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An independent expert panel within the Centers for Disease Control and Prevention (CDC) has studied the potential benefits and risks of the Pfizer-BioNTech COVID-19 vaccine and voted unanimously to recommend the shots for all Americans ages 16 and older.

All 14 members of the Advisory Committee on Immunization Practices (ACIP) voted ‘yes’ to recommend the vaccine for Americans ages 16 and up. The vaccine was fully approved by the U.S. Food and Drug Administration (FDA) last week.

The inoculation is still available to teens ages 12 to 15 under an emergency use authorization from the FDA.

ACIP now sends its recommendation to the CDC Director Rochelle Walensky, MD, for her sign off.

After reviewing the evidence behind the vaccine, panel member Sarah Long, MD, a professor of pediatrics at Drexel University College of Medicine, Philadelphia, said she couldn’t recall another instance where panelists had so much data on which to base their recommendation.

“This vaccine is worthy of the trust of the American people,” she said.

Doctors across the country use vaccines in line with the recommendations made by the ACIP. Their approval typically means that private and government insurers will cover the cost of the shots. In the case of the COVID-19 vaccines, the government is already picking up the tab.

Few surprises

The panel’s independent review of the vaccine’s effectiveness from nine studies held few surprises. 

They found the Pfizer vaccine prevented a COVID infection with symptoms about 90%–92% of the time, at least for the first 4 months after the second shot. Protection against hospitalization and death was even higher.

The vaccine was about 89% effective at preventing a COVID infection without symptoms, according to a pooled estimate of five studies.

The data included in the review was updated only through March 13 of this year, however, and does not reflect the impact of further waning of immunity or the impact of the Delta variant.

In making their recommendation, the panel got an update on the safety of the vaccines, which have now been used in the United States for about 9 months.

The rate of anaphylaxis has settled at around five cases for every million shots given, according to the ACIP’s review of the evidence. 

Cases of myocarditis and pericarditis were more common after getting a Pfizer-BioNTech vaccine than would be expected to happen naturally in the general population, but the risk was still very rare, and elevated primarily for men younger than age 30. 

Out of 17 million second doses of Pfizer-BioNTech vaccines in the United States, there have been 327 confirmed cases of myocarditis reported to the Vaccine Adverse Event Reporting System in people who are younger than age 30. The average hospital stay for a myocarditis cases is 1 to 2 days. 

So far, no one in the United States diagnosed with myocarditis after vaccination has died.

What’s more, the risk of myocarditis after vaccination was dwarfed by the risk of myocarditis after a COVID infection. The risk of myocarditis after a COVID infection was 6 to 34 times higher than the risk after receiving an mRNA vaccine.

About 11% of people who get the vaccine experience a serious reaction to the shot, compared with about 3% in the placebo group. Serious reactions were defined as pain; swelling or redness at the injection site that interferes with activity; needing to visit the hospital or ER for pain; tissue necrosis, or having skin slough off; high fever; vomiting that requires hydration; persistent diarrhea; severe headache;  or muscle pain/severe joint pain.

“Safe and effective”

After hearing a presentation on the state of the pandemic in the US, some panel members were struck and shaken that 38% of Americans who are eligible are still not fully vaccinated.

Pablo Sanchez, MD, a pediatrician at Nationwide Children’s Hospital in Columbus, Ohio, said, “We’re doing an abysmal job vaccinating the American people. The message has to go out that the vaccines are safe and effective.”



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

An independent expert panel within the Centers for Disease Control and Prevention (CDC) has studied the potential benefits and risks of the Pfizer-BioNTech COVID-19 vaccine and voted unanimously to recommend the shots for all Americans ages 16 and older.

All 14 members of the Advisory Committee on Immunization Practices (ACIP) voted ‘yes’ to recommend the vaccine for Americans ages 16 and up. The vaccine was fully approved by the U.S. Food and Drug Administration (FDA) last week.

The inoculation is still available to teens ages 12 to 15 under an emergency use authorization from the FDA.

ACIP now sends its recommendation to the CDC Director Rochelle Walensky, MD, for her sign off.

After reviewing the evidence behind the vaccine, panel member Sarah Long, MD, a professor of pediatrics at Drexel University College of Medicine, Philadelphia, said she couldn’t recall another instance where panelists had so much data on which to base their recommendation.

“This vaccine is worthy of the trust of the American people,” she said.

Doctors across the country use vaccines in line with the recommendations made by the ACIP. Their approval typically means that private and government insurers will cover the cost of the shots. In the case of the COVID-19 vaccines, the government is already picking up the tab.

Few surprises

The panel’s independent review of the vaccine’s effectiveness from nine studies held few surprises. 

They found the Pfizer vaccine prevented a COVID infection with symptoms about 90%–92% of the time, at least for the first 4 months after the second shot. Protection against hospitalization and death was even higher.

The vaccine was about 89% effective at preventing a COVID infection without symptoms, according to a pooled estimate of five studies.

The data included in the review was updated only through March 13 of this year, however, and does not reflect the impact of further waning of immunity or the impact of the Delta variant.

In making their recommendation, the panel got an update on the safety of the vaccines, which have now been used in the United States for about 9 months.

The rate of anaphylaxis has settled at around five cases for every million shots given, according to the ACIP’s review of the evidence. 

Cases of myocarditis and pericarditis were more common after getting a Pfizer-BioNTech vaccine than would be expected to happen naturally in the general population, but the risk was still very rare, and elevated primarily for men younger than age 30. 

Out of 17 million second doses of Pfizer-BioNTech vaccines in the United States, there have been 327 confirmed cases of myocarditis reported to the Vaccine Adverse Event Reporting System in people who are younger than age 30. The average hospital stay for a myocarditis cases is 1 to 2 days. 

So far, no one in the United States diagnosed with myocarditis after vaccination has died.

What’s more, the risk of myocarditis after vaccination was dwarfed by the risk of myocarditis after a COVID infection. The risk of myocarditis after a COVID infection was 6 to 34 times higher than the risk after receiving an mRNA vaccine.

About 11% of people who get the vaccine experience a serious reaction to the shot, compared with about 3% in the placebo group. Serious reactions were defined as pain; swelling or redness at the injection site that interferes with activity; needing to visit the hospital or ER for pain; tissue necrosis, or having skin slough off; high fever; vomiting that requires hydration; persistent diarrhea; severe headache;  or muscle pain/severe joint pain.

“Safe and effective”

After hearing a presentation on the state of the pandemic in the US, some panel members were struck and shaken that 38% of Americans who are eligible are still not fully vaccinated.

Pablo Sanchez, MD, a pediatrician at Nationwide Children’s Hospital in Columbus, Ohio, said, “We’re doing an abysmal job vaccinating the American people. The message has to go out that the vaccines are safe and effective.”



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

An independent expert panel within the Centers for Disease Control and Prevention (CDC) has studied the potential benefits and risks of the Pfizer-BioNTech COVID-19 vaccine and voted unanimously to recommend the shots for all Americans ages 16 and older.

All 14 members of the Advisory Committee on Immunization Practices (ACIP) voted ‘yes’ to recommend the vaccine for Americans ages 16 and up. The vaccine was fully approved by the U.S. Food and Drug Administration (FDA) last week.

The inoculation is still available to teens ages 12 to 15 under an emergency use authorization from the FDA.

ACIP now sends its recommendation to the CDC Director Rochelle Walensky, MD, for her sign off.

After reviewing the evidence behind the vaccine, panel member Sarah Long, MD, a professor of pediatrics at Drexel University College of Medicine, Philadelphia, said she couldn’t recall another instance where panelists had so much data on which to base their recommendation.

“This vaccine is worthy of the trust of the American people,” she said.

Doctors across the country use vaccines in line with the recommendations made by the ACIP. Their approval typically means that private and government insurers will cover the cost of the shots. In the case of the COVID-19 vaccines, the government is already picking up the tab.

Few surprises

The panel’s independent review of the vaccine’s effectiveness from nine studies held few surprises. 

They found the Pfizer vaccine prevented a COVID infection with symptoms about 90%–92% of the time, at least for the first 4 months after the second shot. Protection against hospitalization and death was even higher.

The vaccine was about 89% effective at preventing a COVID infection without symptoms, according to a pooled estimate of five studies.

The data included in the review was updated only through March 13 of this year, however, and does not reflect the impact of further waning of immunity or the impact of the Delta variant.

In making their recommendation, the panel got an update on the safety of the vaccines, which have now been used in the United States for about 9 months.

The rate of anaphylaxis has settled at around five cases for every million shots given, according to the ACIP’s review of the evidence. 

Cases of myocarditis and pericarditis were more common after getting a Pfizer-BioNTech vaccine than would be expected to happen naturally in the general population, but the risk was still very rare, and elevated primarily for men younger than age 30. 

Out of 17 million second doses of Pfizer-BioNTech vaccines in the United States, there have been 327 confirmed cases of myocarditis reported to the Vaccine Adverse Event Reporting System in people who are younger than age 30. The average hospital stay for a myocarditis cases is 1 to 2 days. 

So far, no one in the United States diagnosed with myocarditis after vaccination has died.

What’s more, the risk of myocarditis after vaccination was dwarfed by the risk of myocarditis after a COVID infection. The risk of myocarditis after a COVID infection was 6 to 34 times higher than the risk after receiving an mRNA vaccine.

About 11% of people who get the vaccine experience a serious reaction to the shot, compared with about 3% in the placebo group. Serious reactions were defined as pain; swelling or redness at the injection site that interferes with activity; needing to visit the hospital or ER for pain; tissue necrosis, or having skin slough off; high fever; vomiting that requires hydration; persistent diarrhea; severe headache;  or muscle pain/severe joint pain.

“Safe and effective”

After hearing a presentation on the state of the pandemic in the US, some panel members were struck and shaken that 38% of Americans who are eligible are still not fully vaccinated.

Pablo Sanchez, MD, a pediatrician at Nationwide Children’s Hospital in Columbus, Ohio, said, “We’re doing an abysmal job vaccinating the American people. The message has to go out that the vaccines are safe and effective.”



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

A Maryland-based physician assistant was sentenced to 37 months in federal prison for conspiracy to distribute and dispense oxycodone, fentanyl, methadone, and alprazolam at a pain management clinic.

Niyazz/ThinkStock

A U.S. District Judge sentenced William Soyke, 68, of Hanover, Penn., for acting outside the scope of professional practice and not for a legitimate medical purpose, according to the U.S. Attorney’s Office in Maryland. The 37-month prison term will be followed by 3 years of supervised release.

According to the plea agreement, Mr. Soyke worked as a physician assistant with Rosen-Hoffberg Rehabilitation and Pain Management from 2011 to 2018, where he treated patients during follow-up doctor appointments. As a physician assistant, Mr. Soyke had privileges to prescribe controlled substance medications, but was required to operate under a delegation agreement with the Rosen-Hoffberg owners.  

In his plea, Mr. Soyke said that he believed the owners, Norman Rosen, MD, and Howard Hoffberg, MD, prescribed excessive levels of opioids. Despite Mr. Soyke’s attempts to lower patient’s prescription doses, both doctors overruled the PA’s opinion, according to the plea agreement. Also, if another health care provider within the practice declined to treat a patient because of the patient’s aberrant behavior – such as failing a drug screening test for illicit drugs or selling their prescriptions – Dr. Rosen and Dr. Hoffberg would assume that patient’s care, the report continued.

As stated in the plea agreement, Mr. Sokye was aware that many of the patients presenting to Rosen-Hoffberg Rehabilitation and Pain Management did not have a legitimate medical need for the oxycodone, fentanyl, alprazolam, and methadone they were being prescribed. Nevertheless, Mr. Soyke issued prescriptions for these drugs to patients without a legitimate medical need and outside the bounds of acceptable medical practice, according to the release.

Mr. Soyke also admitted that in several instances he engaged in sexual, physical contact with female patients who were attempting to get prescriptions, the plea agreement stated. Specifically, Mr. Soyke asked some female customers to engage in a range of motion test, and while they were bending over, he would position himself behind them such that his genitalia would rub against the customers’ buttocks through their clothes. These patients often submitted to this sexual abuse for fear of not getting the medications to which they were addicted, according to the press release.

Although the female patients complained to Dr. Rosen and Dr. Hoffberg about Mr. Soyke’s behavior, the doctors did not fire Mr. Soyke because the PA saw the largest number of patients at the practice and generated significant revenue, according to federal officials.

Dr. Hoffberg, the associate medical director and part-owner of the practice, pleaded guilty in June to accepting kickbacks from pharmaceutical company Insys Therapeutics in exchange for prescribing an opioid drug called Subsys (a fentanyl sublingual spray) marketed by Insys for breakthrough pain in cancer patients for off-label purposes. He will be sentenced in September and faces a maximum of 5 years in federal prison.

Mr. Soyke pled guilty to a federal drug charge in July 2019. In announcing the guilty plea then, U.S. Attorney Robert Hur said, “Opioid overdoses are killing thousands of Marylanders each year, and opioid addiction is fueled by health care providers who prescribe drugs for people without a legitimate medical need. Doctors and other medical professionals who irresponsibly write opioid prescriptions are acting like street-corner drug pushers.”

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

A Maryland-based physician assistant was sentenced to 37 months in federal prison for conspiracy to distribute and dispense oxycodone, fentanyl, methadone, and alprazolam at a pain management clinic.

Niyazz/ThinkStock

A U.S. District Judge sentenced William Soyke, 68, of Hanover, Penn., for acting outside the scope of professional practice and not for a legitimate medical purpose, according to the U.S. Attorney’s Office in Maryland. The 37-month prison term will be followed by 3 years of supervised release.

According to the plea agreement, Mr. Soyke worked as a physician assistant with Rosen-Hoffberg Rehabilitation and Pain Management from 2011 to 2018, where he treated patients during follow-up doctor appointments. As a physician assistant, Mr. Soyke had privileges to prescribe controlled substance medications, but was required to operate under a delegation agreement with the Rosen-Hoffberg owners.  

In his plea, Mr. Soyke said that he believed the owners, Norman Rosen, MD, and Howard Hoffberg, MD, prescribed excessive levels of opioids. Despite Mr. Soyke’s attempts to lower patient’s prescription doses, both doctors overruled the PA’s opinion, according to the plea agreement. Also, if another health care provider within the practice declined to treat a patient because of the patient’s aberrant behavior – such as failing a drug screening test for illicit drugs or selling their prescriptions – Dr. Rosen and Dr. Hoffberg would assume that patient’s care, the report continued.

As stated in the plea agreement, Mr. Sokye was aware that many of the patients presenting to Rosen-Hoffberg Rehabilitation and Pain Management did not have a legitimate medical need for the oxycodone, fentanyl, alprazolam, and methadone they were being prescribed. Nevertheless, Mr. Soyke issued prescriptions for these drugs to patients without a legitimate medical need and outside the bounds of acceptable medical practice, according to the release.

Mr. Soyke also admitted that in several instances he engaged in sexual, physical contact with female patients who were attempting to get prescriptions, the plea agreement stated. Specifically, Mr. Soyke asked some female customers to engage in a range of motion test, and while they were bending over, he would position himself behind them such that his genitalia would rub against the customers’ buttocks through their clothes. These patients often submitted to this sexual abuse for fear of not getting the medications to which they were addicted, according to the press release.

Although the female patients complained to Dr. Rosen and Dr. Hoffberg about Mr. Soyke’s behavior, the doctors did not fire Mr. Soyke because the PA saw the largest number of patients at the practice and generated significant revenue, according to federal officials.

Dr. Hoffberg, the associate medical director and part-owner of the practice, pleaded guilty in June to accepting kickbacks from pharmaceutical company Insys Therapeutics in exchange for prescribing an opioid drug called Subsys (a fentanyl sublingual spray) marketed by Insys for breakthrough pain in cancer patients for off-label purposes. He will be sentenced in September and faces a maximum of 5 years in federal prison.

Mr. Soyke pled guilty to a federal drug charge in July 2019. In announcing the guilty plea then, U.S. Attorney Robert Hur said, “Opioid overdoses are killing thousands of Marylanders each year, and opioid addiction is fueled by health care providers who prescribe drugs for people without a legitimate medical need. Doctors and other medical professionals who irresponsibly write opioid prescriptions are acting like street-corner drug pushers.”

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

A Maryland-based physician assistant was sentenced to 37 months in federal prison for conspiracy to distribute and dispense oxycodone, fentanyl, methadone, and alprazolam at a pain management clinic.

Niyazz/ThinkStock

A U.S. District Judge sentenced William Soyke, 68, of Hanover, Penn., for acting outside the scope of professional practice and not for a legitimate medical purpose, according to the U.S. Attorney’s Office in Maryland. The 37-month prison term will be followed by 3 years of supervised release.

According to the plea agreement, Mr. Soyke worked as a physician assistant with Rosen-Hoffberg Rehabilitation and Pain Management from 2011 to 2018, where he treated patients during follow-up doctor appointments. As a physician assistant, Mr. Soyke had privileges to prescribe controlled substance medications, but was required to operate under a delegation agreement with the Rosen-Hoffberg owners.  

In his plea, Mr. Soyke said that he believed the owners, Norman Rosen, MD, and Howard Hoffberg, MD, prescribed excessive levels of opioids. Despite Mr. Soyke’s attempts to lower patient’s prescription doses, both doctors overruled the PA’s opinion, according to the plea agreement. Also, if another health care provider within the practice declined to treat a patient because of the patient’s aberrant behavior – such as failing a drug screening test for illicit drugs or selling their prescriptions – Dr. Rosen and Dr. Hoffberg would assume that patient’s care, the report continued.

As stated in the plea agreement, Mr. Sokye was aware that many of the patients presenting to Rosen-Hoffberg Rehabilitation and Pain Management did not have a legitimate medical need for the oxycodone, fentanyl, alprazolam, and methadone they were being prescribed. Nevertheless, Mr. Soyke issued prescriptions for these drugs to patients without a legitimate medical need and outside the bounds of acceptable medical practice, according to the release.

Mr. Soyke also admitted that in several instances he engaged in sexual, physical contact with female patients who were attempting to get prescriptions, the plea agreement stated. Specifically, Mr. Soyke asked some female customers to engage in a range of motion test, and while they were bending over, he would position himself behind them such that his genitalia would rub against the customers’ buttocks through their clothes. These patients often submitted to this sexual abuse for fear of not getting the medications to which they were addicted, according to the press release.

Although the female patients complained to Dr. Rosen and Dr. Hoffberg about Mr. Soyke’s behavior, the doctors did not fire Mr. Soyke because the PA saw the largest number of patients at the practice and generated significant revenue, according to federal officials.

Dr. Hoffberg, the associate medical director and part-owner of the practice, pleaded guilty in June to accepting kickbacks from pharmaceutical company Insys Therapeutics in exchange for prescribing an opioid drug called Subsys (a fentanyl sublingual spray) marketed by Insys for breakthrough pain in cancer patients for off-label purposes. He will be sentenced in September and faces a maximum of 5 years in federal prison.

Mr. Soyke pled guilty to a federal drug charge in July 2019. In announcing the guilty plea then, U.S. Attorney Robert Hur said, “Opioid overdoses are killing thousands of Marylanders each year, and opioid addiction is fueled by health care providers who prescribe drugs for people without a legitimate medical need. Doctors and other medical professionals who irresponsibly write opioid prescriptions are acting like street-corner drug pushers.”

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

An internist will never forget the dark secret his patient revealed during a routine visit – or the grim aftermath. 

The patient, who had a progressive, incurable neurological condition, confided that he planned to kill himself. The patient intended to conceal the true manner and make the death look natural.

“[He planned to do it] very carefully at home so no one would know,” said the internist, who remains anonymous. “[He shared] the methods he would use.”

Perhaps more shocking than the patient’s confession was the physician’s response. 

“He did not require my help to do what he planned, and I did not try to stop him,” said the internist. “I reported his death as ‘natural causes’ and never told anyone.”

The account comes from a response to Medscape’s 2020 Ethics Report in which physicians were asked about their toughest ethical dilemmas. Many physicians shared secrets and dilemmas that have haunted them for years.  An ob.gyn., for instance, wrote about struggling with whether to tell a father that his newborn baby was not his genetic child. The newborn had a blood type that made it impossible for the father to be biologically related to the infant, the anonymous doctor wrote.

“I told the wife who then informed me she had a lover,” the ob.gyn. said. “I never told the husband.”

It’s uncertain whether carrying the burden of such hidden knowledge affected the physicians involved in these cases. However, in general, secrets can weigh heavily on the minds of those who keep them and can contribute to stress, said Malia Mason, PhD, a psychologist and dean of research at Columbia Business School in New York. Holding onto secrets can cause depression and anxiety, research shows. The more often people think about the secret, the greater the impact, according to a recent study coauthored by Dr. Mason.

“Keeping a secret diminishes well-being,” Dr. Mason said. “It makes people feel socially distant. It lowers relationship satisfaction, and it leads people to feel inauthentic. The reason that secrets do this is because people think about them all the time. The more you think about it, the more you see these consequences.”

Feelings that stem from a secret depend on the content. The more immoral a secret is thought to be, the more people feel ashamed, according to a 2021 analysis of thousands of secrets, reported by Michael L. Slepian, PhD, and Alex Koch, PhD. However, secrets more related to a person’s profession are often internalized differently, the study found. The more a secret fell higher on the profession/goal-oriented dimension, the more people felt they had insight into the secret, according to the analysis. For example, having clear thinking about the secret and/or knowing how to handle it. 

“The more shame participants felt from their secret, the more they indicated the secret hurt their well-being,” Dr. Slepian and Dr. Koch wrote in the study. “The more insight participants felt they had into their secret, the less they indicated the secret hurt their well-being.”
 

Suspicious deaths exposed after investigations

The internist’s account of keeping his patient’s suicide a secret raises many questions, such as how the patient masked his manner of death. The internist did not share any more details about the incident. 

Suicides are among the most challenging manners of deaths to certify, according to James Gill, MD, a pathologist and president of the National Association of Medical Examiners. Death investigators must demonstrate intent, meaning the individuals caused the injury to intentionally harm themselves. Fewer than half of people who die by suicide leave a note, Dr. Gill said, so investigators can’t rely on the absence or the presence of a note in making their determination.

A decedent who had cancer or a severe neurological disorder presents further challenges, said Dr. Gill, who serves as chief medical examiner for the state of Connecticut.

“These [deaths] may not be unexpected and may not be reported to the medical examiner/coroner,” Dr. Gill said. “If there is no suspicion and the treating doctor is willing to sign the death certificate, the death will not come under the jurisdiction of the medical examiner.”

Dr. Gill recalled a death his colleague once investigated that appeared to be natural but emerged as something else after a deeper look. 

A woman with metastatic breast cancer was about to be discharged from a hospital into hospice the next morning. The night before, she had a “going away” party with friends who came to visit her in the hospital. Shortly after the friends left, the woman was found dead. Because of her condition, she could have died at any time, Dr. Gill said, but she also had a history of depression and hospital staff were suspicious. The death was reported to the medical examiner’s office.

Toxicology testing found markedly elevated concentrations of phenytoin and pentobarbital, neither of which were prescribed during her hospital stay. Dr. Gill said it turned out that the woman and her friends worked at a veterinarian’s office, and the medication they used to euthanize dogs was a combination of phenytoin and pentobarbital.

“The death was certified as a homicide because of the direct actions of another, but a reasonable argument could be made for suicide,” Dr. Gill said.

In a similar case reported in the journal Science & Justice, a 64-year-old cardiologist was found lifeless by his wife after he collapsed near the stairs of his home. Next to his body was a bottle of whiskey and two cups, one that appeared to be used for the alcohol and one with a yellowish liquid smelling of honey. The wife reported that her husband always drank whiskey with honey before bed. The death was initially classified as natural, but after vehement protest by the family, a forensic autopsy was performed. 

Prior to the autopsy, death investigators learned the decedent, who was a well-known and successful practitioner in his community, had Parkinson’s disease. At times, he could not sign his prescriptions because of the increasing tremor in his hands, according to the case study. Investigators learned the patient’s mother had also suffered from Parkinson’s, and that her son had witnessed her decline. 

The autopsy revealed only nonspecific lesions such as acute stasis of the viscera, moderate pulmonary and cerebral edema, and moderate generalized atheromatosis. Histological examinations did not yield any unusual findings.

An analysis of the beverage containers detected pentobarbital in the yellowish syrup residue of the second cup. Testing of the doctor’s peripheral blood revealed the presence of a metabolite of pentobarbital, ethanol, and traces of phenobarbital. In addition, a urine analysis showed the presence of venlafaxine, an antidepressant, as well as the benzophenone of lorazepam, a sedating benzodiazepine, and metoclopramide, an antiemetic.

Lead author C. Brandt-Casadevall, MD, and colleagues wrote that the levels were clearly compatible with a scenario of a pentobarbital overdose with a lethal outcome.

“... It is obvious that the victim attempted to hide his suicide from his family circle,” Dr. Brandt-Casadevall and colleagues wrote. “Thus, we obtained no evidence indicating that he might have spoken at any point of putting an end to his life. There was no written note. The victim did not wait to be alone at home. Instead, he committed his act in a routine situation: his wife was watching television late at night and he was upstairs, presumably going to sleep. Thus, he had one to two hours at his disposal, and he ingested a very fast-acting drug which would make any attempt at reanimation impossible, even after a brief period of time. This may have induced the physician in charge to believe that the cause of death was cardiac origin, a likely hypothesis given the age of the victim.”
 

What to do when a terminally ill patient talks suicide

When a terminally ill patient expresses the desire to end his or her life, it’s important to understand that desire is often a result of existential suffering, a sense of hopelessness, and lack of social support, said Lynn A. Jansen, PhD, a bioethicist at the University of Arizona in Tucson.

“The duty of beneficence requires that physicians attempt to provide the support and care that is needed,” said Dr. Jansen. “Here, interdisciplinary teamwork is important and should be utilized. Physicians should refer patients to professionals, such as social workers, pastoral care, psychologists, etc., who are better able to address these issues.”

The rate of desire for a hastened death among terminally ill patients ranges from 17% to 45%, depending on the population studied and how the desire is evaluated, according to an analysis in the Primary Care Companion to the Journal of Clinical Psychiatry. In one study, 14% of about 130 palliative care patients with cancer had a strong desire to quicken the dying process.

In addition, patients with neurologic disorders have a significantly higher suicide rate than that of those without neurologic disorders, a recent JAMA study found. About 1 in 150 patients diagnosed with a neurological disorder dies by suicide, the analysis determined. 

A tricky point to remember is that a desire by a terminally ill patient to hasten his or her death by suicide should not be taken by itself to indicate depression, Dr. Jansen noted.

“In principle, such patients can make an autonomous decision to end their lives,” she said. “However, the expression of such a desire is very often associated with depression and forms of suffering that can be effectively addressed by the health care team.”

Physicians can also explore other avenues with the patient such as palliative care or making sure adequate pain relief is available, added Robert Klitzman, MD, professor of psychiatry and academic director of the master of science in bioethics program at Columbia University, New York.

“If they are saying it’s because they are distressed, ethically, a doctor can and should find ways to decrease their distress,” he said.

Of course, those who practice in the U.S. jurisdictions that have physician-assisted-dying laws have different legal and ethical elements to consider. Physicians in these areas have no ethical duty to participate in the process, Dr. Jansen said, but they have a duty to refer patients who express a desire to pursue physician aid-in-dying to another provider who can assist them.

Physician aid-in-dying laws vary somewhat so it’s important that physicians in these areas be aware of their specific statute, Dr. Klitzman said. California, Colorado, Hawaii, Maine, New Jersey, New Mexico, Oregon, Vermont, Washington, and the District of Columbia have these laws.

“In these states, if a terminally ill patient says they don’t want to live anymore, a physician would first decide if this is a result of depression or if it’s a request for physician aid-in-dying,” he said. “Even then, in most cases, the patient would be evaluated by not one, but two different health professionals at two different points. We want to see if it is a consistent decision that the person has made that they want physician aid-in-dying, and not just that they’ve had a bad day or a setback in their treatment.”

In the case of the internist who told no one of his patient’s suicide plan, Dr. Klitzman said he would have dug deeper into the patient’s mindset.

“Not knowing anything about the patient or the doctor, I would have responded differently,” he said. “I think a physician should address why a patient feels that way. They may feel their pain is unbearable, and we potentially offer more pain relief. Maybe the patient shows evidence of having depression, which may be treatable [with medication]. The patient would then feel better and be able to spend quality time with family and loved ones, make sure their affairs are in order, and have a chance to say goodbye.”

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

An internist will never forget the dark secret his patient revealed during a routine visit – or the grim aftermath. 

The patient, who had a progressive, incurable neurological condition, confided that he planned to kill himself. The patient intended to conceal the true manner and make the death look natural.

“[He planned to do it] very carefully at home so no one would know,” said the internist, who remains anonymous. “[He shared] the methods he would use.”

Perhaps more shocking than the patient’s confession was the physician’s response. 

“He did not require my help to do what he planned, and I did not try to stop him,” said the internist. “I reported his death as ‘natural causes’ and never told anyone.”

The account comes from a response to Medscape’s 2020 Ethics Report in which physicians were asked about their toughest ethical dilemmas. Many physicians shared secrets and dilemmas that have haunted them for years.  An ob.gyn., for instance, wrote about struggling with whether to tell a father that his newborn baby was not his genetic child. The newborn had a blood type that made it impossible for the father to be biologically related to the infant, the anonymous doctor wrote.

“I told the wife who then informed me she had a lover,” the ob.gyn. said. “I never told the husband.”

It’s uncertain whether carrying the burden of such hidden knowledge affected the physicians involved in these cases. However, in general, secrets can weigh heavily on the minds of those who keep them and can contribute to stress, said Malia Mason, PhD, a psychologist and dean of research at Columbia Business School in New York. Holding onto secrets can cause depression and anxiety, research shows. The more often people think about the secret, the greater the impact, according to a recent study coauthored by Dr. Mason.

“Keeping a secret diminishes well-being,” Dr. Mason said. “It makes people feel socially distant. It lowers relationship satisfaction, and it leads people to feel inauthentic. The reason that secrets do this is because people think about them all the time. The more you think about it, the more you see these consequences.”

Feelings that stem from a secret depend on the content. The more immoral a secret is thought to be, the more people feel ashamed, according to a 2021 analysis of thousands of secrets, reported by Michael L. Slepian, PhD, and Alex Koch, PhD. However, secrets more related to a person’s profession are often internalized differently, the study found. The more a secret fell higher on the profession/goal-oriented dimension, the more people felt they had insight into the secret, according to the analysis. For example, having clear thinking about the secret and/or knowing how to handle it. 

“The more shame participants felt from their secret, the more they indicated the secret hurt their well-being,” Dr. Slepian and Dr. Koch wrote in the study. “The more insight participants felt they had into their secret, the less they indicated the secret hurt their well-being.”
 

Suspicious deaths exposed after investigations

The internist’s account of keeping his patient’s suicide a secret raises many questions, such as how the patient masked his manner of death. The internist did not share any more details about the incident. 

Suicides are among the most challenging manners of deaths to certify, according to James Gill, MD, a pathologist and president of the National Association of Medical Examiners. Death investigators must demonstrate intent, meaning the individuals caused the injury to intentionally harm themselves. Fewer than half of people who die by suicide leave a note, Dr. Gill said, so investigators can’t rely on the absence or the presence of a note in making their determination.

A decedent who had cancer or a severe neurological disorder presents further challenges, said Dr. Gill, who serves as chief medical examiner for the state of Connecticut.

“These [deaths] may not be unexpected and may not be reported to the medical examiner/coroner,” Dr. Gill said. “If there is no suspicion and the treating doctor is willing to sign the death certificate, the death will not come under the jurisdiction of the medical examiner.”

Dr. Gill recalled a death his colleague once investigated that appeared to be natural but emerged as something else after a deeper look. 

A woman with metastatic breast cancer was about to be discharged from a hospital into hospice the next morning. The night before, she had a “going away” party with friends who came to visit her in the hospital. Shortly after the friends left, the woman was found dead. Because of her condition, she could have died at any time, Dr. Gill said, but she also had a history of depression and hospital staff were suspicious. The death was reported to the medical examiner’s office.

Toxicology testing found markedly elevated concentrations of phenytoin and pentobarbital, neither of which were prescribed during her hospital stay. Dr. Gill said it turned out that the woman and her friends worked at a veterinarian’s office, and the medication they used to euthanize dogs was a combination of phenytoin and pentobarbital.

“The death was certified as a homicide because of the direct actions of another, but a reasonable argument could be made for suicide,” Dr. Gill said.

In a similar case reported in the journal Science & Justice, a 64-year-old cardiologist was found lifeless by his wife after he collapsed near the stairs of his home. Next to his body was a bottle of whiskey and two cups, one that appeared to be used for the alcohol and one with a yellowish liquid smelling of honey. The wife reported that her husband always drank whiskey with honey before bed. The death was initially classified as natural, but after vehement protest by the family, a forensic autopsy was performed. 

Prior to the autopsy, death investigators learned the decedent, who was a well-known and successful practitioner in his community, had Parkinson’s disease. At times, he could not sign his prescriptions because of the increasing tremor in his hands, according to the case study. Investigators learned the patient’s mother had also suffered from Parkinson’s, and that her son had witnessed her decline. 

The autopsy revealed only nonspecific lesions such as acute stasis of the viscera, moderate pulmonary and cerebral edema, and moderate generalized atheromatosis. Histological examinations did not yield any unusual findings.

An analysis of the beverage containers detected pentobarbital in the yellowish syrup residue of the second cup. Testing of the doctor’s peripheral blood revealed the presence of a metabolite of pentobarbital, ethanol, and traces of phenobarbital. In addition, a urine analysis showed the presence of venlafaxine, an antidepressant, as well as the benzophenone of lorazepam, a sedating benzodiazepine, and metoclopramide, an antiemetic.

Lead author C. Brandt-Casadevall, MD, and colleagues wrote that the levels were clearly compatible with a scenario of a pentobarbital overdose with a lethal outcome.

“... It is obvious that the victim attempted to hide his suicide from his family circle,” Dr. Brandt-Casadevall and colleagues wrote. “Thus, we obtained no evidence indicating that he might have spoken at any point of putting an end to his life. There was no written note. The victim did not wait to be alone at home. Instead, he committed his act in a routine situation: his wife was watching television late at night and he was upstairs, presumably going to sleep. Thus, he had one to two hours at his disposal, and he ingested a very fast-acting drug which would make any attempt at reanimation impossible, even after a brief period of time. This may have induced the physician in charge to believe that the cause of death was cardiac origin, a likely hypothesis given the age of the victim.”
 

What to do when a terminally ill patient talks suicide

When a terminally ill patient expresses the desire to end his or her life, it’s important to understand that desire is often a result of existential suffering, a sense of hopelessness, and lack of social support, said Lynn A. Jansen, PhD, a bioethicist at the University of Arizona in Tucson.

“The duty of beneficence requires that physicians attempt to provide the support and care that is needed,” said Dr. Jansen. “Here, interdisciplinary teamwork is important and should be utilized. Physicians should refer patients to professionals, such as social workers, pastoral care, psychologists, etc., who are better able to address these issues.”

The rate of desire for a hastened death among terminally ill patients ranges from 17% to 45%, depending on the population studied and how the desire is evaluated, according to an analysis in the Primary Care Companion to the Journal of Clinical Psychiatry. In one study, 14% of about 130 palliative care patients with cancer had a strong desire to quicken the dying process.

In addition, patients with neurologic disorders have a significantly higher suicide rate than that of those without neurologic disorders, a recent JAMA study found. About 1 in 150 patients diagnosed with a neurological disorder dies by suicide, the analysis determined. 

A tricky point to remember is that a desire by a terminally ill patient to hasten his or her death by suicide should not be taken by itself to indicate depression, Dr. Jansen noted.

“In principle, such patients can make an autonomous decision to end their lives,” she said. “However, the expression of such a desire is very often associated with depression and forms of suffering that can be effectively addressed by the health care team.”

Physicians can also explore other avenues with the patient such as palliative care or making sure adequate pain relief is available, added Robert Klitzman, MD, professor of psychiatry and academic director of the master of science in bioethics program at Columbia University, New York.

“If they are saying it’s because they are distressed, ethically, a doctor can and should find ways to decrease their distress,” he said.

Of course, those who practice in the U.S. jurisdictions that have physician-assisted-dying laws have different legal and ethical elements to consider. Physicians in these areas have no ethical duty to participate in the process, Dr. Jansen said, but they have a duty to refer patients who express a desire to pursue physician aid-in-dying to another provider who can assist them.

Physician aid-in-dying laws vary somewhat so it’s important that physicians in these areas be aware of their specific statute, Dr. Klitzman said. California, Colorado, Hawaii, Maine, New Jersey, New Mexico, Oregon, Vermont, Washington, and the District of Columbia have these laws.

“In these states, if a terminally ill patient says they don’t want to live anymore, a physician would first decide if this is a result of depression or if it’s a request for physician aid-in-dying,” he said. “Even then, in most cases, the patient would be evaluated by not one, but two different health professionals at two different points. We want to see if it is a consistent decision that the person has made that they want physician aid-in-dying, and not just that they’ve had a bad day or a setback in their treatment.”

In the case of the internist who told no one of his patient’s suicide plan, Dr. Klitzman said he would have dug deeper into the patient’s mindset.

“Not knowing anything about the patient or the doctor, I would have responded differently,” he said. “I think a physician should address why a patient feels that way. They may feel their pain is unbearable, and we potentially offer more pain relief. Maybe the patient shows evidence of having depression, which may be treatable [with medication]. The patient would then feel better and be able to spend quality time with family and loved ones, make sure their affairs are in order, and have a chance to say goodbye.”

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

An internist will never forget the dark secret his patient revealed during a routine visit – or the grim aftermath. 

The patient, who had a progressive, incurable neurological condition, confided that he planned to kill himself. The patient intended to conceal the true manner and make the death look natural.

“[He planned to do it] very carefully at home so no one would know,” said the internist, who remains anonymous. “[He shared] the methods he would use.”

Perhaps more shocking than the patient’s confession was the physician’s response. 

“He did not require my help to do what he planned, and I did not try to stop him,” said the internist. “I reported his death as ‘natural causes’ and never told anyone.”

The account comes from a response to Medscape’s 2020 Ethics Report in which physicians were asked about their toughest ethical dilemmas. Many physicians shared secrets and dilemmas that have haunted them for years.  An ob.gyn., for instance, wrote about struggling with whether to tell a father that his newborn baby was not his genetic child. The newborn had a blood type that made it impossible for the father to be biologically related to the infant, the anonymous doctor wrote.

“I told the wife who then informed me she had a lover,” the ob.gyn. said. “I never told the husband.”

It’s uncertain whether carrying the burden of such hidden knowledge affected the physicians involved in these cases. However, in general, secrets can weigh heavily on the minds of those who keep them and can contribute to stress, said Malia Mason, PhD, a psychologist and dean of research at Columbia Business School in New York. Holding onto secrets can cause depression and anxiety, research shows. The more often people think about the secret, the greater the impact, according to a recent study coauthored by Dr. Mason.

“Keeping a secret diminishes well-being,” Dr. Mason said. “It makes people feel socially distant. It lowers relationship satisfaction, and it leads people to feel inauthentic. The reason that secrets do this is because people think about them all the time. The more you think about it, the more you see these consequences.”

Feelings that stem from a secret depend on the content. The more immoral a secret is thought to be, the more people feel ashamed, according to a 2021 analysis of thousands of secrets, reported by Michael L. Slepian, PhD, and Alex Koch, PhD. However, secrets more related to a person’s profession are often internalized differently, the study found. The more a secret fell higher on the profession/goal-oriented dimension, the more people felt they had insight into the secret, according to the analysis. For example, having clear thinking about the secret and/or knowing how to handle it. 

“The more shame participants felt from their secret, the more they indicated the secret hurt their well-being,” Dr. Slepian and Dr. Koch wrote in the study. “The more insight participants felt they had into their secret, the less they indicated the secret hurt their well-being.”
 

Suspicious deaths exposed after investigations

The internist’s account of keeping his patient’s suicide a secret raises many questions, such as how the patient masked his manner of death. The internist did not share any more details about the incident. 

Suicides are among the most challenging manners of deaths to certify, according to James Gill, MD, a pathologist and president of the National Association of Medical Examiners. Death investigators must demonstrate intent, meaning the individuals caused the injury to intentionally harm themselves. Fewer than half of people who die by suicide leave a note, Dr. Gill said, so investigators can’t rely on the absence or the presence of a note in making their determination.

A decedent who had cancer or a severe neurological disorder presents further challenges, said Dr. Gill, who serves as chief medical examiner for the state of Connecticut.

“These [deaths] may not be unexpected and may not be reported to the medical examiner/coroner,” Dr. Gill said. “If there is no suspicion and the treating doctor is willing to sign the death certificate, the death will not come under the jurisdiction of the medical examiner.”

Dr. Gill recalled a death his colleague once investigated that appeared to be natural but emerged as something else after a deeper look. 

A woman with metastatic breast cancer was about to be discharged from a hospital into hospice the next morning. The night before, she had a “going away” party with friends who came to visit her in the hospital. Shortly after the friends left, the woman was found dead. Because of her condition, she could have died at any time, Dr. Gill said, but she also had a history of depression and hospital staff were suspicious. The death was reported to the medical examiner’s office.

Toxicology testing found markedly elevated concentrations of phenytoin and pentobarbital, neither of which were prescribed during her hospital stay. Dr. Gill said it turned out that the woman and her friends worked at a veterinarian’s office, and the medication they used to euthanize dogs was a combination of phenytoin and pentobarbital.

“The death was certified as a homicide because of the direct actions of another, but a reasonable argument could be made for suicide,” Dr. Gill said.

In a similar case reported in the journal Science & Justice, a 64-year-old cardiologist was found lifeless by his wife after he collapsed near the stairs of his home. Next to his body was a bottle of whiskey and two cups, one that appeared to be used for the alcohol and one with a yellowish liquid smelling of honey. The wife reported that her husband always drank whiskey with honey before bed. The death was initially classified as natural, but after vehement protest by the family, a forensic autopsy was performed. 

Prior to the autopsy, death investigators learned the decedent, who was a well-known and successful practitioner in his community, had Parkinson’s disease. At times, he could not sign his prescriptions because of the increasing tremor in his hands, according to the case study. Investigators learned the patient’s mother had also suffered from Parkinson’s, and that her son had witnessed her decline. 

The autopsy revealed only nonspecific lesions such as acute stasis of the viscera, moderate pulmonary and cerebral edema, and moderate generalized atheromatosis. Histological examinations did not yield any unusual findings.

An analysis of the beverage containers detected pentobarbital in the yellowish syrup residue of the second cup. Testing of the doctor’s peripheral blood revealed the presence of a metabolite of pentobarbital, ethanol, and traces of phenobarbital. In addition, a urine analysis showed the presence of venlafaxine, an antidepressant, as well as the benzophenone of lorazepam, a sedating benzodiazepine, and metoclopramide, an antiemetic.

Lead author C. Brandt-Casadevall, MD, and colleagues wrote that the levels were clearly compatible with a scenario of a pentobarbital overdose with a lethal outcome.

“... It is obvious that the victim attempted to hide his suicide from his family circle,” Dr. Brandt-Casadevall and colleagues wrote. “Thus, we obtained no evidence indicating that he might have spoken at any point of putting an end to his life. There was no written note. The victim did not wait to be alone at home. Instead, he committed his act in a routine situation: his wife was watching television late at night and he was upstairs, presumably going to sleep. Thus, he had one to two hours at his disposal, and he ingested a very fast-acting drug which would make any attempt at reanimation impossible, even after a brief period of time. This may have induced the physician in charge to believe that the cause of death was cardiac origin, a likely hypothesis given the age of the victim.”
 

What to do when a terminally ill patient talks suicide

When a terminally ill patient expresses the desire to end his or her life, it’s important to understand that desire is often a result of existential suffering, a sense of hopelessness, and lack of social support, said Lynn A. Jansen, PhD, a bioethicist at the University of Arizona in Tucson.

“The duty of beneficence requires that physicians attempt to provide the support and care that is needed,” said Dr. Jansen. “Here, interdisciplinary teamwork is important and should be utilized. Physicians should refer patients to professionals, such as social workers, pastoral care, psychologists, etc., who are better able to address these issues.”

The rate of desire for a hastened death among terminally ill patients ranges from 17% to 45%, depending on the population studied and how the desire is evaluated, according to an analysis in the Primary Care Companion to the Journal of Clinical Psychiatry. In one study, 14% of about 130 palliative care patients with cancer had a strong desire to quicken the dying process.

In addition, patients with neurologic disorders have a significantly higher suicide rate than that of those without neurologic disorders, a recent JAMA study found. About 1 in 150 patients diagnosed with a neurological disorder dies by suicide, the analysis determined. 

A tricky point to remember is that a desire by a terminally ill patient to hasten his or her death by suicide should not be taken by itself to indicate depression, Dr. Jansen noted.

“In principle, such patients can make an autonomous decision to end their lives,” she said. “However, the expression of such a desire is very often associated with depression and forms of suffering that can be effectively addressed by the health care team.”

Physicians can also explore other avenues with the patient such as palliative care or making sure adequate pain relief is available, added Robert Klitzman, MD, professor of psychiatry and academic director of the master of science in bioethics program at Columbia University, New York.

“If they are saying it’s because they are distressed, ethically, a doctor can and should find ways to decrease their distress,” he said.

Of course, those who practice in the U.S. jurisdictions that have physician-assisted-dying laws have different legal and ethical elements to consider. Physicians in these areas have no ethical duty to participate in the process, Dr. Jansen said, but they have a duty to refer patients who express a desire to pursue physician aid-in-dying to another provider who can assist them.

Physician aid-in-dying laws vary somewhat so it’s important that physicians in these areas be aware of their specific statute, Dr. Klitzman said. California, Colorado, Hawaii, Maine, New Jersey, New Mexico, Oregon, Vermont, Washington, and the District of Columbia have these laws.

“In these states, if a terminally ill patient says they don’t want to live anymore, a physician would first decide if this is a result of depression or if it’s a request for physician aid-in-dying,” he said. “Even then, in most cases, the patient would be evaluated by not one, but two different health professionals at two different points. We want to see if it is a consistent decision that the person has made that they want physician aid-in-dying, and not just that they’ve had a bad day or a setback in their treatment.”

In the case of the internist who told no one of his patient’s suicide plan, Dr. Klitzman said he would have dug deeper into the patient’s mindset.

“Not knowing anything about the patient or the doctor, I would have responded differently,” he said. “I think a physician should address why a patient feels that way. They may feel their pain is unbearable, and we potentially offer more pain relief. Maybe the patient shows evidence of having depression, which may be treatable [with medication]. The patient would then feel better and be able to spend quality time with family and loved ones, make sure their affairs are in order, and have a chance to say goodbye.”

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

MRI results may not be effective at indicating disability for patients with secondary progressive multiple sclerosis (SPMS), new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.

The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.

However, “it is unclear if these associations are clinically meaningful,” they added.

Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.

The findings were published online July 26 in the Multiple Sclerosis Journal.
 

ASCEND data analysis

Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.

However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.

In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.

Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.

The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
 

Few significant associations

The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.

Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.

For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.

Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.

Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.

After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
 

Important disability contributors missed

The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).

Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).

Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.

From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.

“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.

The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.

“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
 

‘Interesting and provocative’

Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”

“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.

The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.

Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.

She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.

“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.

“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.

These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.

The investigators and Dr. Yeh have reported no relevant financial relationships.

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

MRI results may not be effective at indicating disability for patients with secondary progressive multiple sclerosis (SPMS), new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.

The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.

However, “it is unclear if these associations are clinically meaningful,” they added.

Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.

The findings were published online July 26 in the Multiple Sclerosis Journal.
 

ASCEND data analysis

Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.

However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.

In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.

Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.

The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
 

Few significant associations

The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.

Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.

For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.

Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.

Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.

After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
 

Important disability contributors missed

The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).

Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).

Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.

From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.

“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.

The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.

“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
 

‘Interesting and provocative’

Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”

“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.

The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.

Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.

She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.

“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.

“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.

These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.

The investigators and Dr. Yeh have reported no relevant financial relationships.

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

MRI results may not be effective at indicating disability for patients with secondary progressive multiple sclerosis (SPMS), new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.

The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.

However, “it is unclear if these associations are clinically meaningful,” they added.

Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.

The findings were published online July 26 in the Multiple Sclerosis Journal.
 

ASCEND data analysis

Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.

However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.

In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.

Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.

The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
 

Few significant associations

The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.

Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.

For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.

Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.

Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.

After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
 

Important disability contributors missed

The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).

Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).

Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.

From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.

“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.

The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.

“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
 

‘Interesting and provocative’

Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”

“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.

The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.

Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.

She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.

“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.

“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.

These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.

The investigators and Dr. Yeh have reported no relevant financial relationships.

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

Among middle-aged people without heart disease, drinking up to three cups of coffee per day was linked with a lower risk for stroke or death over the next decade, along with better heart structure and function, in a large, observational study.

S_Bachstroem/Getty Images

Specifically, light-to-moderate coffee drinking, defined as 0.5 to 3 cups per day, was associated with a 21% lower risk for stroke, a 17% lower risk for death from cardiovascular disease (CVD), and a 12% lower risk for death from all causes, as well as more favorable cardiac MRI findings, compared with nondrinkers (< 0.5 cup per day) during a median 11-year follow-up.

Heavy coffee drinkers, defined as those consuming more than three cups per day, on the other hand, likewise had more favorable cardiac MRI findings, but with similar (not lower) rates of stroke and CVD or all-cause mortality compared with nondrinkers.

Judit Simon, MD, presented these findings, from close to 500,000 participants in the UK Biobank study, at a press conference before an e-poster session at the virtual annual congress of the European Society of Cardiology.

“To our knowledge, this is the largest study to systematically assess the cardiovascular effects of regular coffee consumption in a population without diagnosed heart disease,” Dr. Simon, a PhD student at the Heart and Vascular Centre, Semmelweis University, Budapest, Hungary, said in an ESC press release.

The results “suggest that regular coffee consumption is safe, as even high daily intake was not associated with adverse cardiovascular outcomes and all-cause mortality after a follow-up of 10 to 15 years,” she said.

The imaging analysis showed that “compared with participants who did not drink coffee regularly, daily consumers had healthier sized and better functioning hearts,” Dr. Simon continued, “consistent with reversing the detrimental effects of aging on the heart.”

“The observed benefits might be partly explained by positive alterations in cardiac structure and function,” she speculated, adding that further studies are needed to explain the underlying mechanisms.

Instant coffee most popular

In this population, the coffee drinkers mostly drank instant coffee (55%), followed by filtered/ground (23%), decaffeinated (20%), or other types of coffee (2%), Dr. Simon said in an interview.

Risk for myocardial infarction (MI) or heart failure did not significantly differ for different categories of coffee intake, she added. The researchers did not study the effect of coffee consumption on atrial fibrillation (AF), she noted. 

Study limitations, Dr. Simon acknowledged, include that it was observational, so it cannot show causation, and that coffee consumption was self-reported in a questionnaire.

Invited to comment, Alice H. Lichtenstein, DSc, who was not involved with the research, said, “Consistent with prior data, this new study indicates there is no adverse effect of coffee consumption on cardiovascular health and there may be a benefit.”

However, “because of the nature of the data, it would not be recommended that an individual starting drinking coffee to improve cardiovascular health,” added Dr. Lichtenstein, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston.

But if people already drink coffee, “it is fine to continue, assuming that the coffee drinks are not high in added sugar and cream,” she said in an interview.
 

Coffee intake, CVD outcomes, and heart structure

To study the relationship between coffee intake and incident MI, stroke, and death, as well as heart structure, the researchers examined data from the UK Biobank, which recruited 500,000 people aged 40-69 years in 2006-2010 from across the United Kingdom.

They identified 468,629 participants with no signs of heart disease at recruitment and an average age of 56 years, of whom 56% were women.

The participants were divided into three groups based on usual coffee intake: none (22% of participants), light-to-moderate (58%), and high (20%).

Median tea intake was three cups per day overall, four cups per day in noncoffee drinkers, three cups per day in light-to-moderate coffee drinkers, and one cup per day in high coffee drinkers.

Compared to not drinking coffee, light-to-moderate coffee consumption was associated with lower risks for all-cause death (hazard ratio [HR], 0.88; P < .001), CVD death (HR, 0.83; P = .006), and stroke (HR, 0.79; P = .037), over a median follow-up of 11 years, after adjustment for sex; weight; height; smoking status; physical activity; high blood pressure; diabetes; cholesterol level; socioeconomic status; and usual intake of alcohol, meat, tea, fruit, and vegetables.  

In the 30,650 participants who had cardiac MRI data, the study found that compared with not drinking coffee, both light-to-moderate and high coffee consumption were associated with significantly increased left and right ventricular end-systolic and end-diastolic volumes, and with greater left ventricular mass (all P < .001).

These differences were small but significant, Dr. Simon stressed, because this was a cohort of healthy patients who did not have CVD (heart failure, MI, stroke, AF) at baseline, although some had hypertension or diabetes.

Press conference chairperson, Steen Dalby Kristensen, MD, professor and cardiologist, Aarhus University Hospital, Denmark, a coffee lover himself, wanted to know if an amount such as two, three, or four cups of coffee was optimal to see these heart benefits, and whether there were differences in benefits seen with drinking different types of coffee.

The analysis did not identify an optimal coffee intake, Dr. Simon said. Compared with not drinking coffee, she continued, drinking instant coffee was associated with a lower risk for all-cause mortality, but not CVD mortality or stroke.

Drinking filtered coffee was associated with lower risks for all three outcomes, but there was no significant difference in risk for MI. Drinking decaffeinated coffee was associated with a lower risk for all-cause and CVD mortality.

“Decaffeinated coffee contains a small amount of caffeine,” Dr. Simon pointed out. “Something other than caffeine might have this protective impact,” she suggested.

The researchers and Dr. Lichtenstein declared having no relevant financial disclosures.  

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

Among middle-aged people without heart disease, drinking up to three cups of coffee per day was linked with a lower risk for stroke or death over the next decade, along with better heart structure and function, in a large, observational study.

S_Bachstroem/Getty Images

Specifically, light-to-moderate coffee drinking, defined as 0.5 to 3 cups per day, was associated with a 21% lower risk for stroke, a 17% lower risk for death from cardiovascular disease (CVD), and a 12% lower risk for death from all causes, as well as more favorable cardiac MRI findings, compared with nondrinkers (< 0.5 cup per day) during a median 11-year follow-up.

Heavy coffee drinkers, defined as those consuming more than three cups per day, on the other hand, likewise had more favorable cardiac MRI findings, but with similar (not lower) rates of stroke and CVD or all-cause mortality compared with nondrinkers.

Judit Simon, MD, presented these findings, from close to 500,000 participants in the UK Biobank study, at a press conference before an e-poster session at the virtual annual congress of the European Society of Cardiology.

“To our knowledge, this is the largest study to systematically assess the cardiovascular effects of regular coffee consumption in a population without diagnosed heart disease,” Dr. Simon, a PhD student at the Heart and Vascular Centre, Semmelweis University, Budapest, Hungary, said in an ESC press release.

The results “suggest that regular coffee consumption is safe, as even high daily intake was not associated with adverse cardiovascular outcomes and all-cause mortality after a follow-up of 10 to 15 years,” she said.

The imaging analysis showed that “compared with participants who did not drink coffee regularly, daily consumers had healthier sized and better functioning hearts,” Dr. Simon continued, “consistent with reversing the detrimental effects of aging on the heart.”

“The observed benefits might be partly explained by positive alterations in cardiac structure and function,” she speculated, adding that further studies are needed to explain the underlying mechanisms.

Instant coffee most popular

In this population, the coffee drinkers mostly drank instant coffee (55%), followed by filtered/ground (23%), decaffeinated (20%), or other types of coffee (2%), Dr. Simon said in an interview.

Risk for myocardial infarction (MI) or heart failure did not significantly differ for different categories of coffee intake, she added. The researchers did not study the effect of coffee consumption on atrial fibrillation (AF), she noted. 

Study limitations, Dr. Simon acknowledged, include that it was observational, so it cannot show causation, and that coffee consumption was self-reported in a questionnaire.

Invited to comment, Alice H. Lichtenstein, DSc, who was not involved with the research, said, “Consistent with prior data, this new study indicates there is no adverse effect of coffee consumption on cardiovascular health and there may be a benefit.”

However, “because of the nature of the data, it would not be recommended that an individual starting drinking coffee to improve cardiovascular health,” added Dr. Lichtenstein, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston.

But if people already drink coffee, “it is fine to continue, assuming that the coffee drinks are not high in added sugar and cream,” she said in an interview.
 

Coffee intake, CVD outcomes, and heart structure

To study the relationship between coffee intake and incident MI, stroke, and death, as well as heart structure, the researchers examined data from the UK Biobank, which recruited 500,000 people aged 40-69 years in 2006-2010 from across the United Kingdom.

They identified 468,629 participants with no signs of heart disease at recruitment and an average age of 56 years, of whom 56% were women.

The participants were divided into three groups based on usual coffee intake: none (22% of participants), light-to-moderate (58%), and high (20%).

Median tea intake was three cups per day overall, four cups per day in noncoffee drinkers, three cups per day in light-to-moderate coffee drinkers, and one cup per day in high coffee drinkers.

Compared to not drinking coffee, light-to-moderate coffee consumption was associated with lower risks for all-cause death (hazard ratio [HR], 0.88; P < .001), CVD death (HR, 0.83; P = .006), and stroke (HR, 0.79; P = .037), over a median follow-up of 11 years, after adjustment for sex; weight; height; smoking status; physical activity; high blood pressure; diabetes; cholesterol level; socioeconomic status; and usual intake of alcohol, meat, tea, fruit, and vegetables.  

In the 30,650 participants who had cardiac MRI data, the study found that compared with not drinking coffee, both light-to-moderate and high coffee consumption were associated with significantly increased left and right ventricular end-systolic and end-diastolic volumes, and with greater left ventricular mass (all P < .001).

These differences were small but significant, Dr. Simon stressed, because this was a cohort of healthy patients who did not have CVD (heart failure, MI, stroke, AF) at baseline, although some had hypertension or diabetes.

Press conference chairperson, Steen Dalby Kristensen, MD, professor and cardiologist, Aarhus University Hospital, Denmark, a coffee lover himself, wanted to know if an amount such as two, three, or four cups of coffee was optimal to see these heart benefits, and whether there were differences in benefits seen with drinking different types of coffee.

The analysis did not identify an optimal coffee intake, Dr. Simon said. Compared with not drinking coffee, she continued, drinking instant coffee was associated with a lower risk for all-cause mortality, but not CVD mortality or stroke.

Drinking filtered coffee was associated with lower risks for all three outcomes, but there was no significant difference in risk for MI. Drinking decaffeinated coffee was associated with a lower risk for all-cause and CVD mortality.

“Decaffeinated coffee contains a small amount of caffeine,” Dr. Simon pointed out. “Something other than caffeine might have this protective impact,” she suggested.

The researchers and Dr. Lichtenstein declared having no relevant financial disclosures.  

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

Among middle-aged people without heart disease, drinking up to three cups of coffee per day was linked with a lower risk for stroke or death over the next decade, along with better heart structure and function, in a large, observational study.

S_Bachstroem/Getty Images

Specifically, light-to-moderate coffee drinking, defined as 0.5 to 3 cups per day, was associated with a 21% lower risk for stroke, a 17% lower risk for death from cardiovascular disease (CVD), and a 12% lower risk for death from all causes, as well as more favorable cardiac MRI findings, compared with nondrinkers (< 0.5 cup per day) during a median 11-year follow-up.

Heavy coffee drinkers, defined as those consuming more than three cups per day, on the other hand, likewise had more favorable cardiac MRI findings, but with similar (not lower) rates of stroke and CVD or all-cause mortality compared with nondrinkers.

Judit Simon, MD, presented these findings, from close to 500,000 participants in the UK Biobank study, at a press conference before an e-poster session at the virtual annual congress of the European Society of Cardiology.

“To our knowledge, this is the largest study to systematically assess the cardiovascular effects of regular coffee consumption in a population without diagnosed heart disease,” Dr. Simon, a PhD student at the Heart and Vascular Centre, Semmelweis University, Budapest, Hungary, said in an ESC press release.

The results “suggest that regular coffee consumption is safe, as even high daily intake was not associated with adverse cardiovascular outcomes and all-cause mortality after a follow-up of 10 to 15 years,” she said.

The imaging analysis showed that “compared with participants who did not drink coffee regularly, daily consumers had healthier sized and better functioning hearts,” Dr. Simon continued, “consistent with reversing the detrimental effects of aging on the heart.”

“The observed benefits might be partly explained by positive alterations in cardiac structure and function,” she speculated, adding that further studies are needed to explain the underlying mechanisms.

Instant coffee most popular

In this population, the coffee drinkers mostly drank instant coffee (55%), followed by filtered/ground (23%), decaffeinated (20%), or other types of coffee (2%), Dr. Simon said in an interview.

Risk for myocardial infarction (MI) or heart failure did not significantly differ for different categories of coffee intake, she added. The researchers did not study the effect of coffee consumption on atrial fibrillation (AF), she noted. 

Study limitations, Dr. Simon acknowledged, include that it was observational, so it cannot show causation, and that coffee consumption was self-reported in a questionnaire.

Invited to comment, Alice H. Lichtenstein, DSc, who was not involved with the research, said, “Consistent with prior data, this new study indicates there is no adverse effect of coffee consumption on cardiovascular health and there may be a benefit.”

However, “because of the nature of the data, it would not be recommended that an individual starting drinking coffee to improve cardiovascular health,” added Dr. Lichtenstein, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston.

But if people already drink coffee, “it is fine to continue, assuming that the coffee drinks are not high in added sugar and cream,” she said in an interview.
 

Coffee intake, CVD outcomes, and heart structure

To study the relationship between coffee intake and incident MI, stroke, and death, as well as heart structure, the researchers examined data from the UK Biobank, which recruited 500,000 people aged 40-69 years in 2006-2010 from across the United Kingdom.

They identified 468,629 participants with no signs of heart disease at recruitment and an average age of 56 years, of whom 56% were women.

The participants were divided into three groups based on usual coffee intake: none (22% of participants), light-to-moderate (58%), and high (20%).

Median tea intake was three cups per day overall, four cups per day in noncoffee drinkers, three cups per day in light-to-moderate coffee drinkers, and one cup per day in high coffee drinkers.

Compared to not drinking coffee, light-to-moderate coffee consumption was associated with lower risks for all-cause death (hazard ratio [HR], 0.88; P < .001), CVD death (HR, 0.83; P = .006), and stroke (HR, 0.79; P = .037), over a median follow-up of 11 years, after adjustment for sex; weight; height; smoking status; physical activity; high blood pressure; diabetes; cholesterol level; socioeconomic status; and usual intake of alcohol, meat, tea, fruit, and vegetables.  

In the 30,650 participants who had cardiac MRI data, the study found that compared with not drinking coffee, both light-to-moderate and high coffee consumption were associated with significantly increased left and right ventricular end-systolic and end-diastolic volumes, and with greater left ventricular mass (all P < .001).

These differences were small but significant, Dr. Simon stressed, because this was a cohort of healthy patients who did not have CVD (heart failure, MI, stroke, AF) at baseline, although some had hypertension or diabetes.

Press conference chairperson, Steen Dalby Kristensen, MD, professor and cardiologist, Aarhus University Hospital, Denmark, a coffee lover himself, wanted to know if an amount such as two, three, or four cups of coffee was optimal to see these heart benefits, and whether there were differences in benefits seen with drinking different types of coffee.

The analysis did not identify an optimal coffee intake, Dr. Simon said. Compared with not drinking coffee, she continued, drinking instant coffee was associated with a lower risk for all-cause mortality, but not CVD mortality or stroke.

Drinking filtered coffee was associated with lower risks for all three outcomes, but there was no significant difference in risk for MI. Drinking decaffeinated coffee was associated with a lower risk for all-cause and CVD mortality.

“Decaffeinated coffee contains a small amount of caffeine,” Dr. Simon pointed out. “Something other than caffeine might have this protective impact,” she suggested.

The researchers and Dr. Lichtenstein declared having no relevant financial disclosures.  

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

Artificial intelligence (AI)–powered neural networks modeled on real human brain connectivity patterns perform cognitive tasks better than traditional AI systems, new research suggests. “This work opens new opportunities to discover how the network organization of the brain optimizes cognitive capacity,” wrote researchers from The Neuro (Montreal Neurological Institute–Hospital) and the Quebec Artificial Intelligence Institute.

Courtesy Dr. Bratislav Misic

Senior investigator Bratislav Misic, PhD, said the research has potential clinical application for studying diseases of the brain, which is something his team is actively working on. “For example, using MRI techniques, we can measure different patterns of atrophy in neurodegenerative diseases such as Alzheimer’s disease,” he said.

“We can use these disease patterns from real patients to artificially lesion these connectomes and to ask how a particular disease causes a particular pattern of symptoms and cognitive deficits,” he added.

The findings were published online in Nature Machine Intelligence.

Unique approach

Using brain imaging data, the investigators reconstructed a human brain connectivity pattern and applied it to an artificial neural network. After training, the artificial neural network successfully performed a working memory task more flexibly and efficiently than other “benchmark” AI systems.

The researchers noted that their approach is unique because previous work on brain connectivity, also known as connectomics, has focused on describing brain organization without regard to how it actually functions.

Traditional artificial neural network have arbitrary structures that do not reflect how real brain networks are organized. Integrating brain connectomics into the construction of artificial neural network can reveal how the wiring of the brain supports specific cognitive skills, the investigators wrote.

“Up until now, if you look at how neural networks are constructed, the architectures that are used are very ad hoc and very problem specific,” Dr. Misic said. “But the connectomics revolution that’s happened in neuroscience over the past 20 years or so has given us the ability to really measure and trace out connection patterns in a variety of organisms, including the human brain.”

He noted that the researchers took wiring patterns of the real human brain and implemented it as an artificial neural network. They then “trained that network to perform a very simple cognitive task, and when you compare it to other benchmark architectures, it actually does better.”

This shows that there is “something fundamentally different about how the human brain is wired up and that the design principles that we can see in the human brain could be used to potentially build better artificial networks,” Dr. Misic concluded.

Funding for the research was provided by the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains, Healthy Lives initiative, and by the Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Quebec – Santé, the Canadian Institute for Advanced Research, Canada Research Chairs, Fonds de Recherche du Quebec – Nature et Technologies, and the Centre UNIQUE (Union of Neuroscience and Artificial Intelligence). The investigators have reported no relevant financial relationships.

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

Artificial intelligence (AI)–powered neural networks modeled on real human brain connectivity patterns perform cognitive tasks better than traditional AI systems, new research suggests. “This work opens new opportunities to discover how the network organization of the brain optimizes cognitive capacity,” wrote researchers from The Neuro (Montreal Neurological Institute–Hospital) and the Quebec Artificial Intelligence Institute.

Courtesy Dr. Bratislav Misic

Senior investigator Bratislav Misic, PhD, said the research has potential clinical application for studying diseases of the brain, which is something his team is actively working on. “For example, using MRI techniques, we can measure different patterns of atrophy in neurodegenerative diseases such as Alzheimer’s disease,” he said.

“We can use these disease patterns from real patients to artificially lesion these connectomes and to ask how a particular disease causes a particular pattern of symptoms and cognitive deficits,” he added.

The findings were published online in Nature Machine Intelligence.

Unique approach

Using brain imaging data, the investigators reconstructed a human brain connectivity pattern and applied it to an artificial neural network. After training, the artificial neural network successfully performed a working memory task more flexibly and efficiently than other “benchmark” AI systems.

The researchers noted that their approach is unique because previous work on brain connectivity, also known as connectomics, has focused on describing brain organization without regard to how it actually functions.

Traditional artificial neural network have arbitrary structures that do not reflect how real brain networks are organized. Integrating brain connectomics into the construction of artificial neural network can reveal how the wiring of the brain supports specific cognitive skills, the investigators wrote.

“Up until now, if you look at how neural networks are constructed, the architectures that are used are very ad hoc and very problem specific,” Dr. Misic said. “But the connectomics revolution that’s happened in neuroscience over the past 20 years or so has given us the ability to really measure and trace out connection patterns in a variety of organisms, including the human brain.”

He noted that the researchers took wiring patterns of the real human brain and implemented it as an artificial neural network. They then “trained that network to perform a very simple cognitive task, and when you compare it to other benchmark architectures, it actually does better.”

This shows that there is “something fundamentally different about how the human brain is wired up and that the design principles that we can see in the human brain could be used to potentially build better artificial networks,” Dr. Misic concluded.

Funding for the research was provided by the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains, Healthy Lives initiative, and by the Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Quebec – Santé, the Canadian Institute for Advanced Research, Canada Research Chairs, Fonds de Recherche du Quebec – Nature et Technologies, and the Centre UNIQUE (Union of Neuroscience and Artificial Intelligence). The investigators have reported no relevant financial relationships.

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

Artificial intelligence (AI)–powered neural networks modeled on real human brain connectivity patterns perform cognitive tasks better than traditional AI systems, new research suggests. “This work opens new opportunities to discover how the network organization of the brain optimizes cognitive capacity,” wrote researchers from The Neuro (Montreal Neurological Institute–Hospital) and the Quebec Artificial Intelligence Institute.

Courtesy Dr. Bratislav Misic

Senior investigator Bratislav Misic, PhD, said the research has potential clinical application for studying diseases of the brain, which is something his team is actively working on. “For example, using MRI techniques, we can measure different patterns of atrophy in neurodegenerative diseases such as Alzheimer’s disease,” he said.

“We can use these disease patterns from real patients to artificially lesion these connectomes and to ask how a particular disease causes a particular pattern of symptoms and cognitive deficits,” he added.

The findings were published online in Nature Machine Intelligence.

Unique approach

Using brain imaging data, the investigators reconstructed a human brain connectivity pattern and applied it to an artificial neural network. After training, the artificial neural network successfully performed a working memory task more flexibly and efficiently than other “benchmark” AI systems.

The researchers noted that their approach is unique because previous work on brain connectivity, also known as connectomics, has focused on describing brain organization without regard to how it actually functions.

Traditional artificial neural network have arbitrary structures that do not reflect how real brain networks are organized. Integrating brain connectomics into the construction of artificial neural network can reveal how the wiring of the brain supports specific cognitive skills, the investigators wrote.

“Up until now, if you look at how neural networks are constructed, the architectures that are used are very ad hoc and very problem specific,” Dr. Misic said. “But the connectomics revolution that’s happened in neuroscience over the past 20 years or so has given us the ability to really measure and trace out connection patterns in a variety of organisms, including the human brain.”

He noted that the researchers took wiring patterns of the real human brain and implemented it as an artificial neural network. They then “trained that network to perform a very simple cognitive task, and when you compare it to other benchmark architectures, it actually does better.”

This shows that there is “something fundamentally different about how the human brain is wired up and that the design principles that we can see in the human brain could be used to potentially build better artificial networks,” Dr. Misic concluded.

Funding for the research was provided by the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains, Healthy Lives initiative, and by the Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Quebec – Santé, the Canadian Institute for Advanced Research, Canada Research Chairs, Fonds de Recherche du Quebec – Nature et Technologies, and the Centre UNIQUE (Union of Neuroscience and Artificial Intelligence). The investigators have reported no relevant financial relationships.

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

In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the National Institute of Allergy and Infectious Diseases has begun a phase 2 trial to assess the antibody response to a booster dose of the Pfizer-BioNTech, Moderna, or Janssen vaccine in people with autoimmune disease who did not respond to their original COVID-19 vaccine regimen, according to an announcement.

The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.

The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.

The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.

The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.

Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:

• Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
• Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.

A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.

Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.

The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.

Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.

The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.

[email protected]

In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the National Institute of Allergy and Infectious Diseases has begun a phase 2 trial to assess the antibody response to a booster dose of the Pfizer-BioNTech, Moderna, or Janssen vaccine in people with autoimmune disease who did not respond to their original COVID-19 vaccine regimen, according to an announcement.

The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.

The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.

The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.

The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.

Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:

• Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
• Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.

A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.

Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.

The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.

Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.

The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.

[email protected]

In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the National Institute of Allergy and Infectious Diseases has begun a phase 2 trial to assess the antibody response to a booster dose of the Pfizer-BioNTech, Moderna, or Janssen vaccine in people with autoimmune disease who did not respond to their original COVID-19 vaccine regimen, according to an announcement.

The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.

The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.

The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.

The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.

Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:

• Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
• Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.

A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.

Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.

The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.

Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.

The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.

[email protected]

Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.

This pattern in schizophrenia makes it all the more important to ensure that patients stay on medication to prevent future episodes. “The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.

That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
 

Reconceptualizing the illness

Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.

The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.

Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.

Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine_2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.

In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.

“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”

Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”

During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.

Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.

This pattern in schizophrenia makes it all the more important to ensure that patients stay on medication to prevent future episodes. “The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.

That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
 

Reconceptualizing the illness

Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.

The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.

Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.

Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine_2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.

In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.

“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”

Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”

During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.

Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.

This pattern in schizophrenia makes it all the more important to ensure that patients stay on medication to prevent future episodes. “The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.

That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
 

Reconceptualizing the illness

Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.

The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.

Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.

Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine_2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.

In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.

“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”

Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”

During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.

The hallmark of Parkinson’s disease is the accompanying motor symptoms, but the condition can bring other challenges. Among those are nonmotor symptoms, including depression, dementia, and even psychosis.

The culprit is Lewy bodies, which are also responsible for Lewy body dementia. “What we call Lewy body dementia and Parkinson’s disease are caused by the same pathological process – the formation of Lewy bodies in the brain,” Leslie Citrome, MD, MPH, said in an interview. Dr. Citrome discussed some of the psychiatric comorbidities associated with Parkinson’s disease at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

In fact, the association goes both ways. “Many people with Parkinson’s disease develop a dementia. Many people with Lewy body dementia develop motor symptoms that look just like Parkinson’s disease,” said Dr. Citrome, professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, and president of the American Society for Clinical Psychopharmacology.

The motor symptoms of Parkinson’s disease are generally attributable to loss of striatal dopaminergic neurons, while nonmotor symptoms can be traced to loss of neurons in nondopaminergic regions. Nonmotor symptoms – often including sleep disorders, depression, cognitive changes, and psychosis – may occur before motor symptoms. Other problems may include autonomic dysfunction, such as constipation, sexual dysfunction, sweating, or urinary retention.

Patients might not be aware that nonmotor symptoms can occur with Parkinson’s disease and may not even consider mentioning mood changes or hallucinations to their neurologist. Family members may also be unaware.

Sleep problems are common in Parkinson’s disease, including rapid eye-movement sleep behavior disorders, vivid dreams, restless legs syndrome, insomnia, and daytime somnolence. Dopamine agonists may also cause unintended sleep.

Depression is extremely common, affecting up to 90% of Parkinson’s disease patients, and this may be related to dopaminergic losses. Antidepressant medications can worsen Parkinson’s disease symptoms: Tricyclic antidepressants increase risk of adverse events from anticholinergic drugs. Selective serotonin reuptake inhibitors (SSRIs) can exacerbate tremor and may increase risk of serotonin syndrome when combined with MAO‐B inhibitors.

Dr. Citrome was not aware of any antidepressant drugs that have been tested specifically in Parkinson’s disease patients, though “I’d be surprised if there wasn’t,” he said during the Q&A session. “There’s no one perfect antidepressant for people with depression associated with Parkinson’s disease. I would make sure to select one that they would tolerate and be willing to take and that doesn’t interfere with their treatment of their movement disorder, and (I would make sure) that there’s no drug-drug interaction,” he said.

Cognitive impairment or dementia is also very common, affecting about 75% of Parkinson’s patients. This can include reduced working memory, learning, and planning, and generally does not manifest until at least 1 year after motor symptoms have begun. Rivastigmine is Food and Drug Administration–approved for treatment of cognitive impairment in Parkinson’s disease.

As many as 60% of Parkinson’s disease patients suffer from psychosis at some point, often visual hallucinations or delusions, which can include beliefs of spousal infidelity.

Many clinicians prescribe quetiapine off label, but there are not compelling data to support that it reduces intensity and frequency of hallucinations and delusions, according to Dr. Citrome. However, it is relatively easy to prescribe, requiring no preauthorizations, it is inexpensive, and it may improve sleep.

The FDA approved pimavanserin in 2016 for hallucinations and delusions in Parkinson’s disease, and it doesn’t worsen motor symptoms, Dr. Citrome said. That’s because pimavanserin is a highly selective antagonist of the 5-HT2A receptor, with no effect on dopaminergic, histaminergic, adrenergic, or muscarinic receptors.

The drug improves positive symptoms beginning at days 29 and 43, compared with placebo. An analysis by Dr. Citrome’s group found a number needed to treat (NNT) of 7 to gain a benefit over placebo if the metric is a ≥ 30% reduction in baseline symptom score. The drug had an NNT of 9 to achieve a ≥ 50% reduction, and an NNT of 5 to achieve a score of much improved or very much improved on the Clinical Global Impression–Improvement (CGI-I) scale. In general, an NNT less than 10 suggests that a drug is clinically useful.

In contrast, the number needed to harm (NNH) represents the number of patients who would need to receive a therapy to add one adverse event, compared with placebo. A number greater than 10 indicates that the therapy may be tolerable.

Using various measures, the NNH was well over 10 for pimavanserin. With respect to somnolence, the NNH over placebo was 138, and for a weight gain of 7% or more, the NNH was 594.

Overall, the study found that 4 patients would need to be treated to achieve a benefit over placebo with respect to a ≥ 3–point improvement in the Scale of Positive Symptoms–Parkinson’s Disease (SAPS-PD), while 21 would need to receive the drug to lead to one additional discontinuation because of an adverse event, compared to placebo.

When researchers compared pimavanserin to off-label use of quetiapine, olanzapine, and clozapine, they found a Cohen’s d value of 0.50, which was better than quetiapine and olanzapine, but lower than for clozapine. However, there is no requirement of blood monitoring, and clozapine can potentially worsen motor symptoms.

Dr. Citrome’s presentation should be a reminder to neurologists that psychiatric disorders are an important patient concern, said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who moderated the session.

“I think this serves as a model to recognize that many neurological disorders actually present with numerous psychiatric disorders,” Dr. Nasrallah said during the meeting, presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

Dr. Citrome has consulted for AbbVie, Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer-Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular, Janssen, Karuna, Lundbeck, Lyndra, MedAvante-ProPhase, Merck, Neurocrine, Noven, Otsuka, Ovid, Relmada, Sage, Sunovion, and Teva. He has been a speaker for most of those companies, and he holds stock in Bristol Myers Squibb, Eli Lilly, J&J, Merck, and Pfizer.

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has served on a speakers bureau for most of those companies, in addition to that of Noven.

The hallmark of Parkinson’s disease is the accompanying motor symptoms, but the condition can bring other challenges. Among those are nonmotor symptoms, including depression, dementia, and even psychosis.

The culprit is Lewy bodies, which are also responsible for Lewy body dementia. “What we call Lewy body dementia and Parkinson’s disease are caused by the same pathological process – the formation of Lewy bodies in the brain,” Leslie Citrome, MD, MPH, said in an interview. Dr. Citrome discussed some of the psychiatric comorbidities associated with Parkinson’s disease at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

In fact, the association goes both ways. “Many people with Parkinson’s disease develop a dementia. Many people with Lewy body dementia develop motor symptoms that look just like Parkinson’s disease,” said Dr. Citrome, professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, and president of the American Society for Clinical Psychopharmacology.

The motor symptoms of Parkinson’s disease are generally attributable to loss of striatal dopaminergic neurons, while nonmotor symptoms can be traced to loss of neurons in nondopaminergic regions. Nonmotor symptoms – often including sleep disorders, depression, cognitive changes, and psychosis – may occur before motor symptoms. Other problems may include autonomic dysfunction, such as constipation, sexual dysfunction, sweating, or urinary retention.

Patients might not be aware that nonmotor symptoms can occur with Parkinson’s disease and may not even consider mentioning mood changes or hallucinations to their neurologist. Family members may also be unaware.

Sleep problems are common in Parkinson’s disease, including rapid eye-movement sleep behavior disorders, vivid dreams, restless legs syndrome, insomnia, and daytime somnolence. Dopamine agonists may also cause unintended sleep.

Depression is extremely common, affecting up to 90% of Parkinson’s disease patients, and this may be related to dopaminergic losses. Antidepressant medications can worsen Parkinson’s disease symptoms: Tricyclic antidepressants increase risk of adverse events from anticholinergic drugs. Selective serotonin reuptake inhibitors (SSRIs) can exacerbate tremor and may increase risk of serotonin syndrome when combined with MAO‐B inhibitors.

Dr. Citrome was not aware of any antidepressant drugs that have been tested specifically in Parkinson’s disease patients, though “I’d be surprised if there wasn’t,” he said during the Q&A session. “There’s no one perfect antidepressant for people with depression associated with Parkinson’s disease. I would make sure to select one that they would tolerate and be willing to take and that doesn’t interfere with their treatment of their movement disorder, and (I would make sure) that there’s no drug-drug interaction,” he said.

Cognitive impairment or dementia is also very common, affecting about 75% of Parkinson’s patients. This can include reduced working memory, learning, and planning, and generally does not manifest until at least 1 year after motor symptoms have begun. Rivastigmine is Food and Drug Administration–approved for treatment of cognitive impairment in Parkinson’s disease.

As many as 60% of Parkinson’s disease patients suffer from psychosis at some point, often visual hallucinations or delusions, which can include beliefs of spousal infidelity.

Many clinicians prescribe quetiapine off label, but there are not compelling data to support that it reduces intensity and frequency of hallucinations and delusions, according to Dr. Citrome. However, it is relatively easy to prescribe, requiring no preauthorizations, it is inexpensive, and it may improve sleep.

The FDA approved pimavanserin in 2016 for hallucinations and delusions in Parkinson’s disease, and it doesn’t worsen motor symptoms, Dr. Citrome said. That’s because pimavanserin is a highly selective antagonist of the 5-HT2A receptor, with no effect on dopaminergic, histaminergic, adrenergic, or muscarinic receptors.

The drug improves positive symptoms beginning at days 29 and 43, compared with placebo. An analysis by Dr. Citrome’s group found a number needed to treat (NNT) of 7 to gain a benefit over placebo if the metric is a ≥ 30% reduction in baseline symptom score. The drug had an NNT of 9 to achieve a ≥ 50% reduction, and an NNT of 5 to achieve a score of much improved or very much improved on the Clinical Global Impression–Improvement (CGI-I) scale. In general, an NNT less than 10 suggests that a drug is clinically useful.

In contrast, the number needed to harm (NNH) represents the number of patients who would need to receive a therapy to add one adverse event, compared with placebo. A number greater than 10 indicates that the therapy may be tolerable.

Using various measures, the NNH was well over 10 for pimavanserin. With respect to somnolence, the NNH over placebo was 138, and for a weight gain of 7% or more, the NNH was 594.

Overall, the study found that 4 patients would need to be treated to achieve a benefit over placebo with respect to a ≥ 3–point improvement in the Scale of Positive Symptoms–Parkinson’s Disease (SAPS-PD), while 21 would need to receive the drug to lead to one additional discontinuation because of an adverse event, compared to placebo.

When researchers compared pimavanserin to off-label use of quetiapine, olanzapine, and clozapine, they found a Cohen’s d value of 0.50, which was better than quetiapine and olanzapine, but lower than for clozapine. However, there is no requirement of blood monitoring, and clozapine can potentially worsen motor symptoms.

Dr. Citrome’s presentation should be a reminder to neurologists that psychiatric disorders are an important patient concern, said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who moderated the session.

“I think this serves as a model to recognize that many neurological disorders actually present with numerous psychiatric disorders,” Dr. Nasrallah said during the meeting, presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

Dr. Citrome has consulted for AbbVie, Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer-Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular, Janssen, Karuna, Lundbeck, Lyndra, MedAvante-ProPhase, Merck, Neurocrine, Noven, Otsuka, Ovid, Relmada, Sage, Sunovion, and Teva. He has been a speaker for most of those companies, and he holds stock in Bristol Myers Squibb, Eli Lilly, J&J, Merck, and Pfizer.

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has served on a speakers bureau for most of those companies, in addition to that of Noven.

The hallmark of Parkinson’s disease is the accompanying motor symptoms, but the condition can bring other challenges. Among those are nonmotor symptoms, including depression, dementia, and even psychosis.

The culprit is Lewy bodies, which are also responsible for Lewy body dementia. “What we call Lewy body dementia and Parkinson’s disease are caused by the same pathological process – the formation of Lewy bodies in the brain,” Leslie Citrome, MD, MPH, said in an interview. Dr. Citrome discussed some of the psychiatric comorbidities associated with Parkinson’s disease at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

In fact, the association goes both ways. “Many people with Parkinson’s disease develop a dementia. Many people with Lewy body dementia develop motor symptoms that look just like Parkinson’s disease,” said Dr. Citrome, professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, and president of the American Society for Clinical Psychopharmacology.

The motor symptoms of Parkinson’s disease are generally attributable to loss of striatal dopaminergic neurons, while nonmotor symptoms can be traced to loss of neurons in nondopaminergic regions. Nonmotor symptoms – often including sleep disorders, depression, cognitive changes, and psychosis – may occur before motor symptoms. Other problems may include autonomic dysfunction, such as constipation, sexual dysfunction, sweating, or urinary retention.

Patients might not be aware that nonmotor symptoms can occur with Parkinson’s disease and may not even consider mentioning mood changes or hallucinations to their neurologist. Family members may also be unaware.

Sleep problems are common in Parkinson’s disease, including rapid eye-movement sleep behavior disorders, vivid dreams, restless legs syndrome, insomnia, and daytime somnolence. Dopamine agonists may also cause unintended sleep.

Depression is extremely common, affecting up to 90% of Parkinson’s disease patients, and this may be related to dopaminergic losses. Antidepressant medications can worsen Parkinson’s disease symptoms: Tricyclic antidepressants increase risk of adverse events from anticholinergic drugs. Selective serotonin reuptake inhibitors (SSRIs) can exacerbate tremor and may increase risk of serotonin syndrome when combined with MAO‐B inhibitors.

Dr. Citrome was not aware of any antidepressant drugs that have been tested specifically in Parkinson’s disease patients, though “I’d be surprised if there wasn’t,” he said during the Q&A session. “There’s no one perfect antidepressant for people with depression associated with Parkinson’s disease. I would make sure to select one that they would tolerate and be willing to take and that doesn’t interfere with their treatment of their movement disorder, and (I would make sure) that there’s no drug-drug interaction,” he said.

Cognitive impairment or dementia is also very common, affecting about 75% of Parkinson’s patients. This can include reduced working memory, learning, and planning, and generally does not manifest until at least 1 year after motor symptoms have begun. Rivastigmine is Food and Drug Administration–approved for treatment of cognitive impairment in Parkinson’s disease.

As many as 60% of Parkinson’s disease patients suffer from psychosis at some point, often visual hallucinations or delusions, which can include beliefs of spousal infidelity.

Many clinicians prescribe quetiapine off label, but there are not compelling data to support that it reduces intensity and frequency of hallucinations and delusions, according to Dr. Citrome. However, it is relatively easy to prescribe, requiring no preauthorizations, it is inexpensive, and it may improve sleep.

The FDA approved pimavanserin in 2016 for hallucinations and delusions in Parkinson’s disease, and it doesn’t worsen motor symptoms, Dr. Citrome said. That’s because pimavanserin is a highly selective antagonist of the 5-HT2A receptor, with no effect on dopaminergic, histaminergic, adrenergic, or muscarinic receptors.

The drug improves positive symptoms beginning at days 29 and 43, compared with placebo. An analysis by Dr. Citrome’s group found a number needed to treat (NNT) of 7 to gain a benefit over placebo if the metric is a ≥ 30% reduction in baseline symptom score. The drug had an NNT of 9 to achieve a ≥ 50% reduction, and an NNT of 5 to achieve a score of much improved or very much improved on the Clinical Global Impression–Improvement (CGI-I) scale. In general, an NNT less than 10 suggests that a drug is clinically useful.

In contrast, the number needed to harm (NNH) represents the number of patients who would need to receive a therapy to add one adverse event, compared with placebo. A number greater than 10 indicates that the therapy may be tolerable.

Using various measures, the NNH was well over 10 for pimavanserin. With respect to somnolence, the NNH over placebo was 138, and for a weight gain of 7% or more, the NNH was 594.

Overall, the study found that 4 patients would need to be treated to achieve a benefit over placebo with respect to a ≥ 3–point improvement in the Scale of Positive Symptoms–Parkinson’s Disease (SAPS-PD), while 21 would need to receive the drug to lead to one additional discontinuation because of an adverse event, compared to placebo.

When researchers compared pimavanserin to off-label use of quetiapine, olanzapine, and clozapine, they found a Cohen’s d value of 0.50, which was better than quetiapine and olanzapine, but lower than for clozapine. However, there is no requirement of blood monitoring, and clozapine can potentially worsen motor symptoms.

Dr. Citrome’s presentation should be a reminder to neurologists that psychiatric disorders are an important patient concern, said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who moderated the session.

“I think this serves as a model to recognize that many neurological disorders actually present with numerous psychiatric disorders,” Dr. Nasrallah said during the meeting, presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

Dr. Citrome has consulted for AbbVie, Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer-Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular, Janssen, Karuna, Lundbeck, Lyndra, MedAvante-ProPhase, Merck, Neurocrine, Noven, Otsuka, Ovid, Relmada, Sage, Sunovion, and Teva. He has been a speaker for most of those companies, and he holds stock in Bristol Myers Squibb, Eli Lilly, J&J, Merck, and Pfizer.

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has served on a speakers bureau for most of those companies, in addition to that of Noven.

Differences in lesion evolution may help neurologists distinguish between multiple sclerosis (MS) and other demyelinating disorders in new findings that may help explain differences in disease course, particularly progressive disability in MS.

Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).

“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.

The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.

The findings were published online July 14 in Neurology.
 

Lesion evolution

MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.

Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.

Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.

They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.

Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.

Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.

An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.

Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.

In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.

Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.

Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
 

Complete resolution

Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).

Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).

Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.

For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.

Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm²) than in those with NMOSD (104 mm²; P = .02) or MS (36 mm²; P < .001).

Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm²) and NMOSD (309 mm²) groups; both experienced greater reductions than the MS group (23 mm²; P < .001).
 

Lesion prevention

Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.

Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.

“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.

He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.

“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
 

Differences in pathology

Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.

“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.

The study’s cross-sectional comparison was its main strength, he noted.

“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”

The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.

Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.

“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”

The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.

Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.

The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.

This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.

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

Differences in lesion evolution may help neurologists distinguish between multiple sclerosis (MS) and other demyelinating disorders in new findings that may help explain differences in disease course, particularly progressive disability in MS.

Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).

“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.

The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.

The findings were published online July 14 in Neurology.
 

Lesion evolution

MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.

Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.

Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.

They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.

Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.

Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.

An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.

Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.

In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.

Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.

Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
 

Complete resolution

Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).

Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).

Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.

For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.

Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm²) than in those with NMOSD (104 mm²; P = .02) or MS (36 mm²; P < .001).

Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm²) and NMOSD (309 mm²) groups; both experienced greater reductions than the MS group (23 mm²; P < .001).
 

Lesion prevention

Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.

Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.

“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.

He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.

“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
 

Differences in pathology

Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.

“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.

The study’s cross-sectional comparison was its main strength, he noted.

“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”

The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.

Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.

“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”

The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.

Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.

The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.

This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.

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

Differences in lesion evolution may help neurologists distinguish between multiple sclerosis (MS) and other demyelinating disorders in new findings that may help explain differences in disease course, particularly progressive disability in MS.

Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).

“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.

The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.

The findings were published online July 14 in Neurology.
 

Lesion evolution

MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.

Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.

Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.

They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.

Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.

Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.

An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.

Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.

In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.

Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.

Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
 

Complete resolution

Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).

Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).

Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.

For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.

Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm²) than in those with NMOSD (104 mm²; P = .02) or MS (36 mm²; P < .001).

Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm²) and NMOSD (309 mm²) groups; both experienced greater reductions than the MS group (23 mm²; P < .001).
 

Lesion prevention

Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.

Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.

“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.

He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.

“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
 

Differences in pathology

Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.

“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.

The study’s cross-sectional comparison was its main strength, he noted.

“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”

The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.

Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.

“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”

The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.

Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.

The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.

This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.

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