction. Because the experience of taste is largely driven by a sense of smell, patients may be less interested in eating. Duda recommended increasing herbs, spices, and other flavors in food. High caloric–density foods, including nuts, nut butters, and seeds, can boost weight, he said. However, he added, any patient with significant weight loss should consult a nutritionist.
Constipation is one of the most debilitating symptoms of Parkinson’s disease, affecting up to 66% of patients. Duda advised increasing fluid intake, exercise, and dietary fiber and use of stool softeners and laxatives. The MeDi may reduce symptoms of constipation and have a beneficial effect on gut microbiota.
Coffee may be helpful for sleepiness in Parkinson’s disease and may also confer neuroprotective, motor, and cognitive benefits. As an adjuvant treatment, caffeine may alter levodopa pharmacokinetics, reduce dyskinesia, improve gait in patients with freezing and may even reduce the risk of developing Parkinson’s disease, with a maximum benefit reached at approximately three cups of coffee daily.
Problematic Foods
There is also a growing body of evidence regarding the deleterious effects of ultraprocessed foods (UPFs), Duda said. He noted that a recent systematic review and meta-analysis of 28 studies showed that higher UPF intake was significantly associated with an enhanced risk for Parkinson’s disease (relative risk, 1.56; 95% CI, 1.21-2.02). As previously reported, UPFs have been tied to a host of adverse neurologic outcomes, including cognitive decline and stroke.
Although protein is a necessary nutrient, incorporating it into the diet of Parkinson’s disease patients taking levodopa is complicated. Levodopa, a large neutral amino acid (LNAA), competes with other LNAAs for transport to the brain from the small intestine, Duda explained.
“Some people notice that carbidopa-levodopa doesn’t work as well if taken with a high-protein meal.” He recommended taking carbidopa-levodopa 30 minutes before or 60 minutes after meals.
Rebecca Gilbert, MD, PhD, chief mission officer of the American Parkinson’s Disease Association, said that patients with Parkinson’s disease might want to avoid eating protein during the day, concentrating instead on carbohydrates and vegetables and saving the protein for the evening, which is closer to bedtime. Some evidence also supports the use of protein redistribution diets to enhance the clinical response to levodopa and reduce motor fluctuations.
What About Supplements?
It’s “hard to prove that one specific supplement can be protective against Parkinson’s disease because diet consists of many different components and the whole diet may be worth more than the sum of its parts,” Gilbert said. The evidence for individual supplements “isn’t robust enough to say they prevent or treat Parkinson’s disease.”
Research on the role of specific nutrients in Parkinson’s disease is conflicting, with no clear evidence supporting or refuting their benefits. For example, a study that followed participants for about 30 years showed no link between reduced Parkinson’s disease risk and vitamin B or folate intake.
On the other hand, there is research suggesting that certain vitamins may help reduce Parkinson’s disease risk, although these nutrients do not operate in isolation. For instance, one recent study showed a connection between vitamins C and E and reduced Parkinson’s disease risk, but factors such as body mass index and coffee consumption appeared to influence the strength of this association.
Consuming polyunsaturated fatty acids along with reducing saturated fatty acid intake has been tied to a reduced risk for Parkinson’s disease.
Additionally, certain foods may offer protective effects, including green and black tea, with consumption of three or more cups per day associated with a delay in motor symptom onset by 7.7 years. Foods high in nicotine content, such as those from the Solanaceae family — including peppers, tomatoes, tomato juice, and potatoes — have also been linked to potential protective benefits.
Diets rich in antioxidants, including carotenoids, lutein, and vitamins E and C, have been robustly linked to a reduced risk for parkinsonism and progression of parkinsonian symptoms in older adults.
Increasing the intake of dietary flavonoids, particularly tea, berry fruits, apples, red wine, and oranges or orange juice, can reduce Parkinson’s disease risk. One study showed that male participants in the highest quintile of total flavonoid consumption had a 40% lower Parkinson’s disease risk compared with those in the lowest quintile. Another study showed that flavonoid-rich foods were also associated with a lower risk for death in patients with Parkinson’s disease.
Food as Medicine
Although recent research shows that the drug development pipeline for Parkinson’s disease is robust, with a wide variety of approaches being developed and evaluated in phase 1 and 2, investigators note that only a limited number of disease-modifying treatments are transitioning to phase 3.
Duda noted that phytochemicals incorporated into the diet might target some of the same mechanisms that are targets of these drugs in development.
“Flavonoids have been shown to stabilize alpha-synuclein in vitro,” he said. “Caffeine, curcumin, resveratrol, and eliminating meat and dairy inhibit mTOR [mammalian target of rapamycin], and mTOR inhibition results in increased autophagy that may help clear alpha-synuclein. Genestein, an isoflavone in soybeans, protects dopaminergic neurons by inhibiting microglia activation. Flavonoids inhibit inflammation by inhibiting release of NO [nitric oxide] and pro-inflammatory cytokines,” he noted.
Ongoing studies of dietary interventions for Parkinson’s disease are exploring various areas, including the potential role of the ketogenic diet in protecting the gut microbiome, optimizing protein intake for muscle preservation and sleep, the effects of psyllium and wheat bran on weight and constipation, and the impact of a gluten-free diet.
Practical Tips for Healthy Eating
Gilbert emphasized that there are no medications or interventions currently available that can delay a Parkinson’s disease diagnosis by up to 17 years, as some dietary patterns have been shown to do, and she noted that it’s not possible to replicate the MeDi diet in a pill. However, she recommended a practical approach to eating that includes a diet low in ultraprocessed foods and high in beneficial nutrients. She encouraged people to shop for “real food” and enjoy a variety of colorful fruits and vegetables.
Duda acknowledged that motivating patients to follow a healthy diet can be difficult. As a result, the focus often shifts to making small adjustments and modifications. For example, he suggested that instead of pairing meat with French fries, people could opt for vegetables or add greens to their meals. Similarly, instead of having eggs and bacon for breakfast, they might choose oatmeal.
Preparing whole-food, plant-based meals may take more time than patients are accustomed to, so Duda suggests that, if possible, patients involve loved ones in both the meal preparation and the meal itself. He explained that a healthy meal can become an opportunity for bonding and that the key is educating them about new meal-related concepts.
Duda reported no relevant financial relationships with the pharmaceutical or food industries. He has received compensation from the Physicians Committee for Responsible Medicine for his lecture delivered at the conference and research grant support from the VA, the National Institutes of Health, the Michael J. Fox Foundation, and the Department of Defense unrelated to this topic. Gilbert reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
For 15 years, John Duda, MD, national director of the VA Parkinson’s Disease Research, Education and Clinical Centers, has urged his patients to “keep waiting” for effective treatments to manage both motor and nonmotor symptoms of Parkinson’s disease.
However, Duda, who also serves as director of the Brain Wellness Clinic at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania, recognized the persistent lack of effective drugs to address these symptoms. This prompted him to consider what other evidence-based strategies he could use to support his patients.
“I recognized that nutritional approaches within a broader program that includes medication review, stress management, social connections, adequate sleep, and physical exercise could make a real difference,” he said.
Observational studies have shown an inverse association between dietary patterns and Parkinson’s disease risk, age of onset, symptom severity, and mortality rates — particularly with the Mediterranean diet (MeDi) and the MIND diet, which combines elements of MeDi and the Dietary Approaches to Stop Hypertension (DASH) diet. Although randomized controlled trials are still limited, the epidemiologic evidence supporting dietary interventions is “compelling,” said Duda.
For example, a cross-sectional study comparing 167 participants with Parkinson’s disease vs 119 controls showed that later age of Parkinson’s disease onset correlated with adherence to the MIND diet in women, with a difference of up to 17.4 years (P < .001) between low and high dietary tertiles.
The MeDi was correlated with later onset in men, with differences of up to 8.4 years (P = .002). As previously reported, a healthy diet emphasizing vegetables, fruits, nuts, and grains was inversely associated with prodromal features of Parkinson’s disease, including constipation, excessive daytime sleepiness, and depression. In addition, lower rates of Parkinson’s disease have been shown in populations following vegetarian and vegan dietary patterns.
Does Parkinson’s disease Start in the Gut?
Parkinson’s disease is characterized by decreased short-chain fatty acid–producing bacteria and increased pro-inflammatory species linked to intestinal inflammation and alpha-synuclein aggregation. “There are reasons to believe that a-synuclein accumulation may start in the gut,” Duda noted.
Numerous studies implicate gut microbiome dysbiosis as a pathogenic mechanism in Parkinson’s disease, with gastrointestinal symptoms often predating motor symptoms. Dysbiosis might result in a pro-inflammatory state potentially linked to the recurrent gastrointestinal symptoms. Fecal microbiota transplant may restore a healthier gut environment and beneficially affect Parkinson’s disease symptoms, he said.
Some of the benefits conferred by the MeDi and other healthy diets may be mediated by improving the gut microbiome. Duda cited a study that showed that a 14-day ovo-lacto vegetarian diet intervention and a daily fecal enema for 8 days improved not only the microbiome but also Movement Disorder Society Unified Parkinson’s Disease Rating Scale—part III scores.
Duda also reviewed the role of dietary interventions in addressing common Parkinson’s disease symptoms, such as orthostatic hypotension. He recommended that Parkinson’s disease patients with this condition should avoid eating large meals, increase dietary salt intake, increase fluid intake, and decrease alcohol intake.
Malnutrition affects close to 25% of those with Parkinson’s disease, which is partially attributable to diminished olfaction. Because the experience of taste is largely driven by a sense of smell, patients may be less interested in eating. Duda recommended increasing herbs, spices, and other flavors in food. High caloric–density foods, including nuts, nut butters, and seeds, can boost weight, he said. However, he added, any patient with significant weight loss should consult a nutritionist.
Constipation is one of the most debilitating symptoms of Parkinson’s disease, affecting up to 66% of patients. Duda advised increasing fluid intake, exercise, and dietary fiber and use of stool softeners and laxatives. The MeDi may reduce symptoms of constipation and have a beneficial effect on gut microbiota.
Coffee may be helpful for sleepiness in Parkinson’s disease and may also confer neuroprotective, motor, and cognitive benefits. As an adjuvant treatment, caffeine may alter levodopa pharmacokinetics, reduce dyskinesia, improve gait in patients with freezing and may even reduce the risk of developing Parkinson’s disease, with a maximum benefit reached at approximately three cups of coffee daily.
Problematic Foods
There is also a growing body of evidence regarding the deleterious effects of ultraprocessed foods (UPFs), Duda said. He noted that a recent systematic review and meta-analysis of 28 studies showed that higher UPF intake was significantly associated with an enhanced risk for Parkinson’s disease (relative risk, 1.56; 95% CI, 1.21-2.02). As previously reported, UPFs have been tied to a host of adverse neurologic outcomes, including cognitive decline and stroke.
Although protein is a necessary nutrient, incorporating it into the diet of Parkinson’s disease patients taking levodopa is complicated. Levodopa, a large neutral amino acid (LNAA), competes with other LNAAs for transport to the brain from the small intestine, Duda explained.
“Some people notice that carbidopa-levodopa doesn’t work as well if taken with a high-protein meal.” He recommended taking carbidopa-levodopa 30 minutes before or 60 minutes after meals.
Rebecca Gilbert, MD, PhD, chief mission officer of the American Parkinson’s Disease Association, said that patients with Parkinson’s disease might want to avoid eating protein during the day, concentrating instead on carbohydrates and vegetables and saving the protein for the evening, which is closer to bedtime. Some evidence also supports the use of protein redistribution diets to enhance the clinical response to levodopa and reduce motor fluctuations.
What About Supplements?
It’s “hard to prove that one specific supplement can be protective against Parkinson’s disease because diet consists of many different components and the whole diet may be worth more than the sum of its parts,” Gilbert said. The evidence for individual supplements “isn’t robust enough to say they prevent or treat Parkinson’s disease.”
Research on the role of specific nutrients in Parkinson’s disease is conflicting, with no clear evidence supporting or refuting their benefits. For example, a study that followed participants for about 30 years showed no link between reduced Parkinson’s disease risk and vitamin B or folate intake.
On the other hand, there is research suggesting that certain vitamins may help reduce Parkinson’s disease risk, although these nutrients do not operate in isolation. For instance, one recent study showed a connection between vitamins C and E and reduced Parkinson’s disease risk, but factors such as body mass index and coffee consumption appeared to influence the strength of this association.
Consuming polyunsaturated fatty acids along with reducing saturated fatty acid intake has been tied to a reduced risk for Parkinson’s disease.
Additionally, certain foods may offer protective effects, including green and black tea, with consumption of three or more cups per day associated with a delay in motor symptom onset by 7.7 years. Foods high in nicotine content, such as those from the Solanaceae family — including peppers, tomatoes, tomato juice, and potatoes — have also been linked to potential protective benefits.
Diets rich in antioxidants, including carotenoids, lutein, and vitamins E and C, have been robustly linked to a reduced risk for parkinsonism and progression of parkinsonian symptoms in older adults.
Increasing the intake of dietary flavonoids, particularly tea, berry fruits, apples, red wine, and oranges or orange juice, can reduce Parkinson’s disease risk. One study showed that male participants in the highest quintile of total flavonoid consumption had a 40% lower Parkinson’s disease risk compared with those in the lowest quintile. Another study showed that flavonoid-rich foods were also associated with a lower risk for death in patients with Parkinson’s disease.
Food as Medicine
Although recent research shows that the drug development pipeline for Parkinson’s disease is robust, with a wide variety of approaches being developed and evaluated in phase 1 and 2, investigators note that only a limited number of disease-modifying treatments are transitioning to phase 3.
Duda noted that phytochemicals incorporated into the diet might target some of the same mechanisms that are targets of these drugs in development.
“Flavonoids have been shown to stabilize alpha-synuclein in vitro,” he said. “Caffeine, curcumin, resveratrol, and eliminating meat and dairy inhibit mTOR [mammalian target of rapamycin], and mTOR inhibition results in increased autophagy that may help clear alpha-synuclein. Genestein, an isoflavone in soybeans, protects dopaminergic neurons by inhibiting microglia activation. Flavonoids inhibit inflammation by inhibiting release of NO [nitric oxide] and pro-inflammatory cytokines,” he noted.
Ongoing studies of dietary interventions for Parkinson’s disease are exploring various areas, including the potential role of the ketogenic diet in protecting the gut microbiome, optimizing protein intake for muscle preservation and sleep, the effects of psyllium and wheat bran on weight and constipation, and the impact of a gluten-free diet.
Practical Tips for Healthy Eating
Gilbert emphasized that there are no medications or interventions currently available that can delay a Parkinson’s disease diagnosis by up to 17 years, as some dietary patterns have been shown to do, and she noted that it’s not possible to replicate the MeDi diet in a pill. However, she recommended a practical approach to eating that includes a diet low in ultraprocessed foods and high in beneficial nutrients. She encouraged people to shop for “real food” and enjoy a variety of colorful fruits and vegetables.
Duda acknowledged that motivating patients to follow a healthy diet can be difficult. As a result, the focus often shifts to making small adjustments and modifications. For example, he suggested that instead of pairing meat with French fries, people could opt for vegetables or add greens to their meals. Similarly, instead of having eggs and bacon for breakfast, they might choose oatmeal.
Preparing whole-food, plant-based meals may take more time than patients are accustomed to, so Duda suggests that, if possible, patients involve loved ones in both the meal preparation and the meal itself. He explained that a healthy meal can become an opportunity for bonding and that the key is educating them about new meal-related concepts.
Duda reported no relevant financial relationships with the pharmaceutical or food industries. He has received compensation from the Physicians Committee for Responsible Medicine for his lecture delivered at the conference and research grant support from the VA, the National Institutes of Health, the Michael J. Fox Foundation, and the Department of Defense unrelated to this topic. Gilbert reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
Breaking the Cycle: Why Self-Compassion Is Essential for Today’s Physicians
Summary and Key Highlights
Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.
Key Takeaways:
- Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
- Practicing self-compassion can improve long-term resilience and prevent burnout.
- The changing landscape of healthcare supports a more balanced approach to physician well-being.
Our Editors Also Recommend:
Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’
Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance
Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance
A Transformative Rx for Burnout, Grief, and Illness: Dance
Next Medscape Masters Event:
Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.
Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.
A version of this article first appeared on Medscape.com.
Summary and Key Highlights
Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.
Key Takeaways:
- Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
- Practicing self-compassion can improve long-term resilience and prevent burnout.
- The changing landscape of healthcare supports a more balanced approach to physician well-being.
Our Editors Also Recommend:
Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’
Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance
Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance
A Transformative Rx for Burnout, Grief, and Illness: Dance
Next Medscape Masters Event:
Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.
Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.
A version of this article first appeared on Medscape.com.
Summary and Key Highlights
Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.
Key Takeaways:
- Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
- Practicing self-compassion can improve long-term resilience and prevent burnout.
- The changing landscape of healthcare supports a more balanced approach to physician well-being.
Our Editors Also Recommend:
Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’
Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance
Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance
A Transformative Rx for Burnout, Grief, and Illness: Dance
Next Medscape Masters Event:
Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.
Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.
A version of this article first appeared on Medscape.com.
Finding Fulfillment Beyond Metrics: A Physician’s Path to Lasting Well-Being
Summary and Key Highlights
Summary: Dr Tyra Fainstad shares her personal experience with burnout and the journey to recovery through coaching and self-compassion. She describes the pressures of seeking validation through external achievements, which ultimately led to a crisis in self-worth after medical training. Through coaching, she learned to cultivate a sense of internal fulfillment, reconnecting with her passion for medicine and achieving a healthier balance.
Key Takeaways:
- Relying solely on external validation can deepen burnout and affect well-being.
- Coaching empowers physicians to develop self-compassion and sustainable coping strategies.
- Shifting from external to internal validation strengthens long-term fulfillment and job satisfaction.
Our Editors Also Recommend:
Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’
Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance
Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance
A Transformative Rx for Burnout, Grief, and Illness: Dance
Next Medscape Masters Event:
Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.
A version of this article first appeared on Medscape.com.
Summary and Key Highlights
Summary: Dr Tyra Fainstad shares her personal experience with burnout and the journey to recovery through coaching and self-compassion. She describes the pressures of seeking validation through external achievements, which ultimately led to a crisis in self-worth after medical training. Through coaching, she learned to cultivate a sense of internal fulfillment, reconnecting with her passion for medicine and achieving a healthier balance.
Key Takeaways:
- Relying solely on external validation can deepen burnout and affect well-being.
- Coaching empowers physicians to develop self-compassion and sustainable coping strategies.
- Shifting from external to internal validation strengthens long-term fulfillment and job satisfaction.
Our Editors Also Recommend:
Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’
Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance
Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance
A Transformative Rx for Burnout, Grief, and Illness: Dance
Next Medscape Masters Event:
Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.
A version of this article first appeared on Medscape.com.
Summary and Key Highlights
Summary: Dr Tyra Fainstad shares her personal experience with burnout and the journey to recovery through coaching and self-compassion. She describes the pressures of seeking validation through external achievements, which ultimately led to a crisis in self-worth after medical training. Through coaching, she learned to cultivate a sense of internal fulfillment, reconnecting with her passion for medicine and achieving a healthier balance.
Key Takeaways:
- Relying solely on external validation can deepen burnout and affect well-being.
- Coaching empowers physicians to develop self-compassion and sustainable coping strategies.
- Shifting from external to internal validation strengthens long-term fulfillment and job satisfaction.
Our Editors Also Recommend:
Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’
Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance
Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance
A Transformative Rx for Burnout, Grief, and Illness: Dance
Next Medscape Masters Event:
Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.
A version of this article first appeared on Medscape.com.
The Strange Untold Story of How Science Solved Narcolepsy
It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.
The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.
Yanagisawa was about to prove this wasn’t a first-timer’s fluke.
His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.)
Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.
“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.
It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.
No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.
But That’s Basic Science for You
Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.
Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.
“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.
Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.
“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”
As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.
And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.
As in: What happens when two independent teams discover the same thing at the same time?
Back to Yanagisawa’s Lab ...
... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.
“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.
Sure enough, injecting the proteins into rat brains led the rodents to start eating.
Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.
But another group beat them to it.
Introducing the ‘Hypocretins’
In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides
As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.
Weeks later, in February 1998, Yanagisawa’s paper came out.
Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.
“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”
He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.
“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.”
‘Multiple Discovery’ Happens More Often Than You Think
In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.
“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.)
“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.”
While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.
The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.
Yet duplicating research is a key step in confirming the validity of a discovery.
That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.
‘What the Heck Is This Mouse Doing?’
Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.
He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”
The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.
As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.
After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”
While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.
They began monitoring the mice’s brains during these episodes — and made a startling discovery.
The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.
“That’s when we knew these animals had something akin to narcolepsy,” said Willie.
The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.
Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.
These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.
Unless, of course, another team did it first.
The Mystery of Narcolepsy
Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.
It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.
“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.
In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.
Dement, who died in 2020, had found his newest research subjects.
In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.
Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.
Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.
The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.
Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.
A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.
“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”
Narcoleptic Dogs in California, Mutant Mice in Texas
It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.
As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.
The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.
“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”
To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.
After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.”
Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?
“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.
As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.
What Happened Next Is Somewhat Disputed
After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.
According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.”
Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.
Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.
Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.
Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.
“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”
For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.
“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”
Two weeks later, Yanagisawa’s findings followed, also in Cell.
His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.
“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”
Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.
After more than a century, the cause of narcolepsy was starting to come into focus.
“This was blockbuster,” said Willie.
By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.
The Human Brains in Your Fridge Hold Secrets
Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.
“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.”
Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.
When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.
What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.
Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.
“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.”
Now he could do exactly that.
As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)
It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.
To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.
Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.
In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.
“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”
How All of This Changed Medicine
Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.
But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.
“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.
That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.
Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.
Researchers are hopeful a hypocretin/orexin agonist is on the horizon.
“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”
One More Hypocretin/Orexin Surprise — and It Could Be The Biggest
Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.
Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.
Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”
Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.
“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.”
Obviously, opioids affected the orexin system. But how?
“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.”
As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate.
In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.
In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.
This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”
This could powerfully change the way opioids are administered.
“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.
His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.
In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.
If it translates to humans, this discovery could potentially save millions of lives.
“I think it’s just us working on this,” said Siegel.
But with hypocretin/orexin, you never know.
A version of this article appeared on Medscape.com.
It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.
The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.
Yanagisawa was about to prove this wasn’t a first-timer’s fluke.
His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.)
Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.
“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.
It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.
No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.
But That’s Basic Science for You
Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.
Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.
“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.
Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.
“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”
As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.
And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.
As in: What happens when two independent teams discover the same thing at the same time?
Back to Yanagisawa’s Lab ...
... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.
“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.
Sure enough, injecting the proteins into rat brains led the rodents to start eating.
Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.
But another group beat them to it.
Introducing the ‘Hypocretins’
In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides
As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.
Weeks later, in February 1998, Yanagisawa’s paper came out.
Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.
“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”
He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.
“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.”
‘Multiple Discovery’ Happens More Often Than You Think
In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.
“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.)
“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.”
While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.
The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.
Yet duplicating research is a key step in confirming the validity of a discovery.
That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.
‘What the Heck Is This Mouse Doing?’
Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.
He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”
The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.
As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.
After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”
While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.
They began monitoring the mice’s brains during these episodes — and made a startling discovery.
The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.
“That’s when we knew these animals had something akin to narcolepsy,” said Willie.
The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.
Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.
These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.
Unless, of course, another team did it first.
The Mystery of Narcolepsy
Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.
It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.
“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.
In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.
Dement, who died in 2020, had found his newest research subjects.
In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.
Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.
Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.
The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.
Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.
A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.
“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”
Narcoleptic Dogs in California, Mutant Mice in Texas
It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.
As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.
The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.
“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”
To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.
After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.”
Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?
“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.
As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.
What Happened Next Is Somewhat Disputed
After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.
According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.”
Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.
Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.
Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.
Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.
“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”
For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.
“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”
Two weeks later, Yanagisawa’s findings followed, also in Cell.
His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.
“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”
Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.
After more than a century, the cause of narcolepsy was starting to come into focus.
“This was blockbuster,” said Willie.
By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.
The Human Brains in Your Fridge Hold Secrets
Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.
“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.”
Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.
When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.
What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.
Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.
“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.”
Now he could do exactly that.
As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)
It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.
To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.
Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.
In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.
“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”
How All of This Changed Medicine
Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.
But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.
“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.
That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.
Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.
Researchers are hopeful a hypocretin/orexin agonist is on the horizon.
“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”
One More Hypocretin/Orexin Surprise — and It Could Be The Biggest
Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.
Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.
Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”
Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.
“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.”
Obviously, opioids affected the orexin system. But how?
“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.”
As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate.
In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.
In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.
This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”
This could powerfully change the way opioids are administered.
“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.
His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.
In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.
If it translates to humans, this discovery could potentially save millions of lives.
“I think it’s just us working on this,” said Siegel.
But with hypocretin/orexin, you never know.
A version of this article appeared on Medscape.com.
It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.
The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.
Yanagisawa was about to prove this wasn’t a first-timer’s fluke.
His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.)
Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.
“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.
It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.
No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.
But That’s Basic Science for You
Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.
Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.
“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.
Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.
“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”
As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.
And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.
As in: What happens when two independent teams discover the same thing at the same time?
Back to Yanagisawa’s Lab ...
... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.
“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.
Sure enough, injecting the proteins into rat brains led the rodents to start eating.
Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.
But another group beat them to it.
Introducing the ‘Hypocretins’
In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides
As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.
Weeks later, in February 1998, Yanagisawa’s paper came out.
Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.
“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”
He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.
“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.”
‘Multiple Discovery’ Happens More Often Than You Think
In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.
“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.)
“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.”
While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.
The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.
Yet duplicating research is a key step in confirming the validity of a discovery.
That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.
‘What the Heck Is This Mouse Doing?’
Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.
He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”
The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.
As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.
After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”
While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.
They began monitoring the mice’s brains during these episodes — and made a startling discovery.
The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.
“That’s when we knew these animals had something akin to narcolepsy,” said Willie.
The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.
Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.
These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.
Unless, of course, another team did it first.
The Mystery of Narcolepsy
Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.
It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.
“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.
In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.
Dement, who died in 2020, had found his newest research subjects.
In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.
Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.
Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.
The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.
Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.
A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.
“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”
Narcoleptic Dogs in California, Mutant Mice in Texas
It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.
As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.
The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.
“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”
To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.
After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.”
Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?
“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.
As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.
What Happened Next Is Somewhat Disputed
After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.
According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.”
Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.
Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.
Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.
Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.
“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”
For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.
“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”
Two weeks later, Yanagisawa’s findings followed, also in Cell.
His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.
“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”
Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.
After more than a century, the cause of narcolepsy was starting to come into focus.
“This was blockbuster,” said Willie.
By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.
The Human Brains in Your Fridge Hold Secrets
Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.
“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.”
Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.
When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.
What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.
Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.
“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.”
Now he could do exactly that.
As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)
It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.
To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.
Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.
In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.
“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”
How All of This Changed Medicine
Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.
But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.
“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.
That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.
Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.
Researchers are hopeful a hypocretin/orexin agonist is on the horizon.
“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”
One More Hypocretin/Orexin Surprise — and It Could Be The Biggest
Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.
Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.
Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”
Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.
“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.”
Obviously, opioids affected the orexin system. But how?
“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.”
As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate.
In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.
In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.
This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”
This could powerfully change the way opioids are administered.
“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.
His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.
In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.
If it translates to humans, this discovery could potentially save millions of lives.
“I think it’s just us working on this,” said Siegel.
But with hypocretin/orexin, you never know.
A version of this article appeared on Medscape.com.
Cancer Mortality Not Higher for Patients With Autoimmune Disease on Checkpoint Inhibitors
WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found.
Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.
“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.
Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events.
“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.
Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.”
No Difference in Mortality for Those With and Without Autoimmune Disease
Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.
Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use.
At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00).
The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said.
Some Caveats About the Data
Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited.
Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease.
“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.
“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.
Challener and Jeffries had no relevant disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found.
Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.
“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.
Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events.
“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.
Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.”
No Difference in Mortality for Those With and Without Autoimmune Disease
Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.
Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use.
At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00).
The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said.
Some Caveats About the Data
Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited.
Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease.
“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.
“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.
Challener and Jeffries had no relevant disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found.
Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.
“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.
Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events.
“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.
Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.”
No Difference in Mortality for Those With and Without Autoimmune Disease
Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.
Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use.
At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00).
The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said.
Some Caveats About the Data
Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited.
Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease.
“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.
“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.
Challener and Jeffries had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ACR 2024